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1
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Trapé J, Fernández-Galán E, Auge JM, Carbonell-Prat M, Filella X, Miró-Cañís S, González-Fernández C. Factors influencing blood tumor marker concentrations in the absence of neoplasia. Tumour Biol 2024; 46:S35-S63. [PMID: 38517826 DOI: 10.3233/tub-220023] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/24/2024] Open
Abstract
BACKGROUND Tumor markers (TMs) are a heterogeneous group of molecules used in the diagnosis, prognosis and follow-up of cancer patients. During neoplastic differentiation, cells can either directly synthesize or induce the synthesis of TMs, and the release of these molecules into the bloodstream allows their quantification in biological fluids. Although very small concentrations of TMs are usually present in the serum or plasma of healthy subjects, increased concentrations may also be found in the presence of benign diseases or due to technical interference, producing false positive results. MATERIAL AND METHODS AND RESULTS Our review analyses the causes of false positives described between January 1970 to February 2023 for the TMs most frequently used in clinical practice: α-fetoprotein (AFP), β2-microglobulin (β2-M), cancer antigen 15-3 (CA 15-3), cancer antigen CA 19-9 (CA 19-9), cancer antigen CA 72-4 (CA 72-4), cancer antigen 125 (CA 125), carcinoembryonic antigen (CEA), chromogranin A (CgA), choriogonadotropin (hCG), cytokeratin 19 fragment (CYFRA 21-1), neuron-specific enolase (NSE), human epididymis protein 4 (HE4), serum HER2 (sHER2), squamous cell carcinoma antigen (SCCA), protein induced by vitamin K absence-II (PIVKA-II), Pro-gastrin-releasing peptide (Pro-GRP), prostate-specific antigen (PSA), Protein S-100 (S-100) and thyroglobulin (Tg). A total of 247 references were included. CONCLUSIONS A better understanding of pathophysiological processes and other conditions that affect the concentration of TMs might improve the interpretation of results and their clinical application.
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Affiliation(s)
- Jaume Trapé
- Department of Laboratory Medicine, Althaia Xarxa Assistencial Universitària de Manresa, Manresa, Catalonia, Spain
- Tissue Repair and Regeneration Laboratory, Institut de Recerca i Innovació en Ciències de la Vida i de la Salut a la Catalunya Central, Barcelona, Spain
- Faculty of Medicine, University of Vic - Central University of Catalonia, Vic, Spain
| | - Esther Fernández-Galán
- Department of Biochemistry and Molecular Genetics - Hospital Clinic de Barcelona, Barcelona, Spain
| | - Josep Maria Auge
- Department of Biochemistry and Molecular Genetics - Hospital Clinic de Barcelona, Barcelona, Spain
| | | | - Xavier Filella
- Department of Biochemistry and Molecular Genetics - Hospital Clinic de Barcelona, Barcelona, Spain
| | - Sílvia Miró-Cañís
- Laboratori d'Anàlisis Clíniques, CLILAB Diagnòstics, Vilafranca del Penedès, Spain
| | - Carolina González-Fernández
- Department of Laboratory Medicine, Althaia Xarxa Assistencial Universitària de Manresa, Manresa, Catalonia, Spain
- Gastrointestinal Oncology, Endoscopy and Surgery Research Group, Institut de Recerca i Innovació en Ciències de la Vida i de la Salut a la Catalunya Central, Barcelona, Spain
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Iyer DR, Venkatraman J, Tanguy E, Vitale N, Mahapatra NR. Chromogranin A and its derived peptides: potential regulators of cholesterol homeostasis. Cell Mol Life Sci 2023; 80:271. [PMID: 37642733 PMCID: PMC11072126 DOI: 10.1007/s00018-023-04908-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 08/02/2023] [Accepted: 08/03/2023] [Indexed: 08/31/2023]
Abstract
Chromogranin A (CHGA), a member of the granin family of proteins, has been an attractive therapeutic target and candidate biomarker for several cardiovascular, neurological, and inflammatory disorders. The prominence of CHGA stems from the pleiotropic roles of several bioactive peptides (e.g., catestatin, pancreastatin, vasostatins) generated by its proteolytic cleavage and by their wide anatomical distribution. These peptides are emerging as novel modulators of cardiometabolic diseases that are often linked to high blood cholesterol levels. However, their impact on cholesterol homeostasis is poorly understood. The dynamic nature of cholesterol and its multitudinous roles in almost every aspect of normal body function makes it an integral component of metabolic physiology. A tightly regulated coordination of cholesterol homeostasis is imperative for proper functioning of cellular and metabolic processes. The deregulation of cholesterol levels can result in several pathophysiological states. Although studies till date suggest regulatory roles for CHGA and its derived peptides on cholesterol levels, the mechanisms by which this is achieved still remain unclear. This review aims to aggregate and consolidate the available evidence linking CHGA with cholesterol homeostasis in health and disease. In addition, we also look at common molecular regulatory factors (viz., transcription factors and microRNAs) which could govern the expression of CHGA and genes involved in cholesterol homeostasis under basal and pathological conditions. In order to gain further insights into the pathways mediating cholesterol regulation by CHGA/its derived peptides, a few prospective signaling pathways are explored, which could act as primers for future studies.
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Affiliation(s)
- Dhanya R Iyer
- Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, 600036, India
| | - Janani Venkatraman
- Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, 600036, India
| | - Emeline Tanguy
- Institut des Neurosciences Cellulaires et Intégratives, CNRS UPR 3212 and Université de Strasbourg, 5 Rue Blaise Pascal, 67000, Strasbourg, France
| | - Nicolas Vitale
- Institut des Neurosciences Cellulaires et Intégratives, CNRS UPR 3212 and Université de Strasbourg, 5 Rue Blaise Pascal, 67000, Strasbourg, France.
| | - Nitish R Mahapatra
- Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, 600036, India.
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3
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Wei J, Wang Y, Yang S, Hao Z, Pan X, Ma A. Plasma chromogranin A levels are associated with acute ischemic stroke with anterior circulation large vessel occlusion. Nutr Metab Cardiovasc Dis 2022; 32:195-202. [PMID: 34893409 DOI: 10.1016/j.numecd.2021.09.030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 08/17/2021] [Accepted: 09/21/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND AND AIMS To investigate the relationship between chromogranin A (CgA) levels and acute ischemic stroke (AIS), especially anterior circulation large vessel occlusion (LVO). METHODS AND RESULTS 587 subjects were included in this study, including 205 AIS patients with anterior circulation LVO and 205 nonocclusive patients, as well as 177 healthy controls. On admission, plasma CgA levels were measured and neurological deficits were assessed by the NIH Stroke Scale. Outcomes were assessed by the modified Rankin Scale at 3 months. The predictive properties of CgA were evaluated by receiver operating characteristic (ROC) curve analysis. Binary logistic analysis assessed the association of CgA levels and AIS or anterior circulation LVO. AIS patients had lower CgA levels than health controls (p < 0.001). Anterior circulation LVO patients had lower CgA levels than nonocclusive patients (p < 0.001). The area under the ROC curve of plasma CgA levels in predicting anterior circulation LVO from AIS was 0.744 and the optimal cutoff value was 15.49 ng/mL with a Youden value of 0.332. Logistic analysis showed that CgA ≤15.49 ng/mL remained an independent risk factor for anterior circulation LVO after adjusting for related factors (OR = 6.519, 95% CI: 3.790-11.214, p < 0.001). CgA was an independent protective factor for mild stroke and good prognosis (p = 0.009, p = 0.005); however, the association disappeared after adjusting for occlusion (p = 0.768, p = 0.335). CONCLUSION CgA levels were lower in AIS patients, especially in anterior circulation LVO patients. Lower CgA levels are potential biomarker for anterior circulation LVO, and they may indicate good prognosis at 3 months in AIS.
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Affiliation(s)
- Jin Wei
- Department of Neurology, The Affiliated Hospital of Qingdao University, 59 Haier Road, Qingdao, 266100, Shandong, China
| | - Yuan Wang
- Department of Neurology, The Affiliated Hospital of Qingdao University, 59 Haier Road, Qingdao, 266100, Shandong, China
| | - Shaonan Yang
- Department of Neurology, The Affiliated Hospital of Qingdao University, 59 Haier Road, Qingdao, 266100, Shandong, China
| | - Zhongnan Hao
- Department of Neurology, The Affiliated Hospital of Qingdao University, 59 Haier Road, Qingdao, 266100, Shandong, China
| | - Xudong Pan
- Department of Neurology, The Affiliated Hospital of Qingdao University, 59 Haier Road, Qingdao, 266100, Shandong, China.
| | - Aijun Ma
- Department of Neurology, The Affiliated Hospital of Qingdao University, 59 Haier Road, Qingdao, 266100, Shandong, China.
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Vasostatin-1 as a potential novel circulating biomarker in patients with chronic systolic heart failure: A pilot study. Clin Chim Acta 2021; 526:49-54. [PMID: 34973182 DOI: 10.1016/j.cca.2021.12.024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 12/20/2021] [Accepted: 12/26/2021] [Indexed: 11/21/2022]
Abstract
BACKGROUND AND AIMS Previous studies have shown that circulating chromogranin A (CgA) increases in patients with chronic systolic heart failure (HF). Aim of the present study is to evaluate the potential role of circulating vasostatin-1 (VS-1), a cardioregulatory fragment of CgA, as prognostic marker in patients with chronic HF. MATERIALS AND METHODS The plasma levels of CgA and VS-1 were determined in 80 patients with chronic systolic HF. Patients were followed-up to evaluate the occurrence of cardiovascular (CV) events. RESULTS CgA and VS-1 plasma levels were significantly higher in patients with CV events at follow-up. VS-1, but not CgA, was associated to NT-proBNP. No significant association of CgA and VS-1 with left ventricular ejection fraction (LVEF) was observed. CgA, NT-proBNP and age, but not VS-1, were independent predictors of CV events. CONCLUSION In patients with chronic systolic HF those who experienced CV events had higher levels of VS-1 and CgA. Given its established effect on cardiac cells, the association of VS-1 levels with NT-proBNP levels but not with LVEF, suggests that this fragment might provide complementary information to NT-proBNP and CgA in HF patients.
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5
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Catestatin as a Biomarker of Cardiovascular Diseases: A Clinical Perspective. Biomedicines 2021; 9:biomedicines9121757. [PMID: 34944578 PMCID: PMC8698910 DOI: 10.3390/biomedicines9121757] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 11/22/2021] [Accepted: 11/23/2021] [Indexed: 02/07/2023] Open
Abstract
Accounting for almost one-third of the global mortality, cardiovascular diseases (CVDs) represent a major global health issue. Emerging data suggest that most of the well-established mechanistic explanations regarding the cardiovascular pathophysiology are flawed, and cannot fully explain the progression and long-term effects of these diseases. On the other hand, dysregulation of the sympathetic nervous system (SNS) has emerged as an important player in the pathophysiology of CVDs. Even though upregulated SNS activity is an essential compensatory response to various stress conditions, in the long term, it becomes a major contributor to both cardiac dysfunction and vascular damage. Despite the fact that the importance of SNS hyperactivity in the setting of CVDs has been well-appreciated, its exact quantification and clinical application in either diagnostics or therapy of CVDs is still out of reach. Nevertheless, in recent years a number of novel laboratory biomarkers implicated in the pathophysiology of SNS activation have been explored. Specifically, in this review, we aimed to discuss the role of catestatin, a potent physiological inhibitor of catecholamine spillover that offers cardioprotective effects. Limited data indicate that catestatin could also be a reliable indirect marker of SNS activity and it is likely that high CST levels reflect advanced CV disease burden. Consequently, large-scale studies are required to validate these observations in the upcoming future.
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6
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Kim HN, Yang DH, Park BE, Park YJ, Kim HJ, Jang SY, Bae MH, Lee JH, Park HS, Cho Y, Chae SC. Prognostic impact of chromogranin A in patients with acute heart failure. Yeungnam Univ J Med 2021; 38:337-343. [PMID: 34233402 PMCID: PMC8688787 DOI: 10.12701/yujm.2020.00843] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 06/02/2021] [Indexed: 11/23/2022] Open
Abstract
Background Chromogranin A (CgA) levels have been reported to predict mortality in patients with heart failure. However, information on the prognostic value and clinical availability of CgA is limited. We compared the prognostic value of CgA to that of previously proven natriuretic peptide biomarkers in patients with acute heart failure. Methods We retrospectively evaluated 272 patients (mean age, 68.5±15.6 years; 62.9% male) who underwent CgA test in the acute stage of heart failure hospitalization between June 2017 and June 2018. The median follow-up period was 348 days. Prognosis was assessed using the composite events of 1-year death and heart failure hospitalization. Results In-hospital mortality rate during index admission was 7.0% (n=19). During the 1-year follow-up, a composite event rate was observed in 12.1% (n=33) of the patients. The areas under the receiver-operating characteristic curves for predicting 1-year adverse events were 0.737 and 0.697 for N-terminal pro-B-type natriuretic peptide (NT-proBNP) and CgA, respectively. During follow-up, patients with high CgA levels (>158 pmol/L) had worse outcomes than those with low CgA levels (≤158 pmol/L) (85.2% vs. 58.6%, p<0.001). When stratifying the patients into four subgroups based on CgA and NT-proBNP levels, patients with high NT-proBNP and high CgA had the worst outcome. CgA had an incremental prognostic value when added to the combination of NT-proBNP and clinically relevant risk factors. Conclusion The prognostic power of CgA was comparable to that of NT-proBNP in patients with acute heart failure. The combination of CgA and NT-proBNP can improve prognosis prediction in these patients.
