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Jiang K, Su F, Deng R, Xu Y, Qin A, Yuan X, Xing D, Chen Y, Wang D, Shen L, Hwa J, Hou L, Xiang Y. Cardiomyocyte-specific NHE1 overexpression confers protection against myocardial infarction during hyperglycemia. Cardiovasc Diabetol 2025; 24:184. [PMID: 40287728 PMCID: PMC12034198 DOI: 10.1186/s12933-025-02743-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Accepted: 04/15/2025] [Indexed: 04/29/2025] Open
Abstract
BACKGROUND Acute hyperglycemia on admission is frequently observed during the early phase after acute myocardial infarction (MI), even without the history of diabetes mellitus. We previously reported that inhibiting Na+/H+ exchanger 1 (NHE1) activity post-MI may improve outcomes, but not in the setting of MI with acute hyperglycemia. However, the precise role of NHE1 in the pathophysiology of MI with acute hyperglycemia remains to be elucidated, and there are no effective strategies for its prevention or treatment. METHODS AND RESULTS We analyzed 85 post-MI patients, identifying acute hyperglycemia (glucose > 7 mM) in non-diabetic individuals, linked to elevated BNP, CK-MB, and reduced plasma Na+. Using retrospective cohort studies and MI with acute hyperglycemia mouse models, we demonstrated that hyperglycemia exacerbates myocardial injury by reducing extracellular Na+, increasing intracellular Na+, and elevating pH, suggesting NHE1 activation as inferred from the observed intracellular pH (pHi) shift. Cardiomyocyte-specific NHE1 ablation or pharmacological inhibition worsened cardiac dysfunction and fibrosis in MI with acute hyperglycemia, while NHE1 overexpression conferred protection. RNA sequencing and drug screening identified accelerated NHE1 activation via 3% NaCl and lithospermic acid (LA) as a novel strategy to mitigate cardiomyocyte necroptosis, alleviating ischemic injury in MI and ischemia reperfusion models. Hypoxia-hyperglycemia and necroptosis induction models in NHE1-knockout, NHE1-overexpressing, and MLKL-overexpressing cardiomyocytes revealed that NHE1 activation, unlike its protective role in oxygen-glucose deprivation, promotes MLKL degradation via autophagosome-lysosomal pathways, reducing cardiomyocyte death. MLKL knockout and MLKL-NHE1 double knockout mice confirmed that MLKL ablation counteracts NHE1 inhibition's detrimental effects. CONCLUSIONS Activation of myocardial NHE1 promotes MLKL autophagic degradation, mitigating cardiomyocyte necroptosis and acute hyperglycemia-exacerbated MI, highlighting NHE1 as a hyperglycemia-dependent cardioprotective target. Moderate NHE1 activation may represent a novel therapeutic strategy for MI with acute hyperglycemia.
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Affiliation(s)
- Kai Jiang
- Key Laboratory of Cardiology, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Fanghua Su
- Key Laboratory of Cardiology, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
- Institute of Biophysics, Chinese Academy of Science, Beijing, 100101, China
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Ruhua Deng
- Key Laboratory of Cardiology, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Yue Xu
- Key Laboratory of Cardiology, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Anqi Qin
- Key Laboratory of Cardiology, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Xun Yuan
- Key Laboratory of Cardiology, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Dongmei Xing
- The First Affiliated Hospital of Henan University of Chinese Medicine, Henan, 450000, China
| | - Yang Chen
- Key Laboratory of Cardiology, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Dandan Wang
- Key Laboratory of Cardiology, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Lan Shen
- Department of Cardiology, Clinical Research Unit, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, China
| | - John Hwa
- Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT, 06511, USA
| | - Lei Hou
- Cardiology Department, Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine , Shanghai, 201600, China.
| | - Yaozu Xiang
- Key Laboratory of Cardiology, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
- Institute of Biophysics, Chinese Academy of Science, Beijing, 100101, China.
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China.