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Affiliation(s)
- Hong Nyun Kim
- Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Korea.,Cardiology Center, Kyungpook National University Chilgok Hospital, Daegu, Korea
| | - Dong Heon Yang
- Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Korea.,Cardiology Center, Kyungpook National University Chilgok Hospital, Daegu, Korea.,Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Bo Eun Park
- Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Korea
| | - Yoon Jung Park
- Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Korea
| | - Hyeon Jeong Kim
- Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Korea
| | - Se Yong Jang
- Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Korea.,Cardiology Center, Kyungpook National University Chilgok Hospital, Daegu, Korea.,Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Myung Hwan Bae
- Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Korea.,Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Jang Hoon Lee
- Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Korea.,Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Hun Sik Park
- Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Korea.,Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Yongkeun Cho
- Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Korea.,Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Shung Chull Chae
- Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Korea.,Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Korea
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The Emerging Roles of Chromogranins and Derived Polypeptides in Atherosclerosis, Diabetes, and Coronary Heart Disease. Int J Mol Sci 2021; 22:ijms22116118. [PMID: 34204153 PMCID: PMC8201018 DOI: 10.3390/ijms22116118] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 05/31/2021] [Accepted: 06/02/2021] [Indexed: 02/07/2023] Open
Abstract
Chromogranin A (CgA), B (CgB), and C (CgC), the family members of the granin glycoproteins, are associated with diabetes. These proteins are abundantly expressed in neurons, endocrine, and neuroendocrine cells. They are also present in other areas of the body. Patients with diabetic retinopathy have higher levels of CgA, CgB, and CgC in the vitreous humor. In addition, type 1 diabetic patients have high CgA and low CgB levels in the circulating blood. Plasma CgA levels are increased in patients with hypertension, coronary heart disease, and heart failure. CgA is the precursor to several functional peptides, including catestatin, vasostatin-1, vasostatin-2, pancreastatin, chromofungin, and many others. Catestatin, vasostain-1, and vasostatin-2 suppress the expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 in human vascular endothelial cells. Catestatin and vasostatin-1 suppress oxidized low-density lipoprotein-induced foam cell formation in human macrophages. Catestatin and vasostatin-2, but not vasostatin-1, suppress the proliferation and these three peptides suppress the migration in human vascular smooth muscles. Chronic infusion of catestatin, vasostatin-1, or vasostatin-2 suppresses the development of atherosclerosis of the aorta in apolipoprotein E-deficient mice. Catestatin, vasostatin-1, vasostatin-2, and chromofungin protect ischemia/reperfusion-induced myocardial dysfunction in rats. Since pancreastatin inhibits insulin secretion from pancreatic β-cells, and regulates glucose metabolism in liver and adipose tissues, pancreastatin inhibitor peptide-8 (PSTi8) improves insulin resistance and glucose homeostasis. Catestatin stimulates therapeutic angiogenesis in the mouse hind limb ischemia model. Gene therapy with secretoneurin, a CgC-derived peptide, stimulates postischemic neovascularization in apolipoprotein E-deficient mice and streptozotocin-induced diabetic mice, and improves diabetic neuropathy in db/db mice. Therefore, CgA is a biomarker for atherosclerosis, diabetes, hypertension, and coronary heart disease. CgA- and CgC--derived polypeptides provide the therapeutic target for atherosclerosis and ischemia-induced tissue damages. PSTi8 is useful in the treatment of diabetes.
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Borovac JA, D'Amario D, Bozic J, Glavas D. Sympathetic nervous system activation and heart failure: Current state of evidence and the pathophysiology in the light of novel biomarkers. World J Cardiol 2020; 12:373-408. [PMID: 32879702 PMCID: PMC7439452 DOI: 10.4330/wjc.v12.i8.373] [Citation(s) in RCA: 90] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2020] [Revised: 05/19/2020] [Accepted: 07/19/2020] [Indexed: 02/06/2023] Open
Abstract
Heart failure (HF) is a complex clinical syndrome characterized by the activation of at least several neurohumoral pathways that have a common role in maintaining cardiac output and adequate perfusion pressure of target organs and tissues. The sympathetic nervous system (SNS) is upregulated in HF as evident in dysfunctional baroreceptor and chemoreceptor reflexes, circulating and neuronal catecholamine spillover, attenuated parasympathetic response, and augmented sympathetic outflow to the heart, kidneys and skeletal muscles. When these sympathoexcitatory effects on the cardiovascular system are sustained chronically they initiate the vicious circle of HF progression and become associated with cardiomyocyte apoptosis, maladaptive ventricular and vascular remodeling, arrhythmogenesis, and poor prognosis in patients with HF. These detrimental effects of SNS activity on outcomes in HF warrant adequate diagnostic and treatment modalities. Therefore, this review summarizes basic physiological concepts about the interaction of SNS with the cardiovascular system and highlights key pathophysiological mechanisms of SNS derangement in HF. Finally, special emphasis in this review is placed on the integrative and up-to-date overview of diagnostic modalities such as SNS imaging methods and novel laboratory biomarkers that could aid in the assessment of the degree of SNS activation and provide reliable prognostic information among patients with HF.
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Affiliation(s)
- Josip Anđelo Borovac
- Department of Pathophysiology, University of Split School of Medicine, Split 21000, Croatia
- Working Group on Heart Failure of Croatian Cardiac Society, Zagreb 10000, Croatia
| | - Domenico D'Amario
- Department of Cardiovascular and Thoracic Sciences, IRCCS Fondazione Policlinico A. Gemelli, Universita Cattolica Sacro Cuore, Rome 00168, Italy
| | - Josko Bozic
- Department of Pathophysiology, University of Split School of Medicine, Split 21000, Croatia
| | - Duska Glavas
- Working Group on Heart Failure of Croatian Cardiac Society, Zagreb 10000, Croatia
- Clinic for Cardiovascular Diseases, University Hospital of Split, Split 21000, Croatia
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Höglund K, Häggström J, Höglund OV, Stridsberg M, Tidholm A, Ljungvall I. The chromogranin A-derived peptides catestatin and vasostatin in dogs with myxomatous mitral valve disease. Acta Vet Scand 2020; 62:43. [PMID: 32758260 PMCID: PMC7405357 DOI: 10.1186/s13028-020-00541-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Accepted: 07/30/2020] [Indexed: 11/10/2022] Open
Abstract
Background The protein chromogranin A (CgA) is stored and co-released with catecholamines from the stimulated adrenal glands. Increased plasma concentrations of CgA have been shown in people with heart disease. The aim of the study was to investigate whether plasma concentrations of the CgA-derived biologically active peptides catestatin and vasostatin were associated with the severity of myxomatous mitral valve disease (MMVD) in dogs and to assess potential associations between these blood variables and dog characteristics, echocardiographic variables, heart rate (HR), blood pressure (BP) and plasma N-terminal-proBNP (NT-proBNP) concentration. Sixty-seven privately owned dogs with or without MMVD were included. The dogs underwent physical examination, blood pressure measurement, blood sample collection, and echocardiographic examination. Plasma concentrations of catestatin and vasostatin were analyzed using radioimmunoassay. Results Catestatin concentration decreased with increasing left atrial and ventricular size (R2 ≤ 0.09, P ≤ 0.019), and increased with increasing systolic and diastolic blood pressures (R2 ≤ 0.08, P ≤ 0.038). Regression analyses showed no significant associations for vasostatin. No differences in plasma concentrations of catestatin or vasostatin were found between the disease severity groups used in the study. Conclusions In the present dog population, the catestatin concentration showed weak negative associations with left atrial and ventricular sizes, both of which are known to increase with increasing severity of MMVD. Furthermore, the catestatin concentration showed weak positive associations with blood pressure.
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10
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Tarantino N, Santoro F, Di Biase L, Di Terlizzi V, Vitale E, Barone R, Della Rocca DG, De Leon De La Cruz NS, Di Biase M, Brunetti ND. Chromogranin-A serum levels in patients with takotsubo syndrome and ST elevation acute myocardial infarction. Int J Cardiol 2020; 320:12-17. [PMID: 32739447 DOI: 10.1016/j.ijcard.2020.07.040] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2020] [Revised: 06/20/2020] [Accepted: 07/28/2020] [Indexed: 12/16/2022]
Abstract
BACKGROUND Sympathergic hyperactivity is considered one of the main trigger precipitating takotsubo syndrome (TTS). Chromogranin-A (CgA), a prognostic biomarker of sympatho-adrenal activation, is markedly high in acute coronary syndrome (ACS) and heart failure (HF), but its role in TTS is unknown. METHODS CgA serum levels from patients with TTS and symptoms onset <24 hours were consecutively evaluated and compared with anterior ST-elevation myocardial infarction (STEMI) patients from November 2016 to December 2019. Short and long-term follow-up data were recorded. RESULTS Eleven women with TTS and 10 subjects with anterior STEMI were analyzed and compared; differences were not significant in terms of age, gender and cardiovascular risk factors. NT-pro-BNP levels were similar (9,887 ± 12,170 vs 8,969 ± 15,053 pg/ml, p = .88), while troponin-I levels were higher in patients with STEMI (4 ± 3.2 vs 13.3 ± 10 ng/dl, p = .03). CgA admission levels were significantly lower in TTS patients (2.2 ± 1.5 vs 7.3 ± 6.2 nMol/l, p = .017), even after multivariable correction for principal bias. CgA levels correlated with NTproBNP levels (p = .02) and were higher in subjects with in-hospital events (3.7 ± 1.1 vs 1.6 ± 1.2 nMol/l, p = .03), even after multivariable forward stepwise analysis (p < .01). CgA levels <3.25 nMol/l (AUC 0.754, 95% C.I. 0.54-0.968) were able to discriminate TTS from anterior STEMI (negative predictive power of 99%). CONCLUSIONS Systemic CgA levels in the acute phase of TTS are lower than in anterior STEMI, possibly indicating a greater myocardial catecholamine release rather than adrenal.
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Affiliation(s)
- Nicola Tarantino
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy; Arrhythmia Service, Division of Cardiology, Department of Medicine, Montefiore Medical Center, Bronx, NY, USA
| | - Francesco Santoro
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.
| | - Luigi Di Biase
- Arrhythmia Service, Division of Cardiology, Department of Medicine, Montefiore Medical Center, Bronx, NY, USA; Texas Cardiac Arrhyhtmia Institute (TCAI) at St. David's Hospital, Austin, TX, USA; Department of Biomedical Engineering, Cockrell School of Engineering, University of Texas, Austin, TX, USA; Department of Internal Medicine, Dell Medical School, University of Texas, Austin, TX, USA
| | - Vito Di Terlizzi
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Enrica Vitale
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Roberta Barone
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | | | | | - Matteo Di Biase
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
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11
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Mahata SK, Corti A. Chromogranin A and its fragments in cardiovascular, immunometabolic, and cancer regulation. Ann N Y Acad Sci 2019; 1455:34-58. [PMID: 31588572 PMCID: PMC6899468 DOI: 10.1111/nyas.14249] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Revised: 09/09/2019] [Accepted: 09/13/2019] [Indexed: 12/11/2022]
Abstract
Chromogranin A (CgA)-the index member of the chromogranin/secretogranin secretory protein family-is ubiquitously distributed in endocrine, neuroendocrine, and immune cells. Elevated levels of CgA-related polypeptides, consisting of full-length molecules and fragments, are detected in the blood of patients suffering from neuroendocrine tumors, heart failure, renal failure, hypertension, rheumatoid arthritis, and inflammatory bowel disease. Full-length CgA and various CgA-derived peptides, including vasostatin-1, pancreastatin, catestatin, and serpinin, are expressed at different relative levels in normal and pathological conditions and exert diverse, and sometime opposite, biological functions. For example, CgA is overexpressed in genetic hypertension, whereas catestatin is diminished. In rodents, the administration of catestatin decreases hypertension, cardiac contractility, obesity, atherosclerosis, and inflammation, and it improves insulin sensitivity. By contrast, pancreastatin is elevated in diabetic patients, and the administration of this peptide to obese mice decreases insulin sensitivity and increases inflammation. CgA and the N-terminal fragment of vasostatin-1 can enhance the endothelial barrier function, exert antiangiogenic effects, and inhibit tumor growth in animal models, whereas CgA fragments lacking the CgA C-terminal region promote angiogenesis and tumor growth. Overall, the CgA system, consisting of full-length CgA and its fragments, is emerging as an important and complex player in cardiovascular, immunometabolic, and cancer regulation.
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Affiliation(s)
- Sushil K Mahata
- VA San Diego Healthcare System, San Diego, California.,Metabolic Physiology & Ultrastructural Biology Laboratory, Department of Medicine, University of California, San Diego, La Jolla, California
| | - Angelo Corti
- IRCCS San Raffaele Scientific Institute, San Raffaele Vita-Salute University, Milan, Italy
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12
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Chromogranin A in the Laboratory Diagnosis of Pheochromocytoma and Paraganglioma. Cancers (Basel) 2019; 11:cancers11040586. [PMID: 31027285 PMCID: PMC6521298 DOI: 10.3390/cancers11040586] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2019] [Revised: 04/15/2019] [Accepted: 04/17/2019] [Indexed: 02/07/2023] Open
Abstract
This work discusses the clinical performance of chromogranin A (CGA), a commonly measured marker in neuroendocrine neoplasms, for the diagnosis of pheochromocytoma/paraganglioma (PPGL). Plasma CGA (cut-off value 150 µg/L) was determined by an immunoradiometric assay. Free metanephrine (cut-off value 100 ng/L) and normetanephrine (cut-off value 170 ng/L) were determined by radioimmunoassay. Blood samples were collected from PPGL patients preoperatively, one week, six months, one year and two years after adrenal gland surgery. The control patients not diagnosed with PPGL suffered from adrenal problems or from MEN2 and thyroid carcinoma. The clinical sensitivity in the PPGL group of patients (n = 71) based on CGA is 90% and is below the clinical sensitivity determined by metanephrines (97%). The clinical specificity based on all plasma CGA values after surgery (n = 98) is 99% and is the same for metanephrines assays. The clinical specificity of CGA in the control group (n = 85) was 92% or 99% using metanephrines tests. We can conclude that plasma CGA can serve as an appropriate complement to metanephrines assays in laboratory diagnosis of PPGL patients. CGA is elevated in PPGLs, as well as in other neuroendocrine or non-neuroendocrine neoplasia and under clinical conditions increasing adrenergic activity.
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13
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Edwards KL, Edes AN, Brown JL. Stress, Well-Being and Reproductive Success. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1200:91-162. [PMID: 31471796 DOI: 10.1007/978-3-030-23633-5_5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
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14
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Bílek R, Zelinka T, Vlček P, Dušková J, Michalský D, Novák K, Václavíková E, Widimský J. Radioimmunoassay of chromogranin A and free metanephrines in diagnosis of pheochromocytoma. Physiol Res 2018; 66:S397-S408. [PMID: 28948824 DOI: 10.33549/physiolres.933719] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
This work discusses the clinical performance of chromogranin A, free metanephrine and normetanephrine determination in plasma using a radioimmunoanalytical methods for the diagnosis of pheochromocytoma and paraganglioma. Blood samples were collected from 55 patients (46 pheochromocytomas, 9 paragangliomas). A sampling of biological materials was performed preoperatively and about one week, six months and one year after adrenal gland surgery. The comparative group without a diagnosis of pheochromocytoma/paraganglioma consisted of 36 pheochromocytoma/paraganglioma patients more than 4 months after adrenal gland surgery, and of 87 patients, 16 of them with multiple endocrine neoplasia, 9 with medullary and 5 with parafolicullar carcinoma of the thyroid gland. The rest were patients with various adrenal gland disorders. Chromogranin A, metanephrine and normetanephrine were determined in the EDTA-plasma using a radioimmunoassay kits Cisbio Bioassays, France and IBL International GmbH, Germany. Clinical sensitivity was 96 % for the combination of metanephrine and normetanephrine, and 93 % for chromogranin A. Clinical specificity was 100 % for the combination metanephrine and normetanephrine, and 96 % for chromogranin A. Falsely elevated levels of chromogranin A were observed in 1 patient with chronic renal insufficiency and 9 analyses were influenced by the administration of proton pump inhibitors. These results were excluded of CGA specificity. Both the combination of plasma free metanephrine, normetanephrine and chromogranin A as determined by radioimmunoassays, which are simple without the necessity of special laboratory material, are effective markers of pheochromocytoma or paraganglioma. Chromogranin A exerts association to malignity and all markers are associated with tumor mass.
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Affiliation(s)
- R Bílek
- Institute of Endocrinology, Prague, Czech Republic.
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15
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Kruljac I, Vurnek I, Maasberg S, Kust D, Blaslov K, Ladika Davidović B, Štefanović M, Demirović A, Bišćanin A, Filipović-Čugura J, Marić Brozić J, Pape UF, Vrkljan M. A score derived from routine biochemical parameters increases the diagnostic accuracy of chromogranin A in detecting patients with neuroendocrine neoplasms. Endocrine 2018; 60:395-406. [PMID: 29633144 DOI: 10.1007/s12020-018-1592-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Accepted: 04/02/2018] [Indexed: 01/10/2023]
Abstract
BACKGROUND Chromogranin A (CgA) is a valuable biomarker for detection and follow-up of patients with neuroendocrine neoplasms (NENs). However, various comorbidities may influence serum CgA, which decreases its diagnostic accuracy. We aimed to investigate which laboratory parameters are independently associated with increased CgA in real-life setting and to develop a scoring system, which could improve the diagnostic accuracy of CgA in detecting patients with NENs. METHODS This retrospective study included 55 treatment naïve patients with NENs and160 patients with various comorbidities but without NEN (nonNENs). Scoring system (CgA-score) was developed based on z-scores obtained from receiver operating curve analysis for each parameter that was associated with elevated serum CgA in nonNENs. RESULTS CgA correlated positively with serum BUN, creatinine, α2-globulin, red-cell distribution width, erythrocyte sedimentation rate, plasma glucose and correlated inversely with hemoglobin, thrombocytes and serum albumin. Serum CgA was also associated with the presence of chronic renal failure, arterial hypertension and diabetes and the use of PPI. In the entire study population, CgA showed an area under the curve of 0.656. Aforementioned parameters were used to develop a CgA-score. In a cohort of patients with CgA-score <12.0 (N = 87), serum CgA >156.5 ng/ml had 77.8% sensitivity and 91.5% specificity for detecting NENs (AUC 0.841, 95% CI 0.713-0.969, P < 0.001). Serum CgA had no diagnostic value in detecting NENs in patients with CgA-score >12.0 (AUC 0.554, 95% CI 0.405-0.702, P = 0.430). CONCLUSIONS CgA-score encompasses a wide range of comorbidities and represents a promising tool that could improve diagnostic performance of CgA in everyday clinical practice.
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Affiliation(s)
- Ivan Kruljac
- Department of Endocrinology, Diabetes and Metabolic Diseases "Mladen Sekso", University Hospital Center "Sestre Milosrdnice", University of Zagreb School of Medicine, Zagreb, Croatia.
| | - Ivan Vurnek
- University of Zagreb School of Medicine, Zagreb, Croatia
| | - Sebastian Maasberg
- Department of Hepatology and Gastroenterology, ENETS Center of Excellence for Neuroendocrine Tumors, Charité Campus Mitte and Virchow Clinic, Charité University Medicine, Berlin, Germany
| | - Davor Kust
- Department of Oncology and Nuclear Medicine, University Hospital Center "Sestre Milosrdnice", Zagreb, Croatia
| | - Kristina Blaslov
- Department of Endocrinology, Diabetes and Metabolic Diseases "Mladen Sekso", University Hospital Center "Sestre Milosrdnice", University of Zagreb School of Medicine, Zagreb, Croatia
| | - Blaženka Ladika Davidović
- Department of Oncology and Nuclear Medicine, University Hospital Center "Sestre Milosrdnice", Zagreb, Croatia
| | - Mario Štefanović
- Clinical Institute of Chemistry, University Hospital Center "Sestre Milosrdnice", University of Zagreb Faculty of Pharmacy and Biochemistry, Zagreb, Croatia
| | - Alma Demirović
- Department of Pathology, University Hospital Center "Sestre Milosrdnice", University of Zagreb School of Medicine, Zagreb, Croatia
| | - Alen Bišćanin
- Department of Gastroenterology and Hepatology, University Hospital Center "Sestre Milosrdnice", Zagreb, Croatia
| | | | - Jasmina Marić Brozić
- Department of Oncology and Nuclear Medicine, University Hospital Center "Sestre Milosrdnice", Zagreb, Croatia
| | - Ulrich-Frank Pape
- Department of Hepatology and Gastroenterology, ENETS Center of Excellence for Neuroendocrine Tumors, Charité Campus Mitte and Virchow Clinic, Charité University Medicine, Berlin, Germany
| | - Milan Vrkljan
- Department of Endocrinology, Diabetes and Metabolic Diseases "Mladen Sekso", University Hospital Center "Sestre Milosrdnice", University of Zagreb School of Medicine, Zagreb, Croatia
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16
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Corti A, Marcucci F, Bachetti T. Circulating chromogranin A and its fragments as diagnostic and prognostic disease markers. Pflugers Arch 2017; 470:199-210. [PMID: 29018988 DOI: 10.1007/s00424-017-2030-y] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2017] [Revised: 07/04/2017] [Accepted: 07/06/2017] [Indexed: 12/19/2022]
Abstract
Chromogranin A (CgA), a secretory protein released in the blood by neuroendocrine cells and neurons, is the precursor of various bioactive fragments involved in the regulation of the cardiovascular system, metabolism, innate immunity, angiogenesis, and tissue repair. After the original demonstration that circulating CgA can serve as a biomarker for a wide range of neuroendocrine tumors, several studies have shown that increased levels of CgA can be present also in the blood of patients with cardiovascular, gastrointestinal, and inflammatory diseases with, in certain cases, important diagnostic and prognostic implications. Considering the high structural and functional heterogeneity of the CgA system, comprising precursor and fragments, it is not surprising that the different immunoassays used in these studies led, in some cases, to discrepant results. Here, we review these notions and we discuss the importance of measuring total-CgA, full-length CgA, specific fragments, and their relative levels for a more thorough assessment of the pathophysiological function and diagnostic/prognostic value of the CgA system.
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Affiliation(s)
- Angelo Corti
- Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy. .,Vita-Salute San Raffaele University, Milan, Italy.
| | - Fabrizio Marcucci
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
| | - Tiziana Bachetti
- Clinical Trials Centre, Istituti Clinici Scientifici Maugeri, IRCCS Pavia, Pavia, Italy
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18
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Subramanian L, Khan AA, Allu PKR, Kiranmayi M, Sahu BS, Sharma S, Khullar M, Mullasari AS, Mahapatra NR. A haplotype variant of the human chromogranin A gene ( CHGA) promoter increases CHGA expression and the risk for cardiometabolic disorders. J Biol Chem 2017; 292:13970-13985. [PMID: 28667172 PMCID: PMC5572921 DOI: 10.1074/jbc.m117.778134] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2017] [Revised: 06/27/2017] [Indexed: 12/13/2022] Open
Abstract
The acidic glycoprotein chromogranin A (CHGA) is co-stored/co-secreted with catecholamines and crucial for secretory vesicle biogenesis in neuronal/neuroendocrine cells. CHGA is dysregulated in several cardiovascular diseases, but the underlying mechanisms are not well established. Here, we sought to identify common polymorphisms in the CHGA promoter and to explore the mechanistic basis of their plausible contribution to regulating CHGA protein levels in circulation. Resequencing of the CHGA promoter in an Indian population (n = 769) yielded nine single-nucleotide polymorphisms (SNPs): G-1106A, A-1018T, T-1014C, T-988G, G-513A, G-462A, T-415C, C-89A, and C-57T. Linkage disequilibrium (LD) analysis indicated strong LD among SNPs at the -1014, -988, -462, and -89 bp positions and between the -1018 and -57 bp positions. Haplotype analysis predicted five major promoter haplotypes that displayed differential promoter activities in neuronal cells; specifically, haplotype 2 (containing variant T alleles at -1018 and -57 bp) exhibited the highest promoter activity. Systematic computational and experimental analyses revealed that transcription factor c-Rel has a role in activating the CHGA promoter haplotype 2 under basal and pathophysiological conditions (viz. inflammation and hypoxia). Consistent with the higher in vitro CHGA promoter activity of haplotype 2, individuals carrying this haplotype had higher plasma CHGA levels, plasma glucose levels, diastolic blood pressure, and body mass index. In conclusion, these results suggest a functional role of the CHGA promoter haplotype 2 (occurring in a large proportion of the world population) in enhancing CHGA expression in haplotype 2 carriers who may be at higher risk for cardiovascular/metabolic disorders.
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Affiliation(s)
- Lakshmi Subramanian
- From the Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai 600036
| | - Abrar A Khan
- From the Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai 600036
| | - Prasanna K R Allu
- From the Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai 600036
| | - Malapaka Kiranmayi
- From the Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai 600036
| | - Bhavani S Sahu
- From the Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai 600036
| | - Saurabh Sharma
- Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Madhu Khullar
- Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Ajit S Mullasari
- Institute of Cardiovascular Diseases, Madras Medical Mission, Chennai 600037
| | - Nitish R Mahapatra
- From the Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai 600036.
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19
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Ottesen AH, Carlson CR, Louch WE, Dahl MB, Sandbu RA, Johansen RF, Jarstadmarken H, Bjørås M, Høiseth AD, Brynildsen J, Sjaastad I, Stridsberg M, Omland T, Christensen G, Røsjø H. Glycosylated Chromogranin A in Heart Failure: Implications for Processing and Cardiomyocyte Calcium Homeostasis. Circ Heart Fail 2017; 10:CIRCHEARTFAILURE.116.003675. [PMID: 28209766 DOI: 10.1161/circheartfailure.116.003675] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2016] [Accepted: 01/11/2017] [Indexed: 01/02/2023]
Abstract
BACKGROUND Chromogranin A (CgA) levels have previously been found to predict mortality in heart failure (HF), but currently no information is available regarding CgA processing in HF and whether the CgA fragment catestatin (CST) may directly influence cardiomyocyte function. METHODS AND RESULTS CgA processing was characterized in postinfarction HF mice and in patients with acute HF, and the functional role of CST was explored in experimental models. Myocardial biopsies from HF, but not sham-operated mice, demonstrated high molecular weight CgA bands. Deglycosylation treatment attenuated high molecular weight bands, induced a mobility shift, and increased shorter CgA fragments. Adjusting for established risk indices and biomarkers, circulating CgA levels were found to be associated with mortality in patients with acute HF, but not in patients with acute exacerbation of chronic obstructive pulmonary disease. Low CgA-to-CST conversion was also associated with increased mortality in acute HF, thus, supporting functional relevance of impaired CgA processing in cardiovascular disease. CST was identified as a direct inhibitor of CaMKIIδ (Ca2+/calmodulin-dependent protein kinase IIδ) activity, and CST reduced CaMKIIδ-dependent phosphorylation of phospholamban and the ryanodine receptor 2. In line with CaMKIIδ inhibition, CST reduced Ca2+ spark and wave frequency, reduced Ca2+ spark dimensions, increased sarcoplasmic reticulum Ca2+ content, and augmented the magnitude and kinetics of cardiomyocyte Ca2+ transients and contractions. CONCLUSIONS CgA-to-CST conversion in HF is impaired because of hyperglycosylation, which is associated with clinical outcomes in acute HF. The mechanism for increased mortality may be dysregulated cardiomyocyte Ca2+ handling because of reduced CaMKIIδ inhibition.
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Affiliation(s)
- Anett Hellebø Ottesen
- From the Division of Medicine, Akershus University Hospital, Lørenskog, Norway and Center for Heart Failure Research, University of Oslo, Norway (A.H.O., M.B.D., R.A.S., A.D.H., J.B., T.O., H.R.); Institute for Experimental Medical Research, Oslo University Hospital and Center for Heart Failure Research, University of Oslo, Norway (A.H.O., C.R.C., W.E.L., R.A.S., H.J., I.S., G.C.); Department of Clinical Molecular Biology, Akershus University Hospital, Lørenskog, Norway and Institute for Clinical Medicine, University of Oslo, Norway (M.B.D., R.A.S.); Department of Microbiology, Oslo University Hospital, Rikshospitalet, Norway, and University of Oslo, Norway (R.F.J., M.B.); Department of Medical Sciences, Uppsala University, Sweden (M.S.)
| | - Cathrine R Carlson
- From the Division of Medicine, Akershus University Hospital, Lørenskog, Norway and Center for Heart Failure Research, University of Oslo, Norway (A.H.O., M.B.D., R.A.S., A.D.H., J.B., T.O., H.R.); Institute for Experimental Medical Research, Oslo University Hospital and Center for Heart Failure Research, University of Oslo, Norway (A.H.O., C.R.C., W.E.L., R.A.S., H.J., I.S., G.C.); Department of Clinical Molecular Biology, Akershus University Hospital, Lørenskog, Norway and Institute for Clinical Medicine, University of Oslo, Norway (M.B.D., R.A.S.); Department of Microbiology, Oslo University Hospital, Rikshospitalet, Norway, and University of Oslo, Norway (R.F.J., M.B.); Department of Medical Sciences, Uppsala University, Sweden (M.S.)
| | - William E Louch
- From the Division of Medicine, Akershus University Hospital, Lørenskog, Norway and Center for Heart Failure Research, University of Oslo, Norway (A.H.O., M.B.D., R.A.S., A.D.H., J.B., T.O., H.R.); Institute for Experimental Medical Research, Oslo University Hospital and Center for Heart Failure Research, University of Oslo, Norway (A.H.O., C.R.C., W.E.L., R.A.S., H.J., I.S., G.C.); Department of Clinical Molecular Biology, Akershus University Hospital, Lørenskog, Norway and Institute for Clinical Medicine, University of Oslo, Norway (M.B.D., R.A.S.); Department of Microbiology, Oslo University Hospital, Rikshospitalet, Norway, and University of Oslo, Norway (R.F.J., M.B.); Department of Medical Sciences, Uppsala University, Sweden (M.S.)
| | - Mai Britt Dahl
- From the Division of Medicine, Akershus University Hospital, Lørenskog, Norway and Center for Heart Failure Research, University of Oslo, Norway (A.H.O., M.B.D., R.A.S., A.D.H., J.B., T.O., H.R.); Institute for Experimental Medical Research, Oslo University Hospital and Center for Heart Failure Research, University of Oslo, Norway (A.H.O., C.R.C., W.E.L., R.A.S., H.J., I.S., G.C.); Department of Clinical Molecular Biology, Akershus University Hospital, Lørenskog, Norway and Institute for Clinical Medicine, University of Oslo, Norway (M.B.D., R.A.S.); Department of Microbiology, Oslo University Hospital, Rikshospitalet, Norway, and University of Oslo, Norway (R.F.J., M.B.); Department of Medical Sciences, Uppsala University, Sweden (M.S.)
| | - Ragnhild A Sandbu
- From the Division of Medicine, Akershus University Hospital, Lørenskog, Norway and Center for Heart Failure Research, University of Oslo, Norway (A.H.O., M.B.D., R.A.S., A.D.H., J.B., T.O., H.R.); Institute for Experimental Medical Research, Oslo University Hospital and Center for Heart Failure Research, University of Oslo, Norway (A.H.O., C.R.C., W.E.L., R.A.S., H.J., I.S., G.C.); Department of Clinical Molecular Biology, Akershus University Hospital, Lørenskog, Norway and Institute for Clinical Medicine, University of Oslo, Norway (M.B.D., R.A.S.); Department of Microbiology, Oslo University Hospital, Rikshospitalet, Norway, and University of Oslo, Norway (R.F.J., M.B.); Department of Medical Sciences, Uppsala University, Sweden (M.S.)