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2
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Lv Q, Yang Y, Lv Y, Wu Q, Hou X, Li L, Ye X, Yang C, Wang S. Effect of different hypoglycemic drugs and insulin on the risk of new-onset atrial fibrillation in people with diabetes: a network meta-analysis. Eur J Med Res 2024; 29:399. [PMID: 39085898 PMCID: PMC11290211 DOI: 10.1186/s40001-024-01954-w] [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: 04/08/2024] [Accepted: 06/26/2024] [Indexed: 08/02/2024] Open
Abstract
OBJECTIVE Diabetes is considered a significant risk factor for the development of atrial fibrillation/flutter (AF/AFL). However, there is still insufficient evidence to determine the varying effects of different hypoglycemic drugs (HDs) on the incidence of new-onset AF/AFL in diabetic patients. To address this gap, we conducted a network meta-analysis to investigate whether various HDs have different effects on the risk of new-onset AF/AFL compared with insulin. METHOD We conducted a comprehensive search in PubMed, EMBASE, Cochrane Library, and Web of Science to identify all clinical trials investigating the association between various HDs or insulin and incident AF/AFL up until April 1, 2024. Bayesian random-effects model was used for network meta-analysis, and the results were expressed as relative risk (RR) and 95% confidence interval (CI). RESULT After searching 2070 articles, a total of 12 studies (2,349,683 patients) were included in the network meta-analysis. The treatment regimen comprised insulin and 8 HDs hypoglycemic drugs, which are sodium-dependent glucose transporters 2 inhibitor (SGLT2i), glucagon-like peptide 1 receptor agonist (GLP-1RA), dipeptidyl peptidase 4 inhibitors (DPP4i), metformin (Met), sulfonylureas (SU), non-sulfonylureas (nSU), thiazolidinedione (TZD) and α-glycosidase inhibitors (AGI). The use of SGLT2i [RR 0.23, 95%CI (0.11, 0.49)], GLP-1RA [RR 0.28, 95%CI (0.13, 0.57)], and DPP4i [RR 0.34, 95%CI (0.17, 0.67)] demonstrated significant efficacy in reducing the incidence of new-onset AF/AFL when compared to insulin. When HDs were compared in pairs, SGLT2i is more effective than Met [RR 0.35, 95% CI (0.19, 0.62)], SU (RR 0.27, 95% CI (0.14, 0.51)], nSU [RR 0.28, 95% CI (0.08, 0.95)], TZD [RR 0.34, 95% CI (0.17, 0.7)], GLP-1RA is more effective Met [RR 0.42, 95% CI (0.25, 0.71)], SU (RR 0.33, 95% CI (0.18, 0.6)], TZD [RR 0.41, 95% CI (0.21, 0.82)], while Met[RR 1.98, 95% CI (1.23, 3.23)], SU [RR 2.54, 95% CI (1.46, 4.43)], TZD [RR 2.01, 95% CI (1.05, 3.79)] was not as effective as DPP4i. CONCLUSION SGLT-2i, GLP-1RA, and DPP4i showed a superior efficacy in reducing the risk of new-onset AF/AFL compared to insulin therapy.
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Affiliation(s)
- Qianyu Lv
- Guang'anmen Hospital, Chinese Academy of Chinese Medical Sciences, Beijing, 100053, China
| | - Yingtian Yang
- Guang'anmen Hospital, Chinese Academy of Chinese Medical Sciences, Beijing, 100053, China
| | - Yanfei Lv
- Fudan University, Shanghai, 200433, China
| | - Qian Wu
- Guang'anmen Hospital, Chinese Academy of Chinese Medical Sciences, Beijing, 100053, China
| | - Xinzheng Hou
- Guang'anmen Hospital, Chinese Academy of Chinese Medical Sciences, Beijing, 100053, China
| | - Lanlan Li
- Guang'anmen Hospital, Chinese Academy of Chinese Medical Sciences, Beijing, 100053, China
| | - Xuejiao Ye
- Guang'anmen Hospital, Chinese Academy of Chinese Medical Sciences, Beijing, 100053, China
| | - Chenyan Yang
- Guang'anmen Hospital, Chinese Academy of Chinese Medical Sciences, Beijing, 100053, China
| | - Shihan Wang
- Guang'anmen Hospital, Chinese Academy of Chinese Medical Sciences, Beijing, 100053, China.