| | - Rune Forstrøm Johansen
- From the Division of Medicine, Akershus University Hospital, Lørenskog, Norway and Center for Heart Failure Research, University of Oslo, Norway (A.H.O., M.B.D., R.A.S., A.D.H., J.B., T.O., H.R.); Institute for Experimental Medical Research, Oslo University Hospital and Center for Heart Failure Research, University of Oslo, Norway (A.H.O., C.R.C., W.E.L., R.A.S., H.J., I.S., G.C.); Department of Clinical Molecular Biology, Akershus University Hospital, Lørenskog, Norway and Institute for Clinical Medicine, University of Oslo, Norway (M.B.D., R.A.S.); Department of Microbiology, Oslo University Hospital, Rikshospitalet, Norway, and University of Oslo, Norway (R.F.J., M.B.); Department of Medical Sciences, Uppsala University, Sweden (M.S.)
| | - Hilde Jarstadmarken
- From the Division of Medicine, Akershus University Hospital, Lørenskog, Norway and Center for Heart Failure Research, University of Oslo, Norway (A.H.O., M.B.D., R.A.S., A.D.H., J.B., T.O., H.R.); Institute for Experimental Medical Research, Oslo University Hospital and Center for Heart Failure Research, University of Oslo, Norway (A.H.O., C.R.C., W.E.L., R.A.S., H.J., I.S., G.C.); Department of Clinical Molecular Biology, Akershus University Hospital, Lørenskog, Norway and Institute for Clinical Medicine, University of Oslo, Norway (M.B.D., R.A.S.); Department of Microbiology, Oslo University Hospital, Rikshospitalet, Norway, and University of Oslo, Norway (R.F.J., M.B.); Department of Medical Sciences, Uppsala University, Sweden (M.S.)
| | - Magnar Bjørås
- From the Division of Medicine, Akershus University Hospital, Lørenskog, Norway and Center for Heart Failure Research, University of Oslo, Norway (A.H.O., M.B.D., R.A.S., A.D.H., J.B., T.O., H.R.); Institute for Experimental Medical Research, Oslo University Hospital and Center for Heart Failure Research, University of Oslo, Norway (A.H.O., C.R.C., W.E.L., R.A.S., H.J., I.S., G.C.); Department of Clinical Molecular Biology, Akershus University Hospital, Lørenskog, Norway and Institute for Clinical Medicine, University of Oslo, Norway (M.B.D., R.A.S.); Department of Microbiology, Oslo University Hospital, Rikshospitalet, Norway, and University of Oslo, Norway (R.F.J., M.B.); Department of Medical Sciences, Uppsala University, Sweden (M.S.)
| | - Arne Didrik Høiseth
- From the Division of Medicine, Akershus University Hospital, Lørenskog, Norway and Center for Heart Failure Research, University of Oslo, Norway (A.H.O., M.B.D., R.A.S., A.D.H., J.B., T.O., H.R.); Institute for Experimental Medical Research, Oslo University Hospital and Center for Heart Failure Research, University of Oslo, Norway (A.H.O., C.R.C., W.E.L., R.A.S., H.J., I.S., G.C.); Department of Clinical Molecular Biology, Akershus University Hospital, Lørenskog, Norway and Institute for Clinical Medicine, University of Oslo, Norway (M.B.D., R.A.S.); Department of Microbiology, Oslo University Hospital, Rikshospitalet, Norway, and University of Oslo, Norway (R.F.J., M.B.); Department of Medical Sciences, Uppsala University, Sweden (M.S.)
| | - Jon Brynildsen
- From the Division of Medicine, Akershus University Hospital, Lørenskog, Norway and Center for Heart Failure Research, University of Oslo, Norway (A.H.O., M.B.D., R.A.S., A.D.H., J.B., T.O., H.R.); Institute for Experimental Medical Research, Oslo University Hospital and Center for Heart Failure Research, University of Oslo, Norway (A.H.O., C.R.C., W.E.L., R.A.S., H.J., I.S., G.C.); Department of Clinical Molecular Biology, Akershus University Hospital, Lørenskog, Norway and Institute for Clinical Medicine, University of Oslo, Norway (M.B.D., R.A.S.); Department of Microbiology, Oslo University Hospital, Rikshospitalet, Norway, and University of Oslo, Norway (R.F.J., M.B.); Department of Medical Sciences, Uppsala University, Sweden (M.S.)
| | - Ivar Sjaastad
- From the Division of Medicine, Akershus University Hospital, Lørenskog, Norway and Center for Heart Failure Research, University of Oslo, Norway (A.H.O., M.B.D., R.A.S., A.D.H., J.B., T.O., H.R.); Institute for Experimental Medical Research, Oslo University Hospital and Center for Heart Failure Research, University of Oslo, Norway (A.H.O., C.R.C., W.E.L., R.A.S., H.J., I.S., G.C.); Department of Clinical Molecular Biology, Akershus University Hospital, Lørenskog, Norway and Institute for Clinical Medicine, University of Oslo, Norway (M.B.D., R.A.S.); Department of Microbiology, Oslo University Hospital, Rikshospitalet, Norway, and University of Oslo, Norway (R.F.J., M.B.); Department of Medical Sciences, Uppsala University, Sweden (M.S.)
| | - Mats Stridsberg
- From the Division of Medicine, Akershus University Hospital, Lørenskog, Norway and Center for Heart Failure Research, University of Oslo, Norway (A.H.O., M.B.D., R.A.S., A.D.H., J.B., T.O., H.R.); Institute for Experimental Medical Research, Oslo University Hospital and Center for Heart Failure Research, University of Oslo, Norway (A.H.O., C.R.C., W.E.L., R.A.S., H.J., I.S., G.C.); Department of Clinical Molecular Biology, Akershus University Hospital, Lørenskog, Norway and Institute for Clinical Medicine, University of Oslo, Norway (M.B.D., R.A.S.); Department of Microbiology, Oslo University Hospital, Rikshospitalet, Norway, and University of Oslo, Norway (R.F.J., M.B.); Department of Medical Sciences, Uppsala University, Sweden (M.S.)
| | - Torbjørn Omland
- From the Division of Medicine, Akershus University Hospital, Lørenskog, Norway and Center for Heart Failure Research, University of Oslo, Norway (A.H.O., M.B.D., R.A.S., A.D.H., J.B., T.O., H.R.); Institute for Experimental Medical Research, Oslo University Hospital and Center for Heart Failure Research, University of Oslo, Norway (A.H.O., C.R.C., W.E.L., R.A.S., H.J., I.S., G.C.); Department of Clinical Molecular Biology, Akershus University Hospital, Lørenskog, Norway and Institute for Clinical Medicine, University of Oslo, Norway (M.B.D., R.A.S.); Department of Microbiology, Oslo University Hospital, Rikshospitalet, Norway, and University of Oslo, Norway (R.F.J., M.B.); Department of Medical Sciences, Uppsala University, Sweden (M.S.)
| | - Geir Christensen
- From the Division of Medicine, Akershus University Hospital, Lørenskog, Norway and Center for Heart Failure Research, University of Oslo, Norway (A.H.O., M.B.D., R.A.S., A.D.H., J.B., T.O., H.R.); Institute for Experimental Medical Research, Oslo University Hospital and Center for Heart Failure Research, University of Oslo, Norway (A.H.O., C.R.C., W.E.L., R.A.S., H.J., I.S., G.C.); Department of Clinical Molecular Biology, Akershus University Hospital, Lørenskog, Norway and Institute for Clinical Medicine, University of Oslo, Norway (M.B.D., R.A.S.); Department of Microbiology, Oslo University Hospital, Rikshospitalet, Norway, and University of Oslo, Norway (R.F.J., M.B.); Department of Medical Sciences, Uppsala University, Sweden (M.S.)
| | - Helge Røsjø
- From the Division of Medicine, Akershus University Hospital, Lørenskog, Norway and Center for Heart Failure Research, University of Oslo, Norway (A.H.O., M.B.D., R.A.S., A.D.H., J.B., T.O., H.R.); Institute for Experimental Medical Research, Oslo University Hospital and Center for Heart Failure Research, University of Oslo, Norway (A.H.O., C.R.C., W.E.L., R.A.S., H.J., I.S., G.C.); Department of Clinical Molecular Biology, Akershus University Hospital, Lørenskog, Norway and Institute for Clinical Medicine, University of Oslo, Norway (M.B.D., R.A.S.); Department of Microbiology, Oslo University Hospital, Rikshospitalet, Norway, and University of Oslo, Norway (R.F.J., M.B.); Department of Medical Sciences, Uppsala University, Sweden (M.S.).
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20
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Bachetti T, Ferrari Bardile A, Aloi TL, Colombo B, Assi E, Savino G, Vercelli A, Colombo R, Corti A. Plasma levels of vasostatin-1, a chromogranin A fragment, are associated with carotid artery maximum stenosis: A pilot study. Int J Cardiol 2017; 236:438-443. [PMID: 28190616 DOI: 10.1016/j.ijcard.2017.02.019] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2016] [Revised: 01/24/2017] [Accepted: 02/03/2017] [Indexed: 12/26/2022]
Abstract
BACKGROUND Chromogranin A (CgA), a circulating protein released by the neuroendocrine system, can regulate vascular physiology and angiogenesis. Full-length CgA (CgA1-439) and its fragment CgA1-76 (called vasostatin-1, VS-1) preserve the physiological integrity of the endothelial barrier function and are antiangiogenic, whereas CgA1-373 is proangiogenic. We investigated whether these polypeptides are altered in patients with various degrees of carotid artery atherosclerosis. METHODS We studied 81 patients with carotid artery atherosclerosis, asymptomatic for cerebrovascular diseases. Carotid arteries were examined by Doppler ultrasound and plaque characteristics were recorded. Plasma levels of CgA1-439, VS-1, CgA1-373, and total-CgA (CgA1-439 plus truncated fragments lacking part or the entire C-terminal region) were assessed by specific ELISAs. RESULTS Plasma levels of VS-1 and total-CgA correlated with carotid artery maximum stenosis (r=0.349, p=0.001 and r=0.256, p=0.021, respectively). Stepwise multiple regression analysis indicated that VS-1 was a significant predictor of maximum stenosis after adjustment for age, gender, and conventional risk factors for atherosclerosis (regression coefficient=12.42, SE=4.84, p=0.012). In addition, logistic regression analysis indicated that relatively high levels of full-length CgA, but not total-CgA, predict the presence of hypoechoic, lipid-rich plaques (OR=1.47; 95% CI: 1.19-1.81, p=0.0003). CONCLUSION VS-1 is independently associated with carotid artery maximum stenosis. Furthermore, full-length CgA is an independent indicator of hypoechoic plaques, likely reflecting initial stages of atherosclerosis. Given the known capability of CgA and VS-1 to regulate vascular function and angiogenesis these polypeptides might play a role in the regulation of atherosclerosis pathophysiology.
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Affiliation(s)
- Tiziana Bachetti
- Istituti Clinici Scientifici Maugeri, IRCCS Pavia, Clinical Trials Centre, Pavia, Italy.
| | - Alberto Ferrari Bardile
- Istituti Clinici Scientifici Maugeri, IRCCS Pavia and IRCCS Montescano, Angiology Unit, Pavia and Montescano, Italy
| | - Teresa Lucia Aloi
- Istituti Clinici Scientifici Maugeri, IRCCS Pavia and IRCCS Montescano, Angiology Unit, Pavia and Montescano, Italy
| | - Barbara Colombo
- IRCCS San Raffaele Scientific Institute, Tumour Biology and Vascular Targeting Unit, Milan, Italy
| | - Emma Assi
- IRCCS San Raffaele Scientific Institute, Tumour Biology and Vascular Targeting Unit, Milan, Italy
| | - Giuseppina Savino
- Istituti Clinici Scientifici Maugeri, IRCCS Pavia and IRCCS Montescano, Angiology Unit, Pavia and Montescano, Italy
| | - Andrea Vercelli
- Istituti Clinici Scientifici Maugeri, IRCCS Pavia and IRCCS Montescano, Angiology Unit, Pavia and Montescano, Italy
| | - Roberto Colombo
- Istituti Clinici Scientifici Maugeri, IRCCS Pavia, Bioengineering Service, Pavia, Italy
| | - Angelo Corti
- IRCCS San Raffaele Scientific Institute, Tumour Biology and Vascular Targeting Unit, Milan, Italy; San Raffaele Vita-Salute University, Milan, Italy
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21
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Myhre PL, Ottesen AH, Okkonen M, Linko R, Stridsberg M, Nygård S, Christensen G, Pettilä V, Omland T, Røsjø H. Prognostic Value of Secretoneurin in Patients with Acute Respiratory Failure: Data from the FINNALI Study. Clin Chem 2016; 62:1380-9. [DOI: 10.1373/clinchem.2016.258764] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2016] [Accepted: 06/23/2016] [Indexed: 12/16/2022]
Abstract
Abstract
BACKGROUND
We examined whether secretoneurin (SN), a biomarker associated with cardiomyocyte Ca2+ handling, provides prognostic information in patients with acute respiratory failure (ARF).
METHODS
We included 490 patients with ARF, defined as ventilatory support >6 h, with blood samples available on admission to the intensive care unit (ICU). SN concentrations were measured by RIA.
RESULTS
A total of 209 patients (43%) were hospitalized with cardiovascular (CV)-related ARF, and 90-day mortality rates were comparable between CV- and non–CV-related ARF (n = 281): 31% vs 24%, P = 0.11. Admission SN concentrations were higher in nonsurvivors than in survivors in both CV-related (median 148 [quartile 1–3, 117–203] vs 108 [87–143] pmol/L, P < 0.001) and non–CV-related ARF (139 [115–184] vs 113 [91–139] pmol/L, P < 0.001). In patients with CV-related ARF, SN concentrations on ICU admission were associated with 90-day mortality [odds ratio (OR) 1.97 (95% CI, 1.04–3.73, P = 0.04)] after adjusting for established risk indices, including N-terminal-pro-B-type natriuretic peptide (NT-proBNP) concentrations. SN also improved patient classification in CV-related ARF as assessed by the net reclassification index: 0.32 (95% CI, 0.04–0.59), P = 0.03. The area under the curve (AUC) of SN to predict mortality in patients with CV-related ARF was 0.72 (95% CI, 0.65–0.79), and the AUC of NT-proBNP was 0.64 (0.56–0.73). In contrast, SN concentrations on ICU admission did not provide incremental prognostic value to established risk indices in patients with non–CV-related ARF, and the AUC was 0.67 (0.60–0.75).
CONCLUSIONS
SN concentrations measured on ICU admission provided incremental prognostic information to established risk indices in patients with CV-related ARF, but not in patients with non–CV-related ARF.
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Affiliation(s)
- Peder L Myhre
- Division of Medicine, Akershus University Hospital, Lørenskog, Norway and Center for Heart Failure Research, University of Oslo, Oslo, Norway
- Center for Clinical Heart Research, Oslo University Hospital Ullevål, Oslo, Norway
| | - Anett H Ottesen
- Division of Medicine, Akershus University Hospital, Lørenskog, Norway and Center for Heart Failure Research, University of Oslo, Oslo, Norway
| | - Marjatta Okkonen
- Division of Intensive Care Medicine, Department of Anesthesiology, Intensive Care and Pain Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Rita Linko
- Division of Intensive Care Medicine, Department of Anesthesiology, Intensive Care and Pain Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Mats Stridsberg
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Ståle Nygård
- Bioinformatics Core Facility, Oslo University Hospital and the University of Oslo, Oslo, Norway
| | - Geir Christensen
- Institute for Experimental Medical Research, Oslo University Hospital, Ullevål, Oslo, Norway and Center for Heart Failure Research, University of Oslo, Oslo, Norway
| | - Ville Pettilä
- Division of Intensive Care Medicine, Department of Anesthesiology, Intensive Care and Pain Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Department of Intensive Care Medicine, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Torbjørn Omland
- Division of Medicine, Akershus University Hospital, Lørenskog, Norway and Center for Heart Failure Research, University of Oslo, Oslo, Norway
| | - Helge Røsjø
- Division of Medicine, Akershus University Hospital, Lørenskog, Norway and Center for Heart Failure Research, University of Oslo, Oslo, Norway
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22
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Kiranmayi M, Chirasani VR, Allu PKR, Subramanian L, Martelli EE, Sahu BS, Vishnuprabu D, Kumaragurubaran R, Sharma S, Bodhini D, Dixit M, Munirajan AK, Khullar M, Radha V, Mohan V, Mullasari AS, Naga Prasad SV, Senapati S, Mahapatra NR. Catestatin Gly364Ser Variant Alters Systemic Blood Pressure and the Risk for Hypertension in Human Populations via Endothelial Nitric Oxide Pathway. Hypertension 2016; 68:334-47. [PMID: 27324226 DOI: 10.1161/hypertensionaha.116.06568] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2016] [Accepted: 05/17/2016] [Indexed: 12/13/2022]
Abstract
Catestatin (CST), an endogenous antihypertensive/antiadrenergic peptide, is a novel regulator of cardiovascular physiology. Here, we report case-control studies in 2 geographically/ethnically distinct Indian populations (n≈4000) that showed association of the naturally-occurring human CST-Gly364Ser variant with increased risk for hypertension (age-adjusted odds ratios: 1.483; P=0.009 and 2.951; P=0.005). Consistently, 364Ser allele carriers displayed elevated systolic (up to ≈8 mm Hg; P=0.004) and diastolic (up to ≈6 mm Hg; P=0.001) blood pressure. The variant allele was also found to be in linkage disequilibrium with other functional single-nucleotide polymorphisms in the CHGA promoter and nearby coding region. Functional characterization of the Gly364Ser variant was performed using cellular/molecular biological experiments (viz peptide-receptor binding assays, nitric oxide [NO], phosphorylated extracellular regulated kinase, and phosphorylated endothelial NO synthase estimations) and computational approaches (molecular dynamics simulations for structural analysis of wild-type [CST-WT] and variant [CST-364Ser] peptides and docking of peptide/ligand with β-adrenergic receptors [ADRB1/2]). CST-WT and CST-364Ser peptides differed profoundly in their secondary structures and showed differential interactions with ADRB2; although CST-WT displaced the ligand bound to ADRB2, CST-364Ser failed to do the same. Furthermore, CST-WT significantly inhibited ADRB2-stimulated extracellular regulated kinase activation, suggesting an antagonistic role towards ADRB2 unlike CST-364Ser. Consequently, CST-WT was more potent in NO production in human umbilical vein endothelial cells as compared with CST-364Ser. This NO-producing ability of CST-WT was abrogated by ADRB2 antagonist ICI 118551. In conclusion, CST-364Ser allele enhanced the risk for hypertension in human populations, possibly via diminished endothelial NO production because of altered interactions of CST-364Ser peptide with ADRB2 as compared with CST-WT.
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Affiliation(s)
- Malapaka Kiranmayi
- From the Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, Tamil Nadu, India (M.Kiranmayi, V.R.C., P.K.R.A., L.S., B.S.S., R.K., M.D., S.Senapati, N.R.M.); Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, OH (E.E.M., S.V.N.P.); Department of Genetics, Dr. ALM PG Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai, Tamil Nadu, India (D.V., A.K.M.); Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research, Chandigarh, India (S.Sharma, M.Khullar); Department of Molecular Genetics, Madras Diabetes Research Foundation, Chennai, Tamil Nadu, India (D.B., V.R., V.M.); Institute of Cardiovascular Diseases, Madras Medical Mission, Chennai, Tamil Nadu, India (A.S.M.); Department of Medicine, University of California San Francisco (P.K.R.A.); and Department of Clinical Biochemistry, University of Cambridge, Cambridge, United Kingdom (B.S.S.)
| | - Venkat R Chirasani
- From the Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, Tamil Nadu, India (M.Kiranmayi, V.R.C., P.K.R.A., L.S., B.S.S., R.K., M.D., S.Senapati, N.R.M.); Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, OH (E.E.M., S.V.N.P.); Department of Genetics, Dr. ALM PG Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai, Tamil Nadu, India (D.V., A.K.M.); Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research, Chandigarh, India (S.Sharma, M.Khullar); Department of Molecular Genetics, Madras Diabetes Research Foundation, Chennai, Tamil Nadu, India (D.B., V.R., V.M.); Institute of Cardiovascular Diseases, Madras Medical Mission, Chennai, Tamil Nadu, India (A.S.M.); Department of Medicine, University of California San Francisco (P.K.R.A.); and Department of Clinical Biochemistry, University of Cambridge, Cambridge, United Kingdom (B.S.S.)
| | - Prasanna K R Allu
- From the Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, Tamil Nadu, India (M.Kiranmayi, V.R.C., P.K.R.A., L.S., B.S.S., R.K., M.D., S.Senapati, N.R.M.); Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, OH (E.E.M., S.V.N.P.); Department of Genetics, Dr. ALM PG Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai, Tamil Nadu, India (D.V., A.K.M.); Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research, Chandigarh, India (S.Sharma, M.Khullar); Department of Molecular Genetics, Madras Diabetes Research Foundation, Chennai, Tamil Nadu, India (D.B., V.R., V.M.); Institute of Cardiovascular Diseases, Madras Medical Mission, Chennai, Tamil Nadu, India (A.S.M.); Department of Medicine, University of California San Francisco (P.K.R.A.); and Department of Clinical Biochemistry, University of Cambridge, Cambridge, United Kingdom (B.S.S.)
| | - Lakshmi Subramanian
- From the Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, Tamil Nadu, India (M.Kiranmayi, V.R.C., P.K.R.A., L.S., B.S.S., R.K., M.D., S.Senapati, N.R.M.); Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, OH (E.E.M., S.V.N.P.); Department of Genetics, Dr. ALM PG Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai, Tamil Nadu, India (D.V., A.K.M.); Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research, Chandigarh, India (S.Sharma, M.Khullar); Department of Molecular Genetics, Madras Diabetes Research Foundation, Chennai, Tamil Nadu, India (D.B., V.R., V.M.); Institute of Cardiovascular Diseases, Madras Medical Mission, Chennai, Tamil Nadu, India (A.S.M.); Department of Medicine, University of California San Francisco (P.K.R.A.); and Department of Clinical Biochemistry, University of Cambridge, Cambridge, United Kingdom (B.S.S.)
| | - Elizabeth E Martelli
- From the Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, Tamil Nadu, India (M.Kiranmayi, V.R.C., P.K.R.A., L.S., B.S.S., R.K., M.D., S.Senapati, N.R.M.); Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, OH (E.E.M., S.V.N.P.); Department of Genetics, Dr. ALM PG Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai, Tamil Nadu, India (D.V., A.K.M.); Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research, Chandigarh, India (S.Sharma, M.Khullar); Department of Molecular Genetics, Madras Diabetes Research Foundation, Chennai, Tamil Nadu, India (D.B., V.R., V.M.); Institute of Cardiovascular Diseases, Madras Medical Mission, Chennai, Tamil Nadu, India (A.S.M.); Department of Medicine, University of California San Francisco (P.K.R.A.); and Department of Clinical Biochemistry, University of Cambridge, Cambridge, United Kingdom (B.S.S.)
| | - Bhavani S Sahu
- From the Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, Tamil Nadu, India (M.Kiranmayi, V.R.C., P.K.R.A., L.S., B.S.S., R.K., M.D., S.Senapati, N.R.M.); Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, OH (E.E.M., S.V.N.P.); Department of Genetics, Dr. ALM PG Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai, Tamil Nadu, India (D.V., A.K.M.); Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research, Chandigarh, India (S.Sharma, M.Khullar); Department of Molecular Genetics, Madras Diabetes Research Foundation, Chennai, Tamil Nadu, India (D.B., V.R., V.M.); Institute of Cardiovascular Diseases, Madras Medical Mission, Chennai, Tamil Nadu, India (A.S.M.); Department of Medicine, University of California San Francisco (P.K.R.A.); and Department of Clinical Biochemistry, University of Cambridge, Cambridge, United Kingdom (B.S.S.)
| | - Durairajpandian Vishnuprabu
- From the Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, Tamil Nadu, India (M.Kiranmayi, V.R.C., P.K.R.A., L.S., B.S.S., R.K., M.D., S.Senapati, N.R.M.); Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, OH (E.E.M., S.V.N.P.); Department of Genetics, Dr. ALM PG Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai, Tamil Nadu, India (D.V., A.K.M.); Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research, Chandigarh, India (S.Sharma, M.Khullar); Department of Molecular Genetics, Madras Diabetes Research Foundation, Chennai, Tamil Nadu, India (D.B., V.R., V.M.); Institute of Cardiovascular Diseases, Madras Medical Mission, Chennai, Tamil Nadu, India (A.S.M.); Department of Medicine, University of California San Francisco (P.K.R.A.); and Department of Clinical Biochemistry, University of Cambridge, Cambridge, United Kingdom (B.S.S.)
| | - Rathnakumar Kumaragurubaran
- From the Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, Tamil Nadu, India (M.Kiranmayi, V.R.C., P.K.R.A., L.S., B.S.S., R.K., M.D., S.Senapati, N.R.M.); Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, OH (E.E.M., S.V.N.P.); Department of Genetics, Dr. ALM PG Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai, Tamil Nadu, India (D.V., A.K.M.); Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research, Chandigarh, India (S.Sharma, M.Khullar); Department of Molecular Genetics, Madras Diabetes Research Foundation, Chennai, Tamil Nadu, India (D.B., V.R., V.M.); Institute of Cardiovascular Diseases, Madras Medical Mission, Chennai, Tamil Nadu, India (A.S.M.); Department of Medicine, University of California San Francisco (P.K.R.A.); and Department of Clinical Biochemistry, University of Cambridge, Cambridge, United Kingdom (B.S.S.)
| | - Saurabh Sharma
- From the Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, Tamil Nadu, India (M.Kiranmayi, V.R.C., P.K.R.A., L.S., B.S.S., R.K., M.D., S.Senapati, N.R.M.); Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, OH (E.E.M., S.V.N.P.); Department of Genetics, Dr. ALM PG Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai, Tamil Nadu, India (D.V., A.K.M.); Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research, Chandigarh, India (S.Sharma, M.Khullar); Department of Molecular Genetics, Madras Diabetes Research Foundation, Chennai, Tamil Nadu, India (D.B., V.R., V.M.); Institute of Cardiovascular Diseases, Madras Medical Mission, Chennai, Tamil Nadu, India (A.S.M.); Department of Medicine, University of California San Francisco (P.K.R.A.); and Department of Clinical Biochemistry, University of Cambridge, Cambridge, United Kingdom (B.S.S.)
| | - Dhanasekaran Bodhini
- From the Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, Tamil Nadu, India (M.Kiranmayi, V.R.C., P.K.R.A., L.S., B.S.S., R.K., M.D., S.Senapati, N.R.M.); Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, OH (E.E.M., S.V.N.P.); Department of Genetics, Dr. ALM PG Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai, Tamil Nadu, India (D.V., A.K.M.); Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research, Chandigarh, India (S.Sharma, M.Khullar); Department of Molecular Genetics, Madras Diabetes Research Foundation, Chennai, Tamil Nadu, India (D.B., V.R., V.M.); Institute of Cardiovascular Diseases, Madras Medical Mission, Chennai, Tamil Nadu, India (A.S.M.); Department of Medicine, University of California San Francisco (P.K.R.A.); and Department of Clinical Biochemistry, University of Cambridge, Cambridge, United Kingdom (B.S.S.)
| | - Madhulika Dixit
- From the Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, Tamil Nadu, India (M.Kiranmayi, V.R.C., P.K.R.A., L.S., B.S.S., R.K., M.D., S.Senapati, N.R.M.); Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, OH (E.E.M., S.V.N.P.); Department of Genetics, Dr. ALM PG Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai, Tamil Nadu, India (D.V., A.K.M.); Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research, Chandigarh, India (S.Sharma, M.Khullar); Department of Molecular Genetics, Madras Diabetes Research Foundation, Chennai, Tamil Nadu, India (D.B., V.R., V.M.); Institute of Cardiovascular Diseases, Madras Medical Mission, Chennai, Tamil Nadu, India (A.S.M.); Department of Medicine, University of California San Francisco (P.K.R.A.); and Department of Clinical Biochemistry, University of Cambridge, Cambridge, United Kingdom (B.S.S.)
| | - Arasambattu K Munirajan
- From the Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, Tamil Nadu, India (M.Kiranmayi, V.R.C., P.K.R.A., L.S., B.S.S., R.K., M.D., S.Senapati, N.R.M.); Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, OH (E.E.M., S.V.N.P.); Department of Genetics, Dr. ALM PG Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai, Tamil Nadu, India (D.V., A.K.M.); Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research, Chandigarh, India (S.Sharma, M.Khullar); Department of Molecular Genetics, Madras Diabetes Research Foundation, Chennai, Tamil Nadu, India (D.B., V.R., V.M.); Institute of Cardiovascular Diseases, Madras Medical Mission, Chennai, Tamil Nadu, India (A.S.M.); Department of Medicine, University of California San Francisco (P.K.R.A.); and Department of Clinical Biochemistry, University of Cambridge, Cambridge, United Kingdom (B.S.S.)
| | - Madhu Khullar
- From the Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, Tamil Nadu, India (M.Kiranmayi, V.R.C., P.K.R.A., L.S., B.S.S., R.K., M.D., S.Senapati, N.R.M.); Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, OH (E.E.M., S.V.N.P.); Department of Genetics, Dr. ALM PG Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai, Tamil Nadu, India (D.V., A.K.M.); Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research, Chandigarh, India (S.Sharma, M.Khullar); Department of Molecular Genetics, Madras Diabetes Research Foundation, Chennai, Tamil Nadu, India (D.B., V.R., V.M.); Institute of Cardiovascular Diseases, Madras Medical Mission, Chennai, Tamil Nadu, India (A.S.M.); Department of Medicine, University of California San Francisco (P.K.R.A.); and Department of Clinical Biochemistry, University of Cambridge, Cambridge, United Kingdom (B.S.S.)