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Madonna R, Biondi F, Alberti M, Ghelardoni S, Mattii L, D'Alleva A. Cardiovascular outcomes and molecular targets for the cardiac effects of Sodium-Glucose Cotransporter 2 Inhibitors: A systematic review. Biomed Pharmacother 2024; 175:116650. [PMID: 38678962 DOI: 10.1016/j.biopha.2024.116650] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Revised: 04/21/2024] [Accepted: 04/24/2024] [Indexed: 05/01/2024] Open
Abstract
Sodium-glucose cotransporter 2 inhibitors (SGLT2i), a new class of glucose-lowering drugs traditionally used to control blood glucose levels in patients with type 2 diabetes mellitus, have been proven to reduce major adverse cardiovascular events, including cardiovascular death, in patients with heart failure irrespective of ejection fraction and independently of the hypoglycemic effect. Because of their favorable effects on the kidney and cardiovascular outcomes, their use has been expanded in all patients with any combination of diabetes mellitus type 2, chronic kidney disease and heart failure. Although mechanisms explaining the effects of these drugs on the cardiovascular system are not well understood, their effectiveness in all these conditions suggests that they act at the intersection of the metabolic, renal and cardiac axes, thus disrupting maladaptive vicious cycles while contrasting direct organ damage. In this systematic review we provide a state of the art of the randomized controlled trials investigating the effect of SGLT2i on cardiovascular outcomes in patients with chronic kidney disease and/or heart failure irrespective of ejection fraction and diabetes. We also discuss the molecular targets and signaling pathways potentially explaining the cardiac effects of these pharmacological agents, from a clinical and experimental perspective.
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Affiliation(s)
- Rosalinda Madonna
- Department of Pathology, Cardiology Division, University of Pisa, Via Paradisa, Pisa 56124, Italy.
| | - Filippo Biondi
- Department of Pathology, Cardiology Division, University of Pisa, Via Paradisa, Pisa 56124, Italy
| | - Mattia Alberti
- Department of Pathology, Cardiology Division, University of Pisa, Via Paradisa, Pisa 56124, Italy
| | - Sandra Ghelardoni
- Department of Pathology, Laboratory of Biochemistry, University of Pisa, Italy
| | - Letizia Mattii
- Department of Clinical and Experimental Medicine, Histology Division, University of Pisa, Pisa, Italy
| | - Alberto D'Alleva
- Cardiac Intensive Care and Interventional Cardiology Unit, Santo Spirito Hospital, Pescara, Italy
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Chen S, Overberg K, Ghouse Z, Hollmann MW, Weber NC, Coronel R, Zuurbier CJ. Empagliflozin mitigates cardiac hypertrophy through cardiac RSK/NHE-1 inhibition. Biomed Pharmacother 2024; 174:116477. [PMID: 38522235 DOI: 10.1016/j.biopha.2024.116477] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 03/16/2024] [Accepted: 03/19/2024] [Indexed: 03/26/2024] Open
Abstract
BACKGROUND SGLT2i reduce cardiac hypertrophy, but underlying mechanisms remain unknown. Here we explore a role for serine/threonine kinases (STK) and sodium hydrogen exchanger 1(NHE1) activities in SGLT2i effects on cardiac hypertrophy. METHODS Isolated hearts from db/db mice were perfused with 1 µM EMPA, and STK phosphorylation sites were examined using unbiased multiplex analysis to detect the most affected STKs by EMPA. Subsequently, hypertrophy was induced in H9c2 cells with 50 µM phenylephrine (PE), and the role of the most affected STK (p90 ribosomal S6 kinase (RSK)) and NHE1 activity in hypertrophy and the protection by EMPA was evaluated. RESULTS In db/db mice hearts, EMPA most markedly reduced STK phosphorylation sites regulated by RSKL1, a member of the RSK family, and by Aurora A and B kinases. GO and KEGG analysis suggested that EMPA inhibits hypertrophy, cell cycle, cell senescence and FOXO pathways, illustrating inhibition of growth pathways. EMPA prevented PE-induced hypertrophy as evaluated by BNP and cell surface area in H9c2 cells. EMPA blocked PE-induced activation of NHE1. The specific NHE1 inhibitor Cariporide also prevented PE-induced hypertrophy without added effect of EMPA. EMPA blocked PE-induced RSK phosphorylation. The RSK inhibitor BIX02565 also suppressed PE-induced hypertrophy without added effect of EMPA. Cariporide mimicked EMPA's effects on PE-treated RSK phosphorylation. BIX02565 decreased PE-induced NHE1 activity, with no further decrease by EMPA. CONCLUSIONS RSK inhibition by EMPA appears as a novel direct cardiac target of SGLT2i. Direct cardiac effects of EMPA exert their anti-hypertrophic effect through NHE-inhibition and subsequent RSK pathway inhibition.
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Affiliation(s)
- Sha Chen
- Department of Anaesthesiology-L.E.I.C.A., Amsterdam University Medical Centers, Location AMC, Cardiovascular Science, Meibergdreef 9, Amsterdam 1105 AZ, the Netherlands
| | - Kenneth Overberg
- Department of Anaesthesiology-L.E.I.C.A., Amsterdam University Medical Centers, Location AMC, Cardiovascular Science, Meibergdreef 9, Amsterdam 1105 AZ, the Netherlands
| | - Zakiya Ghouse
- Department of Anaesthesiology-L.E.I.C.A., Amsterdam University Medical Centers, Location AMC, Cardiovascular Science, Meibergdreef 9, Amsterdam 1105 AZ, the Netherlands
| | - Markus W Hollmann
- Department of Anaesthesiology-L.E.I.C.A., Amsterdam University Medical Centers, Location AMC, Cardiovascular Science, Meibergdreef 9, Amsterdam 1105 AZ, the Netherlands
| | - Nina C Weber
- Department of Anaesthesiology-L.E.I.C.A., Amsterdam University Medical Centers, Location AMC, Cardiovascular Science, Meibergdreef 9, Amsterdam 1105 AZ, the Netherlands
| | - Ruben Coronel
- Department of Experimental Cardiology, Amsterdam UMC, location AMC, Cardiovascular Science, Meibergdreef 9, Amsterdam 1105 AZ, the Netherlands
| | - Coert J Zuurbier
- Department of Anaesthesiology-L.E.I.C.A., Amsterdam University Medical Centers, Location AMC, Cardiovascular Science, Meibergdreef 9, Amsterdam 1105 AZ, the Netherlands.