| | - Venkatesan Radha
- From the Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, Tamil Nadu, India (M.Kiranmayi, V.R.C., P.K.R.A., L.S., B.S.S., R.K., M.D., S.Senapati, N.R.M.); Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, OH (E.E.M., S.V.N.P.); Department of Genetics, Dr. ALM PG Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai, Tamil Nadu, India (D.V., A.K.M.); Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research, Chandigarh, India (S.Sharma, M.Khullar); Department of Molecular Genetics, Madras Diabetes Research Foundation, Chennai, Tamil Nadu, India (D.B., V.R., V.M.); Institute of Cardiovascular Diseases, Madras Medical Mission, Chennai, Tamil Nadu, India (A.S.M.); Department of Medicine, University of California San Francisco (P.K.R.A.); and Department of Clinical Biochemistry, University of Cambridge, Cambridge, United Kingdom (B.S.S.)
| | - Viswanathan Mohan
- From the Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, Tamil Nadu, India (M.Kiranmayi, V.R.C., P.K.R.A., L.S., B.S.S., R.K., M.D., S.Senapati, N.R.M.); Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, OH (E.E.M., S.V.N.P.); Department of Genetics, Dr. ALM PG Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai, Tamil Nadu, India (D.V., A.K.M.); Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research, Chandigarh, India (S.Sharma, M.Khullar); Department of Molecular Genetics, Madras Diabetes Research Foundation, Chennai, Tamil Nadu, India (D.B., V.R., V.M.); Institute of Cardiovascular Diseases, Madras Medical Mission, Chennai, Tamil Nadu, India (A.S.M.); Department of Medicine, University of California San Francisco (P.K.R.A.); and Department of Clinical Biochemistry, University of Cambridge, Cambridge, United Kingdom (B.S.S.)
| | - Ajit S Mullasari
- From the Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, Tamil Nadu, India (M.Kiranmayi, V.R.C., P.K.R.A., L.S., B.S.S., R.K., M.D., S.Senapati, N.R.M.); Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, OH (E.E.M., S.V.N.P.); Department of Genetics, Dr. ALM PG Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai, Tamil Nadu, India (D.V., A.K.M.); Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research, Chandigarh, India (S.Sharma, M.Khullar); Department of Molecular Genetics, Madras Diabetes Research Foundation, Chennai, Tamil Nadu, India (D.B., V.R., V.M.); Institute of Cardiovascular Diseases, Madras Medical Mission, Chennai, Tamil Nadu, India (A.S.M.); Department of Medicine, University of California San Francisco (P.K.R.A.); and Department of Clinical Biochemistry, University of Cambridge, Cambridge, United Kingdom (B.S.S.)
| | - Sathyamangla V Naga Prasad
- From the Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, Tamil Nadu, India (M.Kiranmayi, V.R.C., P.K.R.A., L.S., B.S.S., R.K., M.D., S.Senapati, N.R.M.); Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, OH (E.E.M., S.V.N.P.); Department of Genetics, Dr. ALM PG Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai, Tamil Nadu, India (D.V., A.K.M.); Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research, Chandigarh, India (S.Sharma, M.Khullar); Department of Molecular Genetics, Madras Diabetes Research Foundation, Chennai, Tamil Nadu, India (D.B., V.R., V.M.); Institute of Cardiovascular Diseases, Madras Medical Mission, Chennai, Tamil Nadu, India (A.S.M.); Department of Medicine, University of California San Francisco (P.K.R.A.); and Department of Clinical Biochemistry, University of Cambridge, Cambridge, United Kingdom (B.S.S.)
| | - Sanjib Senapati
- From the Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, Tamil Nadu, India (M.Kiranmayi, V.R.C., P.K.R.A., L.S., B.S.S., R.K., M.D., S.Senapati, N.R.M.); Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, OH (E.E.M., S.V.N.P.); Department of Genetics, Dr. ALM PG Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai, Tamil Nadu, India (D.V., A.K.M.); Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research, Chandigarh, India (S.Sharma, M.Khullar); Department of Molecular Genetics, Madras Diabetes Research Foundation, Chennai, Tamil Nadu, India (D.B., V.R., V.M.); Institute of Cardiovascular Diseases, Madras Medical Mission, Chennai, Tamil Nadu, India (A.S.M.); Department of Medicine, University of California San Francisco (P.K.R.A.); and Department of Clinical Biochemistry, University of Cambridge, Cambridge, United Kingdom (B.S.S.)
| | - Nitish R Mahapatra
- From the Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, Tamil Nadu, India (M.Kiranmayi, V.R.C., P.K.R.A., L.S., B.S.S., R.K., M.D., S.Senapati, N.R.M.); Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, OH (E.E.M., S.V.N.P.); Department of Genetics, Dr. ALM PG Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai, Tamil Nadu, India (D.V., A.K.M.); Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research, Chandigarh, India (S.Sharma, M.Khullar); Department of Molecular Genetics, Madras Diabetes Research Foundation, Chennai, Tamil Nadu, India (D.B., V.R., V.M.); Institute of Cardiovascular Diseases, Madras Medical Mission, Chennai, Tamil Nadu, India (A.S.M.); Department of Medicine, University of California San Francisco (P.K.R.A.); and Department of Clinical Biochemistry, University of Cambridge, Cambridge, United Kingdom (B.S.S.).
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Herold Z, Nagy P, Patócs A, Somogyi A. [The role of chromogranin-A and its derived peptide, WE-14 in the development of type 1 diabetes mellitus]. Orv Hetil 2015; 156:163-170. [PMID: 25618857 DOI: 10.1556/oh.2015.30087] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Chromogranin-A is a member of the granine protein family. It is produced in neuroendocrine cells via secretory granules. Many cleavage proteins are formed from chromogranin-A, from which some have well known biological activity, while the function of others is not yet fully known. Serum chromogranin-A levels are used in neuroendocrine tumour diagnostics. Recent studies showed that one of its cleavage protein, WE-14 may also play a role in the development of type 1 diabetes. WE-14 may function as an autoantigen for T-cells involved in the destruction of β-cells. This mechanism was previously observed only in non-obese diabetic mice. Novel results show that WE-14 also serves as a target for autoreactive cells in newly diagnosed type 1 diabetic patients as well, which reaction can be increased with transglutaminase. In this paper the authors summarize the recent knowledge about chromogranin-A and its potential role in the pathomechanism of type 1 diabetes mellitus.
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Affiliation(s)
- Zoltán Herold
- Szent István Egyetem Állatorvos-tudományi Kar Budapest Semmelweis Egyetem, Általános Orvostudományi Kar II. Belgyógyászati Klinika Budapest Szentkirályi utca 46. 1088
| | - Péter Nagy
- Semmelweis Egyetem, Általános Orvostudományi Kar I. Patológiai és Kísérleti Rákkutató Intézet Budapest
| | - Attila Patócs
- Semmelweis Egyetem, Általános Orvostudományi Kar Laboratóriumi Medicina Intézet Budapest MTA-SE "Lendület" Örökletes Endokrin Daganatok Kutatócsoport Budapest
| | - Anikó Somogyi
- Semmelweis Egyetem, Általános Orvostudományi Kar II. Belgyógyászati Klinika Budapest Szentkirályi utca 46. 1088
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Goetze JP, Alehagen U, Flyvbjerg A, Rehfeld JF. Chromogranin A as a biomarker in cardiovascular disease. Biomark Med 2014; 8:133-40. [DOI: 10.2217/bmm.13.102] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
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Goetze JP, Hilsted LM, Rehfeld JF, Alehagen U. Plasma chromogranin A is a marker of death in elderly patients presenting with symptoms of heart failure. Endocr Connect 2014; 3:47-56. [PMID: 24532383 PMCID: PMC3959729 DOI: 10.1530/ec-14-0017] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Cardiovascular risk assessment remains difficult in elderly patients. We examined whether chromogranin A (CgA) measurement in plasma may be valuable in assessing risk of death in elderly patients with symptoms of heart failure in a primary care setting. A total of 470 patients (mean age 73 years) were followed for 10 years. For CgA plasma measurement, we used a two-step method including a screening test and a confirmative test with plasma pre-treatment with trypsin. Cox multivariable proportional regression and receiver-operating curve (ROC) analyses were used to assess mortality risk. Assessment of cardiovascular mortality during the first 3 years of observation showed that CgA measurement contained useful information with a hazard ratio (HR) of 5.4 (95% CI 1.7-16.4) (CgA confirm). In a multivariate setting, the corresponding HR was 5.9 (95% CI 1.8-19.1). WHEN ADDING N-TERMINAL PROBNP (NT-PROBNP) TO THE MODEL, CGA CONFIRM STILL POSSESSED PROGNOSTIC INFORMATION (HR: 6.1; 95% CI 1.8-20.7). The result for predicting all-cause mortality displayed the same pattern. ROC analyses in comparison to NT-proBNP to identify patients on top of clinical variables at risk of cardiovascular death within 5 years of follow-up showed significant additive value of CgA confirm measurements compared with NT-proBNP and clinical variables. CgA measurement in the plasma of elderly patients with symptoms of heart failure can identify those at increased risk of short- and long-term mortality.
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Affiliation(s)
| | | | | | - Urban Alehagen
- Division of Cardiovascular Medicine, Department of Medicine and Health Sciences, Faculty of Health Sciences, Department of Cardiology UHL, County Council of ÖstergötlandLinköping UniversityLinköpingSweden
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D'amico MA, Ghinassi B, Izzicupo P, Manzoli L, Di Baldassarre A. Biological function and clinical relevance of chromogranin A and derived peptides. Endocr Connect 2014; 3:R45-54. [PMID: 24671122 PMCID: PMC5395093 DOI: 10.1530/ec-14-0027] [Citation(s) in RCA: 90] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Chromogranin A (CgA (CHGA)) is the major soluble protein co-stored and co-released with catecholamines and can function as a pro-hormone by giving rise to several bioactive peptides. This review summarizes the physiological functions, the pathogenic implications, and the recent use of these molecules as biomarkers in several pathological conditions. A thorough literature review of the electronic healthcare databases MEDLINE, from January 1985 to September 2013, was conducted to identify articles and studies concerned with CgA and its processing. The search strategies utilized keywords such as chromogranin A, vasostatins 1 and 2, chromofungin, chromacin, pancreastatin, catestatin, WE14, chromostatin, GE25, parastatin, and serpinin and was supplemented by the screening of references from included papers and review articles. A total of 209 English-language, peer-reviewed original articles or reviews were examined. The analysis of the retrospective literature suggested that CgA and its several bioactive fragments exert a broad spectrum of regulatory activities by influencing the endocrine, the cardiovascular, and the immune systems and by affecting the glucose or calcium homeostasis. As some peptides exert similar effects, but others elicit opposite responses, the regulation of the CgA processing is critical to maintain homeostasis, whereas an unbalanced production of peptides that exert opposing effects can have a pathogenic role in several diseases. These clinical implications entail that CgA and its derived peptides are now used as diagnostic and prognostic markers or to monitor the response to pharmacological intervention not only in endocrine tumors, but also in cardiovascular, inflammatory, and neuropsychiatric diseases.
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Frydland M, Kousholt B, Larsen JR, Burnettr JC, Hilsted L, Hasenkam JM, Goetze JP. Increased N-terminal CgA in circulation associated with cardiac reperfusion in pigs. Biomark Med 2013; 7:959-67. [DOI: 10.2217/bmm.13.92] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Aim: Acute myocardial infarction causes neurohumoral activation characterized by increased sympathetic activity. CgA is a protein released during sympathoadrenal stress from neuroendocrine tissue. Recently, increased CgA concentrations in circulation have been reported and suggested to be an independent predictor of mortality after acute myocardial infarction. Materials & methods: Eighteen pigs underwent 1 h of regional myocardial ischemia followed by 3 h of reperfusion. Blood samples were collected every hour and plasma CgA was measured with two radioimmunoassays. Results: We found a 30% increase in plasma N-terminal CgA 1 h after re-establishment of coronary blood supply. On the other hand, plasma pancreastatin did not change in response to ischemia or reperfusion but decreased during the entire experiment. Conclusion: Our results suggest a differentiated CgA response in myocardial reperfusion after local cardiac anoxia that may reflect tissue-specific post-translational processing and release.
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Affiliation(s)
- Martin Frydland
- Department of Cardiothoracic & Vascular Surgery, Aarhus University Hospital, Skejby, Denmark
| | - Birgitte Kousholt
- Department of Cardiothoracic & Vascular Surgery, Aarhus University Hospital, Skejby, Denmark
| | - Jens Rolighed Larsen
- Department of Cardiothoracic & Vascular Surgery, Anesthesia, Aarhus University Hospital, Skejby, Denmark
| | | | - Linda Hilsted
- Department of Clinical Biochemistry, Copenhagen University Hospital, Rigshospitalet, Denmark
| | - J Michael Hasenkam
- Department of Cardiothoracic & Vascular Surgery, Aarhus University Hospital, Skejby, Denmark
| | - Jens Peter Goetze
- Department of Clinical Biochemistry, Copenhagen University Hospital, Rigshospitalet, Denmark
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Pasqua T, Corti A, Gentile S, Pochini L, Bianco M, Metz-Boutigue MH, Cerra MC, Tota B, Angelone T. Full-length human chromogranin-A cardioactivity: myocardial, coronary, and stimulus-induced processing evidence in normotensive and hypertensive male rat hearts. Endocrinology 2013; 154:3353-65. [PMID: 23751870 DOI: 10.1210/en.2012-2210] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Plasma chromogranin-A (CgA) concentrations correlate with severe cardiovascular diseases, whereas CgA-derived vasostatin-I and catestatin elicit cardiosuppression via an antiadrenergic/nitric oxide-cGMP mediated mechanism. Whether these phenomena are related is unknown. We here investigated whether and to what extent full-length CgA directly influences heart performance and may be subjected to stimulus-elicited intracardiac processing. Using normotensive and hypertensive rats, we evaluated the following: 1) direct myocardial and coronary effects of full-length CgA; 2) the signal-transduction pathway involved in its action mechanism; and 3) CgA intracardiac processing after β-adrenergic [isoproterenol (Iso)]- and endothelin-1(ET-1)-dependent stimulation. The study was performed by using a Langendorff perfusion apparatus, Western blotting, affinity chromatography, and ELISA. We found that CgA (1-4 nM) dilated coronaries and induced negative inotropism and lusitropism, which disappeared at higher concentrations (10-16 nM). In spontaneously hypertensive rats (SHRs), negative inotropism and lusitropism were more potent than in young normotensive rats. We found that perfusion itself, Iso-, and endothelin-1 stimulation induced intracardiac CgA processing in low-molecular-weight fragments in young, Wistar Kyoto, and SHR rats. In young normotensive and adult hypertensive rats, CgA increased endothelial nitric oxide synthase phosphorylation and cGMP levels. Analysis of the perfusate from both Wistar rats and SHRs of untreated and treated (Iso) hearts revealed CgA absence. In conclusion, in normotensive and hypertensive rats, we evidenced the following: 1) full-length CgA directly affects myocardial and coronary function by AkT/nitric oxide synthase/nitric oxide/cGMP/protein kinase G pathway; and 2) the heart generates intracardiac CgA fragments in response to hemodynamic and excitatory challenges. For the first time at the cardiovascular level, our data provide a conceptual link between systemic and intracardiac actions of full-length CgA and its fragments, expanding the knowledge on the sympathochromaffin/CgA axis under normal and physiopathological conditions.
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Affiliation(s)
- Teresa Pasqua
- Department of Biology, Ecology, and Earth Sciences, University of Calabria, 87036 Arcavacata di Rende (CS), Italy
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Affiliation(s)
- Jens P Goetze
- Department of Clinical Biochemistry, University of Copenhagen, DK-2100 Copenhagen, Denmark.
| | - Urban Alehagen
- Division of Cardiovascular Medicine, Linköping University, Sweden
| | - Allan Flyvbjerg
- Medical Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark; Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark
| | - Jens F Rehfeld
- Department of Clinical Biochemistry, University of Copenhagen, DK-2100 Copenhagen, Denmark
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Effect of short- and long-term physical activities on circulating granin protein levels. ACTA ACUST UNITED AC 2013; 185:14-9. [DOI: 10.1016/j.regpep.2013.06.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2012] [Revised: 03/07/2013] [Accepted: 06/19/2013] [Indexed: 11/23/2022]
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Liu L, Ding W, Zhao F, Shi L, Pang Y, Tang C. Plasma levels and potential roles of catestatin in patients with coronary heart disease. SCAND CARDIOVASC J 2013; 47:217-24. [DOI: 10.3109/14017431.2013.794951] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
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Ferraro S, Ardoino I, Bassani N, Santagostino M, Rossi L, Biganzoli E, Bongo AS, Panteghini M. Multi-marker network in ST-elevation myocardial infarction patients undergoing primary percutaneous coronary intervention: when and what to measure. Clin Chim Acta 2013; 417:1-7. [PMID: 23246517 DOI: 10.1016/j.cca.2012.12.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2012] [Revised: 11/29/2012] [Accepted: 12/01/2012] [Indexed: 10/27/2022]
Abstract
BACKGROUND Data on the correlations between biomarkers to suggest cost-effective multi-marker (MM) panels predictive for ST-elevation myocardial infarction (STEMI) patients are lacking. We sought to explore the relationship between cardiac troponin I (cTnI), C-reactive protein (CRP), B-type natriuretic peptide (BNP), and chromogranin A (CgA) accounting for biomarkers' profiles detected within 48h from successful primary percutaneous coronary intervention (PPCI). METHODS In 73 STEMI patients cTnI, CRP, BNP, and CgA were measured before PPCI and 6, 24, and 48h later. STATIS methods generalizing Principal Component Analysis on three-way data sets were employed to extract information about: 1) similarities between patients, 2) contribution of each time of sampling and 3) correlations between biomarkers' profiles. RESULTS STEMI patients who underwent successful PPCI emerged to have a homogeneous profile tailored on biomarkers' evaluation within 48h. Their measurements at 24h contributed the most variability and information both to patients' and to biomarkers' profiles. BNP and cTnI were highly correlated and explained the 40.1% of the total variance, whereas CgA resulted independent and explained the 26.3% of the total variance. CONCLUSIONS Markers' measurements at 24h after PPCI contributed most information to the definition of patients' profile. BNP and cTnI resulted interchangeable in a MM panel for reporting about the extent of necrosis.
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Affiliation(s)
- Simona Ferraro
- Cattedra di Biochimica Clinica e Biologia Molecolare Clinica, Dipartimento di Scienze Biomediche e Cliniche Luigi Sacco, Università degli Studi, Milano, Italy.
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Lu L, Wang YN, Li MC, Wang HB, Pu LJ, Niu WQ, Meng H, Yang EL, Zhang RY, Zhang Q, Zhao Q, Chen QJ, De Caterina R, Shen WF. Reduced serum levels of vasostatin-2, an anti-inflammatory peptide derived from chromogranin A, are associated with the presence and severity of coronary artery disease. Eur Heart J 2012; 33:2297-306. [DOI: 10.1093/eurheartj/ehs122] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
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Røsjø H, Stridsberg M, Florholmen G, Stensløkken KO, Ottesen AH, Sjaastad I, Husberg C, Dahl MB, Øie E, Louch WE, Omland T, Christensen G. Secretogranin II; a protein increased in the myocardium and circulation in heart failure with cardioprotective properties. PLoS One 2012; 7:e37401. [PMID: 22655045 PMCID: PMC3360055 DOI: 10.1371/journal.pone.0037401] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2012] [Accepted: 04/19/2012] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Several beneficial effects have been demonstrated for secretogranin II (SgII) in non-cardiac tissue. As cardiac production of chromogranin A and B, two related proteins, is increased in heart failure (HF), we hypothesized that SgII could play a role in cardiovascular pathophysiology. METHODOLOGY/PRINCIPAL FINDINGS SgII production was characterized in a post-myocardial infarction heart failure (HF) mouse model, functional properties explored in experimental models, and circulating levels measured in mice and patients with stable HF of moderate severity. SgII mRNA levels were 10.5 fold upregulated in the left ventricle (LV) of animals with myocardial infarction and HF (p<0.001 vs. sham-operated animals). SgII protein levels were also increased in the LV, but not in other organs investigated. SgII was produced in several cell types in the myocardium and cardiomyocyte synthesis of SgII was potently induced by transforming growth factor-β and norepinephrine stimulation in vitro. Processing of SgII to shorter peptides was enhanced in the failing myocardium due to increased levels of the proteases PC1/3 and PC2 and circulating SgII levels were increased in mice with HF. Examining a pathophysiological role of SgII in the initial phase of post-infarction HF, the SgII fragment secretoneurin reduced myocardial ischemia-reperfusion injury and cardiomyocyte apoptosis by 30% and rapidly increased cardiomyocyte Erk1/2 and Stat3 phosphorylation. SgII levels were also higher in patients with stable, chronic HF compared to age- and gender-matched control subjects: median 0.16 (Q1-3 0.14-0.18) vs. 0.12 (0.10-0.14) nmol/L, p<0.001. CONCLUSIONS We demonstrate increased myocardial SgII production and processing in the LV in animals with myocardial infarction and HF, which could be beneficial as the SgII fragment secretoneurin protects from ischemia-reperfusion injury and cardiomyocyte apoptosis. Circulating SgII levels are also increased in patients with chronic, stable HF and may represent a new cardiac biomarker.
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Affiliation(s)
- Helge Røsjø
- Division of Medicine, Akershus University Hospital, Lørenskog, Norway.
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Røsjø H, Nygård S, Kaukonen KM, Karlsson S, Stridsberg M, Ruokonen E, Pettilä V, Omland T. Prognostic value of chromogranin A in severe sepsis: data from the FINNSEPSIS study. Intensive Care Med 2012; 38:820-9. [PMID: 22491939 DOI: 10.1007/s00134-012-2546-8] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2011] [Accepted: 01/05/2012] [Indexed: 12/16/2022]
Abstract
PURPOSE To assess the prognostic information of chromogranin A (CgA), a marker associated with adrenergic tone and myocardial function, in patients with severe sepsis. METHODS CgA levels were measured at the time of study inclusion and 72 h later in 232 patients with severe sepsis recruited from 24 ICUs in Finland (FINNSEPSIS study). RESULTS Sixty-five patients (28%) died during the index hospitalization. CgA levels at inclusion and after 72 h correlated with several established indices of risk in sepsis. Patients who died during the hospitalization had higher baseline CgA levels than hospital survivors: 14.0 (Q1-3, 7.4-27.4) versus 9.1 (5.9-15.8) nmol/l, P = 0.002, and after 72 h: 16.2 (9.0-31.1) versus 9.8 (6.0-18.0) nmol/l, P = 0.001. Prior cardiovascular disease (P = 0.04) and cardiovascular SOFA levels on day 3 (P = 0.03) were associated with higher CgA levels after 72 h by linear regression. CgA levels on study inclusion and after 72 h were independently associated with hospital mortality by logistic regression: OR (logarithmically transformed CgA levels) 1.95 (95% CI 1.01-3.77), P = 0.046 and OR 2.03 (95% CI 1.18-3.49), P = 0.01, respectively. The prognostic accuracy was comparable for CgA measurements and SAPS II score, and the addition of CgA measurements to the SAPS II score improved risk stratification of the patients as assessed by the category-free net reclassification index. A CgA level >6.6 nmol/l on study inclusion was associated with septic shock during the hospitalization. CONCLUSION CgA levels measured during hospitalization for severe sepsis are associated with cardiovascular dysfunction and may provide additional prognostic information in patients with severe sepsis.
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Affiliation(s)
- Helge Røsjø
- Division of Medicine, Akershus University Hospital, Sykehusveien 27, 1478, Lørenskog, Norway.
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Genes involved in systemic and arterial bed dependent atherosclerosis--Tampere Vascular study. PLoS One 2012; 7:e33787. [PMID: 22509262 PMCID: PMC3324479 DOI: 10.1371/journal.pone.0033787] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2010] [Accepted: 02/19/2012] [Indexed: 12/23/2022] Open
Abstract
Background Atherosclerosis is a complex disease with hundreds of genes influencing its progression. In addition, the phenotype of the disease varies significantly depending on the arterial bed. Methodology/Principal Findings We characterized the genes generally involved in human advanced atherosclerotic (AHA type V–VI) plaques in carotid and femoral arteries as well as aortas from 24 subjects of Tampere Vascular study and compared the results to non-atherosclerotic internal thoracic arteries (n=6) using genome-wide expression array and QRT-PCR. In addition we determined genes that were typical for each arterial plaque studied. To gain a comprehensive insight into the pathologic processes in the plaques we also analyzed pathways and gene sets dysregulated in this disease using gene set enrichment analysis (GSEA). According to the selection criteria used (>3.0 fold change and p-value <0.05), 235 genes were up-regulated and 68 genes down-regulated in the carotid plaques, 242 genes up-regulated and 116 down-regulated in the femoral plaques and 256 genes up-regulated and 49 genes down-regulated in the aortic plaques. Nine genes were found to be specifically induced predominantly in aortic plaques, e.g., lactoferrin, and three genes in femoral plaques, e.g., chondroadherin, whereas no gene was found to be specific for carotid plaques. In pathway analysis, a total of 28 pathways or gene sets were found to be significantly dysregulated in atherosclerotic plaques (false discovery rate [FDR] <0.25). Conclusions This study describes comprehensively the gene expression changes that generally prevail in human atherosclerotic plaques. In addition, site specific genes induced only in femoral or aortic plaques were found, reflecting that atherosclerotic process has unique features in different vascular beds.
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Bartolomucci A, Possenti R, Mahata SK, Fischer-Colbrie R, Loh YP, Salton SRJ. The extended granin family: structure, function, and biomedical implications. Endocr Rev 2011; 32:755-97. [PMID: 21862681 PMCID: PMC3591675 DOI: 10.1210/er.2010-0027] [Citation(s) in RCA: 254] [Impact Index Per Article: 18.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The chromogranins (chromogranin A and chromogranin B), secretogranins (secretogranin II and secretogranin III), and additional related proteins (7B2, NESP55, proSAAS, and VGF) that together comprise the granin family subserve essential roles in the regulated secretory pathway that is responsible for controlled delivery of peptides, hormones, neurotransmitters, and growth factors. Here we review the structure and function of granins and granin-derived peptides and expansive new genetic evidence, including recent single-nucleotide polymorphism mapping, genomic sequence comparisons, and analysis of transgenic and knockout mice, which together support an important and evolutionarily conserved role for these proteins in large dense-core vesicle biogenesis and regulated secretion. Recent data further indicate that their processed peptides function prominently in metabolic and glucose homeostasis, emotional behavior, pain pathways, and blood pressure modulation, suggesting future utility of granins and granin-derived peptides as novel disease biomarkers.
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Affiliation(s)
- Alessandro Bartolomucci
- Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, Minnesota 55455, USA
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Schillaci G, De Vuono S, Pucci G. An endogenous brake on the sympathetic nervous system: the emerging role of catestatin in hypertension. J Cardiovasc Med (Hagerstown) 2011; 12:609-12. [PMID: 21792021 DOI: 10.2459/jcm.0b013e328348d925] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Trapé J, Filella X, Alsina-Donadeu M, Juan-Pereira L, Bosch-Ferrer Á, Rigo-Bonnin R. Increased plasma concentrations of tumour markers in the absence of neoplasia. Clin Chem Lab Med 2011; 49:1605-20. [PMID: 21892908 DOI: 10.1515/cclm.2011.694] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Tumour markers are a very heterogeneous group of molecules that are generally found in very small concentrations in the plasma and serum of healthy individuals. In the process of neoplastic differentiation the cell can synthesize, release, or induce synthesis of other cells, thus increasing their concentration in plasma and serum. These substances may also increase their plasma concentration in patients without cancer due to processes that increase the release or reduce catabolism, and so give rise to false positives. An understanding of the main physiopathological processes that increase the concentrations of these substances could improve our interpretation of tumour markers and their clinical application. In this study we review the physiopathological processes that may increase the plasma concentrations of tumour markers. We performed a bibliography review in PubMed, searching for causes of false positives for the following tumour markers: α-Fetoprotein, CA 125, CA 15-3, CA 19-9, CA 72-4, carcinoembryonic antigen, CYFRA 21-1, squamous cell carcinoma, prostatic specific antigen, β(2)-microglobulin, choriogonadotropin (β chain), chromogranin A, neuron specific enolase, HER2-neu, progastrin releasing peptide, S-100, and thyroglobulin. The results favour the use of tests which can identify pathological processes that may increase tumour marker concentrations.
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Affiliation(s)
- Jaume Trapé
- Laboratory Medicine, Biological Diagnosis Department, Manresa Althaia Xarxa Assistencial de Manresa, Manresa, Catalonia, Spain.
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Chromogranin A: a novel factor acting at the cross road between the neuroendocrine and the cardiovascular systems. J Hypertens 2011; 29:409-14. [PMID: 21178786 DOI: 10.1097/hjh.0b013e328341a429] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Chromogranin A (CHGA) is a secretory protein stored in and released from neurons and cells of the diffuse neuroendocrine system. Cells of the adrenal medulla and adrenergic terminals are a main source of CHGA but also myocardial cells produce it under stress conditions. After secretion, CHGA is cleaved into several biologically active fragments, including vasostatins and catestatin. CHGA and its proteolytic peptides exert a broad spectrum of activities on the cardiovascular system. They act on blood pressure by controlling the vascular tone and the cardiac inotropic and chronotropic function. CHGA revealed to be a sensitive marker of myocardial dysfunction, with a high predictive power of morbidity and mortality in heart failure and ischemic heart disease. In addition, CHGA has been involved in the control of sustained endothelial inflammation and has been shown to be a good marker of persistent vascular inflammation in rheumatologic disorders affecting vessels.
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Wang X, Xu S, Liang Y, Zhu D, Mi L, Wang G, Gao W. Dramatic changes in catestatin are associated with hemodynamics in acute myocardial infarction. Biomarkers 2011; 16:372-7. [PMID: 21545240 DOI: 10.3109/1354750x.2011.578260] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Acute myocardial infarction (AMI) is characterized by complex neuroendocrine activation. To investigate catestatin profiles, serial catestatin levels were determined by enzyme-linked immunosorbent assay in the first week after AMI in 50 patients. Catestatin levels reduced at admission and negatively correlated with heart rates; it increased significantly on the third day but remained decreased at 1 week and positively with blood pressure. In a subgroup of 20 patients admitted within 4 h after onset, circulating catestatin correlated inversely with norepinephrine. Catestatin might be involved in the course of AMI and act as a tool in monitoring the progression of AMI.