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Chen X, Hocher CF, Shen L, Krämer BK, Hocher B. Reno- and cardioprotective molecular mechanisms of SGLT2 inhibitors beyond glycemic control: from bedside to bench. Am J Physiol Cell Physiol 2023; 325:C661-C681. [PMID: 37519230 DOI: 10.1152/ajpcell.00177.2023] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Revised: 07/18/2023] [Accepted: 07/19/2023] [Indexed: 08/01/2023]
Abstract
Large placebo-controlled clinical trials have shown that sodium-glucose cotransporter-2 inhibitors (SGLT2i) delay the deterioration of renal function and reduce cardiovascular events in a glucose-independent manner, thereby ultimately reducing mortality in patients with chronic kidney disease (CKD) and/or heart failure. These existing clinical data stimulated preclinical studies aiming to understand the observed clinical effects. In animal models, it was shown that the beneficial effect of SGLT2i on the tubuloglomerular feedback (TGF) improves glomerular pressure and reduces tubular workload by improving renal hemodynamics, which appears to be dependent on salt intake. High salt intake might blunt the SGLT2i effects on the TGF. Beyond the salt-dependent effects of SGLT2i on renal hemodynamics, SGLT2i inhibited several key aspects of macrophage-mediated renal inflammation and fibrosis, including inhibiting the differentiation of monocytes to macrophages, promoting the polarization of macrophages from a proinflammatory M1 phenotype to an anti-inflammatory M2 phenotype, and suppressing the activation of inflammasomes and major proinflammatory factors. As macrophages are also important cells mediating atherosclerosis and myocardial remodeling after injury, the inhibitory effects of SGLT2i on macrophage differentiation and inflammatory responses may also play a role in stabilizing atherosclerotic plaques and ameliorating myocardial inflammation and fibrosis. Recent studies suggest that SGLT2i may also act directly on the Na+/H+ exchanger and Late-INa in cardiomyocytes thus reducing Na+ and Ca2+ overload-mediated myocardial damage. In addition, the renal-cardioprotective mechanisms of SGLT2i include systemic effects on the sympathetic nervous system, blood volume, salt excretion, and energy metabolism.
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Affiliation(s)
- Xin Chen
- Department of Nephrology, Charité-Universitätsmedizin Berlin, Berlin, Germany
- Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology/Pneumology), University Medical Centre Mannheim, University of Heidelberg, Heidelberg, Germany
| | - Carl-Friedrich Hocher
- Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology/Pneumology), University Medical Centre Mannheim, University of Heidelberg, Heidelberg, Germany
- Klinik für Innere Medizin, Bundeswehrkrankenhaus Berlin, Berlin, Germany
| | - Linghong Shen
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bernhard K Krämer
- Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology/Pneumology), University Medical Centre Mannheim, University of Heidelberg, Heidelberg, Germany
| | - Berthold Hocher
- Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology/Pneumology), University Medical Centre Mannheim, University of Heidelberg, Heidelberg, Germany
- Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China
- Institute of Reproductive and Stem Cell Engineering, NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, School of Basic Medical Science, Central South University, Changsha, China
- IMD Institut für Medizinische Diagnostik Berlin-Potsdam GbR, Berlin, Germany
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Polyunsaturated ω3 fatty acids prevent the cardiac hypertrophy in hypertensive rats. Biochim Biophys Acta Gen Subj 2023; 1867:130278. [PMID: 36410610 DOI: 10.1016/j.bbagen.2022.130278] [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: 07/08/2022] [Revised: 10/10/2022] [Accepted: 11/08/2022] [Indexed: 11/22/2022]
Abstract
It has been demonstrated that supplementation with the two main omega 3 polyunsaturated fatty acids (ω3 FAs), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA), leads to modifications in the cardiac physiology. ω3 FAs can affect the membrane's lipid composition, as well as proteins' location and/or function. The Na+/H+ exchanger (NHE1) is an integral membrane protein involved in the maintenance of intracellular pH and its hyperactivity has been associated with the development of various cardiovascular diseases such as cardiac hypertrophy. Our aim was to determine the effect of ω3 FAs on systolic blood pressure (SBP), lipid profiles, NHE1 activity, and cardiac function in spontaneously hypertensive rats (SHR) using Wistar rats (W) as normotensive control. After weaning, the rats received orally ω3 FAs (200 mg/kg body mass/day/ 4 months). We measured SBP, lipid profiles, and different echocardiography parameters, which were used to calculate cardiac hypertrophy index, systolic function, and ventricular geometry. The rats were sacrificed, and ventricular cardiomyocytes were obtained to measure NHE1 activity. While the treatment with ω3 FAs did not affect the SBP, lipid analysis of plasma revealed a significant decrease in omega-6/omega-3 ratio, correlated with a significant reduction in left ventricular mass index in SHR. The NHE1 activity was significantly higher in SHR compared with W. While in W the NHE1 activity was similar in both groups, a significant decrease in NHE1 activity was detected in SHRs supplemented with ω3 FAs, reaching values comparable with W. Altogether, these findings revealed that diet supplementation with ω3 FAs since early age prevents the development of cardiac hypertrophy in SHR, perhaps by decreasing NHE1 activity, without altering hemodynamic overload.