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Affiliation(s)
- Xinyu Wang
- Department of Cardiology, Peking University Third Hospital, Beijing, China
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Biswas N, Curello E, O’Connor DT, Mahata SK. Chromogranin/secretogranin proteins in murine heart: myocardial production of chromogranin A fragment catestatin (Chga(364-384)). Cell Tissue Res 2010; 342:353-61. [PMID: 21052719 PMCID: PMC2996542 DOI: 10.1007/s00441-010-1059-4] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2010] [Accepted: 09/10/2010] [Indexed: 02/06/2023]
Abstract
In the heart, the secretory granules containing the atrial natriuretic peptides (ANP) and B-type myocardial natriuretic peptide (BNP) provide the basis for the endocrine function of this organ. We sought to determine whether atrial and myocardial secretory granules contain chromogranin/secretogranin proteins including chromogranin A (CHGA/Chga), chromogranin B (CHGB/Chgb) and secretogranin II (SCG2/Scg2). Deconvolution microscopy on immunolabeled proteins revealed the presence of Chga, Chgb, and Scg2 in murine cardiac secretory granules. The presence of low plasma catestatin (CST: mChga364–384) in older mice indicates diminished processing of Chga to CST with advancement of age, which is comparable to that found in humans. We have previously shown that CST (hCHGA352–372) exerts potent cardio-suppressive effects on frog and rat heart, but the source of CST for such action has remained elusive. In the present study, we found CST-related peptides in cardiomyocytes and in heart, which establishes an autocrine/paracrine function of CST in cardiac tissue. We conclude that cardiac secretory granules contain Chga, Chgb and Scg2 and that Chga is processed to CST in murine heart.
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Affiliation(s)
- Nilima Biswas
- Department of Medicine (0838), UCSD School of Medicine and VASDHS, 9500 Gilman Drive, La Jolla, CA 92093-0838 USA
| | - Erica Curello
- Department of Medicine (0838), UCSD School of Medicine and VASDHS, 9500 Gilman Drive, La Jolla, CA 92093-0838 USA
- Molecular Genetics, University of California, San Diego, CA USA
- VA San Diego Healthcare System, 9500 Gilman Drive, La Jolla, CA 92093-0838 USA
| | - Daniel T. O’Connor
- Department of Medicine (0838), UCSD School of Medicine and VASDHS, 9500 Gilman Drive, La Jolla, CA 92093-0838 USA
- Molecular Genetics, University of California, San Diego, CA USA
- VA San Diego Healthcare System, 9500 Gilman Drive, La Jolla, CA 92093-0838 USA
| | - Sushil K. Mahata
- Department of Medicine (0838), UCSD School of Medicine and VASDHS, 9500 Gilman Drive, La Jolla, CA 92093-0838 USA
- VA San Diego Healthcare System, 9500 Gilman Drive, La Jolla, CA 92093-0838 USA
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Røsjø H, Husberg C, Dahl MB, Stridsberg M, Sjaastad I, Finsen AV, Carlson CR, Oie E, Omland T, Christensen G. Chromogranin B in heart failure: a putative cardiac biomarker expressed in the failing myocardium. Circ Heart Fail 2010; 3:503-11. [PMID: 20519641 DOI: 10.1161/circheartfailure.109.867747] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND Chromogranin B (CgB) is a member of the granin protein family. Because CgB is often colocalized with chromogranin A (CgA), a recently discovered cardiac biomarker, we hypothesized that CgB is regulated during heart failure (HF) development. METHODS AND RESULTS CgB regulation was investigated in patients with chronic HF and in a post-myocardial infarction HF mouse model. Animals were phenotypically characterized by echocardiography and euthanized 1 week after myocardial infarction. CgB mRNA levels were 5.2-fold increased in the noninfarcted part of the left ventricle of HF animals compared with sham-operated animals (P<0.001). CgB mRNA level in HF animals correlated closely with animal lung weight (r=0.74, P=0.04) but not with CgA mRNA levels (r=0.20, P=0.61). CgB protein levels were markedly increased in both the noninfarcted (110%) and the infarcted part of the left ventricle (70%) but unaltered in other tissues investigated. Myocardial CgB immunoreactivity was confined to cardiomyocytes. Norepinephrine, angiotensin II, and transforming growth factor-beta increased CgB gene expression in cardiomyocytes. Circulating CgB levels were increased in HF animals (median levels in HF animals versus sham, 1.23 [interquartile range, 1.03 to 1.93] versus 0.98 [0.90 to 1.04] nmol/L; P=0.003) and in HF patients (HF patients versus control, 1.66 [1.48 to 1.85] versus 1.47 [1.39 to 1.58] nmol/L; P=0.007), with levels increasing in proportion to New York Heart Association functional class (P=0.03 for trend). Circulating CgB levels were only modestly correlated with CgA (r=0.31, P=0.009) and B-type natriuretic peptide levels (r=0.27, P=0.014). CONCLUSIONS CgB production is increased and regulated in proportion to disease severity in the left ventricle and circulation during HF development.
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Affiliation(s)
- Helge Røsjø
- Medical Division and EpiGen, Institute of Clinical Epidemiology and Molecular Biology, Akershus University Hospital, Lørenskog, Norway.
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Røsjø H, Masson S, Latini R, Flyvbjerg A, Milani V, La Rovere MT, Revera M, Mezzani A, Tognoni G, Tavazzi L, Omland T. Prognostic value of chromogranin A in chronic heart failure: data from the GISSI-Heart Failure trial. Eur J Heart Fail 2010; 12:549-56. [PMID: 20388648 DOI: 10.1093/eurjhf/hfq055] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
AIMS To assess the association between circulating levels of chromogranin A (CgA) and outcome in a large population of patients with chronic heart failure (HF). METHODS AND RESULTS Plasma CgA levels were measured at randomization and after 3 months in 1233 patients (median age 68 years, 80% male) with chronic, stable HF from the GISSI-HF trial. Circulating CgA levels were associated with several established risk markers in HF, including increased age, diabetes, reduced renal function, and heart rate variability. During a median follow-up of 3.9 years, 333 patients (27%) died. By univariable analysis, plasma CgA levels at baseline were strongly associated with all-cause mortality during follow-up; 2nd vs. 1st tertile: HR 1.58 (1.17-2.11), P = 0.002; and 3rd vs. 1st tertile: HR 2.35 (1.78-3.10), P < 0.0001. After adjustment for established risk factors of mortality, this association was attenuated and no longer significant. Randomized treatments with n-3 polyunsaturated fatty acid or rosuvastatin did not significantly change plasma CgA concentration over 3 months. CONCLUSION Measurement of circulating CgA levels in patients with chronic, stable HF does not provide incremental prognostic information to that obtained from physical examination, routine biochemical analysis, and contemporary HF biomarkers.
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Affiliation(s)
- Helge Røsjø
- Division of Medicine, Akershus University Hospital, Lørenskog, Norway
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Sahu BS, Sonawane PJ, Mahapatra NR. Chromogranin A: a novel susceptibility gene for essential hypertension. Cell Mol Life Sci 2010; 67:861-74. [PMID: 19943077 PMCID: PMC11115493 DOI: 10.1007/s00018-009-0208-y] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2009] [Revised: 11/06/2009] [Accepted: 11/06/2009] [Indexed: 12/25/2022]
Abstract
Chromogranin A (CHGA) is ubiquitously expressed in secretory cells of the endocrine, neuroendocrine, and neuronal tissues. Although this protein has long been known as a marker for neuroendocrine tumors, its role in cardiovascular disease states including essential hypertension (EH) has only recently been recognized. It acts as a prohormone giving rise to bioactive peptides such as vasostatin-I (human CHGA(1-76)) and catestatin (human CHGA(352-372)) that exhibit several cardiovascular regulatory functions. CHGA is over-expressed but catestatin is diminished in EH. Moreover, genetic variants in the promoter, catestatin, and 3'-untranslated regions of the human CHGA gene alter autonomic activity and blood pressure. Consistent with these findings, targeted ablation of this gene causes severe arterial hypertension and ventricular hypertrophy in mice. Transgenic expression of the human CHGA gene or exogenous administration of catestatin restores blood pressure in these mice. Thus, the accumulated evidence establishes CHGA as a novel susceptibility gene for EH.
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Affiliation(s)
- Bhavani S. Sahu
- Cardiovascular Genetics Laboratory, Department of Biotechnology, Indian Institute of Technology Madras, Chennai, 600036 India
| | - Parshuram J. Sonawane
- Cardiovascular Genetics Laboratory, Department of Biotechnology, Indian Institute of Technology Madras, Chennai, 600036 India
| | - Nitish R. Mahapatra
- Cardiovascular Genetics Laboratory, Department of Biotechnology, Indian Institute of Technology Madras, Chennai, 600036 India
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Mahata SK, Mahata M, Fung MM, O'Connor DT. Catestatin: a multifunctional peptide from chromogranin A. ACTA ACUST UNITED AC 2010; 162:33-43. [PMID: 20116404 DOI: 10.1016/j.regpep.2010.01.006] [Citation(s) in RCA: 88] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2009] [Revised: 01/11/2010] [Accepted: 01/21/2010] [Indexed: 12/16/2022]
Abstract
In 1997, we identified a novel peptide, catestatin (CST: bovine chromogranin A [CHGA](344-364): RSMRLSFRARGYGFRGPGLQL; human CHGA(352-372): SSMKLSFRARGYGFRGPGPQL), which is a potent inhibitor of nicotinic-cholinergic-stimulated catecholamine secretion. CST shows characteristic inhibitory effects on nicotinic cationic (Na(+), Ca(2+)) signal transduction, which are specific to the neuronal nicotinic receptor. Utilizing systematic polymorphism discovery at the human CHGA locus we discovered three human variants of CST: G(364)S, P(370)L, and R(374)Q that showed differential potencies towards the inhibition of catecholamine secretion. In humans, CHGA is elevated and its processing to CST is diminished in hypertension. Diminished CST is observed not only in hypertensive individuals but also in the early-normotensive offspring of patients with hypertension, suggesting that an early deficiency of CST might play a pathogenic role in the subsequent development of the disease. Consistent with human findings, prevention of endogenous CST expression by targeted ablation (knockout) of the mouse Chga locus (Chga-KO) resulted in severe hypertension that can be "rescued" specifically by replacement of the CST peptide. CST acts directly on the heart to inhibit the inotropic and lusitropic properties of the rodent heart and also acts as a potent vasodilator in rats and humans. While the G(364)S CST variant caused profound changes in human autonomic activity and seemed to reduce the risk of developing hypertension, CST replacement rescued Chga-KO mice from dampened baroreflex sensitivity. In addition, CST has been shown to induce chemotaxis and acts as an antimicrobial as well as an antimalarial peptide. The present review summarizes these multiple actions of CST.
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Affiliation(s)
- Sushil K Mahata
- Department of Medicine (0838), University of California at San Diego, and Veterans Affairs San Diego Healthcare System, 9500 Gilman Drive, La Jolla, CA 92093-0838, USA.
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47
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Jeske W, Glinicki P. Prognostic value of circulating chromogranin A levels in acute coronary syndrome: reply. Eur Heart J 2010. [PMID: 19906689 PMCID: PMC2800921 DOI: 10.1093/eurheartj/ehp469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
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Angelone T, Quintieri AM, Goumon Y, Di Felice V, Filice E, Gattuso A, Mazza R, Corti A, Tota B, Metz-Boutigue MH, Cerra MC. Cytoskeleton mediates negative inotropism and lusitropism of chromogranin A-derived peptides (human vasostatin1-78 and rat CgA₁₋₆₄) in the rat heart. ACTA ACUST UNITED AC 2009; 165:78-85. [PMID: 19896507 DOI: 10.1016/j.regpep.2009.10.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2009] [Revised: 10/21/2009] [Accepted: 10/23/2009] [Indexed: 11/24/2022]
Abstract
Cytoskeleton scaffold in cardiac myocytes provides structural support and compartmentalization of intracellular components. It is implicated in cardiac pathologies including hypertrophy and failure, playing a key role in the determinism of contractile and diastolic dysfunctions. Chromogranin A (CgA) and its derived peptides have revealed themselves as novel cardiovascular modulators. In humans, normal CgA levels considerably increase in several pathologies, including heart failure. Recent data have shown on the unstimulated rat heart that human recombinant Vasostatin-1 (hrVS-1) and rat chromogranin A 1-64 (rCgA₁₋₆₄) induce negative inotropic and lusitropic effects counteracting the β-adrenergic-dependent positive inotropism with a functional non-competitive antagonism. This study investigates, on the isolated Langendorff perfused rat heart, whether cardiac cytoskeleton is involved in the modulation of contractility and relaxation exerted by hrVS-1 and rCgA₁₋₆₄. Cytoskeleton impairment by either cytochalasin-D (actin polymerization inhibitor), BDM (myosin ATP-ase antagonist) or wortmannin (inhibitor of PI3-K/Akt transduction cascade), or W-7 (calcium-calmodulin antagonist) abolished hrVS-1 and rCgA₁₋₆₄-mediated inotropism and lusitropism. Using fluorescent phalloidin, we showed on rat cardiac H9C2 cells that hrVS-1 (10 nM÷10 µM) stimulates actin polymerization. Taken together these data indicate that in the rat heart, the actin cytoskeletal network strongly contributes to the cardiotropic action of CgA-derived peptides.
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Affiliation(s)
- Tommaso Angelone
- Department of Cell Biology, University of Calabria, 87030 Arcavacata di Rende (CS), Italy.
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Malaguarnera M, Cristaldi E, Cammalleri L, Colonna V, Lipari H, Capici A, Cavallaro A, Beretta M, Alessandria I, Luca S, Motta M. Elevated chromogranin A (CgA) serum levels in the patients with advanced pancreatic cancer. Arch Gerontol Geriatr 2009; 48:213-217. [PMID: 18329114 DOI: 10.1016/j.archger.2008.01.014] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2007] [Revised: 01/10/2008] [Accepted: 01/14/2008] [Indexed: 11/30/2022]
Abstract
The neuroendocrine differentiation in PC could potentially represent a new finding with diagnostic, prognostic and therapeutic implications. This study aimed at evaluating the clinical usefulness of CgA as a neuroendocrine (NE) serum-marker. We investigated the role of the serum concentration of CgA in a study group of patients with PC. CgA was significantly higher in the patients affected by PC as compared with the group of healthy subjects (HS) and those with chronic pancreatitis (CHP) (p<0.001). Also the HS group differed significantly from the CHP control group in the serum CgA levels (p<0.001). The serum carbohydrate antigen (CA19-9) level displayed a significant difference (p<0.001) between the PC and the HS group. The PC and CHP groups, as well as the HS and CHP groups showed also significant differences in the CA19-9 levels (p<0.001). One can conclude that the patients with higher CgA levels had poorer prognosis and survival, as compared to those with lower CgA levels. These results support the notion that the determination of serum CgA level before treatment may be a potential prognostic factor for PC.
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Affiliation(s)
- Michele Malaguarnera
- Department of Aging Sciences, Research Center on the Extreme Senescence, University of Catania, Via Messina, Catania, Italy
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