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Di Mattia RA, Diaz-Zegarra LA, Blanco PG, Valverde CA, Gonano LA, Jaquenod De Giusti C, Portiansky EL, Vila-Petroff MG, Aiello EA, Orlowski A. The specific inhibition of the cardiac electrogenic sodium/bicarbonate cotransporter leads to cardiac hypertrophy. Life Sci 2022; 312:121219. [PMID: 36435222 DOI: 10.1016/j.lfs.2022.121219] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Revised: 11/10/2022] [Accepted: 11/20/2022] [Indexed: 11/24/2022]
Abstract
Two alkalinizing mechanisms coexist in cardiac myocytes to maintain intracellular pH: sodium/bicarbonate cotransporter (electroneutral isoform NBCn1 and electrogenic isoform NBCe1) and sodium/proton exchanger (NHE1). Dysfunction of these transporters has previously been reported to be responsible for the development of cardiovascular diseases. The aim of this study was to evaluate the contribution of the downregulation of the NBCe1 to the development of cardiac hypertrophy. To specifically reduce NBCe1 expression, we cloned shRNA into a cardiotropic adeno-associated vector (AAV9-shNBCe1). After 28 days of being injected with AAV9-shNBCe1, the expression and the activity of NBCe1 in the rat heart were reduced. Strikingly, downregulation of NBCe1 causes significant hypertrophic heart growth, lengthening of the action potential in isolated myocytes, an increase in the duration of the QT interval and an increase in the frequency of Ca2+ waves without any significant changes in Ca2+ transients. An increased compensatory expression of NBCn1 and NHE1 was also observed. We conclude that reduction of NBCe1 is sufficient to induce cardiac hypertrophy and modify the electrical features of the rat heart.
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Affiliation(s)
- R A Di Mattia
- Centro de Investigaciones Cardiovasculares "Dr. Horacio Cingolani", Facultad de Ciencias Médicas, Universidad Nacional de La Plata, CONICET, La Plata, Argentina
| | - L A Diaz-Zegarra
- Centro de Investigaciones Cardiovasculares "Dr. Horacio Cingolani", Facultad de Ciencias Médicas, Universidad Nacional de La Plata, CONICET, La Plata, Argentina
| | - P G Blanco
- Centro de Fisiología Reproductiva & Métodos Complementarios de Diagnóstico (CEFIRE & MECODIAG), Facultad de Ciencias Veterinarias, Universidad Nacional de La Plata, CONICET, La Plata, Argentina
| | - C A Valverde
- Centro de Investigaciones Cardiovasculares "Dr. Horacio Cingolani", Facultad de Ciencias Médicas, Universidad Nacional de La Plata, CONICET, La Plata, Argentina
| | - L A Gonano
- Centro de Investigaciones Cardiovasculares "Dr. Horacio Cingolani", Facultad de Ciencias Médicas, Universidad Nacional de La Plata, CONICET, La Plata, Argentina
| | - C Jaquenod De Giusti
- Centro de Investigaciones Cardiovasculares "Dr. Horacio Cingolani", Facultad de Ciencias Médicas, Universidad Nacional de La Plata, CONICET, La Plata, Argentina
| | - E L Portiansky
- Laboratorio de Análisis de Imágenes, Facultad de Ciencias Veterinarias, Universidad Nacional de La Plata, CONICET, La Plata, Argentina
| | - M G Vila-Petroff
- Centro de Investigaciones Cardiovasculares "Dr. Horacio Cingolani", Facultad de Ciencias Médicas, Universidad Nacional de La Plata, CONICET, La Plata, Argentina
| | - E A Aiello
- Centro de Investigaciones Cardiovasculares "Dr. Horacio Cingolani", Facultad de Ciencias Médicas, Universidad Nacional de La Plata, CONICET, La Plata, Argentina.
| | - A Orlowski
- Centro de Investigaciones Cardiovasculares "Dr. Horacio Cingolani", Facultad de Ciencias Médicas, Universidad Nacional de La Plata, CONICET, La Plata, Argentina.
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Ma J, Gao X, Li Y, DeCoursey TE, Shull GE, Wang HS. The HVCN1 voltage-gated proton channel contributes to pH regulation in canine ventricular myocytes. J Physiol 2022; 600:2089-2103. [PMID: 35244217 PMCID: PMC9058222 DOI: 10.1113/jp282126] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 02/24/2022] [Indexed: 11/09/2022] Open
Abstract
KEY POINTS Intracellular pH (pHi ) regulation is crucial for cardiac function, as acidification depresses contractility and causes arrhythmias. H+ ions are generated in cardiomyocytes from metabolic processes and particularly from CO2 hydration, which has been shown to facilitate CO2 -venting from mitochondria. Currently, the NHE1 Na+ /H+ exchanger is viewed as the dominant H+ -extrusion mechanism in cardiac muscle. We show that the HVCN1 voltage-gated proton channel is present and functional in canine ventricular myocytes, and that HVCN1 and NHE1 both contribute to pHi regulation. HVCN1 provides an energetically-efficient mechanism of H+ -extrusion that would not cause Na+ -loading, which can cause pathology, and that could contribute to transport-mediated CO2 disposal. These results provide a major advance in our understanding of pHi regulation in cardiac muscle. ABSTRACT Regulation of intracellular pH (pHi ) in cardiomyocytes is crucial for cardiac function; however, currently known mechanisms for direct or indirect extrusion of acid from cardiomyocytes seem insufficient for energetically-efficient extrusion of the massive H+ loads generated under in vivo conditions. In cardiomyocytes, voltage-sensitive H+ channel activity mediated by the HVCN1 proton channel would be a highly efficient means of disposing of H+ , while avoiding Na+ -loading, as occurs during direct acid extrusion via Na+ /H+ exchange or indirect acid extrusion via Na+ -HCO3 - cotransport. PCR and immunoblotting demonstrated expression of HVCN1 mRNA and protein in canine heart. Patch clamp analysis of canine ventricular myocytes revealed a voltage-gated H+ current that was highly H+ -selective. The current was blocked by external Zn2+ and the HVCN1 blocker 5-chloro-2-guanidinobenzimidazole (ClGBI). Both the gating and Zn2+ blockade of the current were strongly influenced by the pH gradient across the membrane. All characteristics of the observed current were consistent with the known hallmarks of HVCN1-mediated H+ current. Inhibition of HVCN1 and the NHE1 Na+ /H+ exchanger, singly and in combination, showed that either mechanism is largely sufficient to maintain pHi in beating cardiomyocytes, but that inhibition of both activities causes rapid acidification. These results show that HVCN1 is expressed in canine ventricular myocytes and provides a major H+ -extrusion activity, with a capacity similar to that of NHE1. In the beating heart in vivo, this activity would allow Na+ -independent extrusion of H+ during each action potential and, when functionally coupled with anion transport mechanisms, could facilitate transport-mediated CO2 disposal. Abstract figure legend The HVCN1 proton channel is expressed in canine ventricular myocytes and contributes to H+ extrusion. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Jianyong Ma
- Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio, 45267, USA
| | - Xiaoqian Gao
- Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio, 45267, USA
| | - Yutian Li
- Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio, 45267, USA
| | - Thomas E DeCoursey
- Department of Physiology & Biophysics, Rush University, Chicago, Illinois, 60612, USA
| | - Gary E Shull
- Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, Ohio, 45267, USA
| | - Hong-Sheng Wang
- Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio, 45267, USA
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Wichaiyo S, Saengklub N. Alterations of sodium-hydrogen exchanger 1 function in response to SGLT2 inhibitors: what is the evidence? Heart Fail Rev 2022; 27:1973-1990. [PMID: 35179683 DOI: 10.1007/s10741-022-10220-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/02/2022] [Indexed: 02/07/2023]
Abstract
This review summarizes and describes the current evidence addressing how sodium-glucose cotransporter 2 (SGLT2) inhibitors alter the function of sodium-hydrogen exchanger 1 (NHE-1), in association with their protective effects against adverse cardiovascular events. In the heart, SGLT2 inhibitors modulate the function of NHE-1 (either by direct inhibition or indirect attenuation of protein expression), which promotes cardiac contraction and an enhanced energy supply, in association with improved mitochondrial function, reduced inflammation/oxidative/endoplasmic reticulum stress, and attenuated fibrosis and apoptotic/autophagic cell death. The vasodilating effect of SGLT2 inhibitors has also been proposed due to NHE-1 inhibition. Moreover, platelet-expressed NHE-1 might serve as a target for SGLT2 inhibitors, since these drugs and selective NHE-1 inhibitors produce comparable activity against adenosine diphosphate-stimulated platelet activation. Overall, it is promising that the modulation of the functions of NHE-1 on the heart, blood vessels, and platelets may act as a contributing pathway for the cardiovascular benefits of SGLT2 inhibitors in diabetes and heart failure.
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Affiliation(s)
- Surasak Wichaiyo
- Department of Pharmacology, Faculty of Pharmacy, Mahidol University, 447 Sri-Ayuthaya Road, Rajathevi, Bangkok, 10400, Thailand. .,Centre of Biopharmaceutical Science for Healthy Ageing, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand.
| | - Nakkawee Saengklub
- Centre of Biopharmaceutical Science for Healthy Ageing, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand.,Department of Physiology, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand
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10
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Al-Shamasi AA, Elkaffash R, Mohamed M, Rayan M, Al-Khater D, Gadeau AP, Ahmed R, Hasan A, Eldassouki H, Yalcin HC, Abdul-Ghani M, Mraiche F. Crosstalk between Sodium-Glucose Cotransporter Inhibitors and Sodium-Hydrogen Exchanger 1 and 3 in Cardiometabolic Diseases. Int J Mol Sci 2021; 22:12677. [PMID: 34884494 PMCID: PMC8657861 DOI: 10.3390/ijms222312677] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 11/08/2021] [Accepted: 11/12/2021] [Indexed: 12/14/2022] Open
Abstract
Abnormality in glucose homeostasis due to hyperglycemia or insulin resistance is the hallmark of type 2 diabetes mellitus (T2DM). These metabolic abnormalities in T2DM lead to cellular dysfunction and the development of diabetic cardiomyopathy leading to heart failure. New antihyperglycemic agents including glucagon-like peptide-1 receptor agonists and the sodium-glucose cotransporter-2 inhibitors (SGLT2i) have been shown to attenuate endothelial dysfunction at the cellular level. In addition, they improved cardiovascular safety by exhibiting cardioprotective effects. The mechanism by which these drugs exert their cardioprotective effects is unknown, although recent studies have shown that cardiovascular homeostasis occurs through the interplay of the sodium-hydrogen exchangers (NHE), specifically NHE1 and NHE3, with SGLT2i. Another theoretical explanation for the cardioprotective effects of SGLT2i is through natriuresis by the kidney. This theory highlights the possible involvement of renal NHE transporters in the management of heart failure. This review outlines the possible mechanisms responsible for causing diabetic cardiomyopathy and discusses the interaction between NHE and SGLT2i in cardiovascular diseases.
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Affiliation(s)
- Al-Anood Al-Shamasi
- Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, Doha P.O. Box 2713, Qatar; (A.-A.A.-S.); (R.E.); (M.M.); (M.R.); (D.A.-K.)
- Biomedical and Pharmaceutical Research Unit, QU Health, Qatar University, Doha P.O. Box 2713, Qatar
| | - Rozina Elkaffash
- Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, Doha P.O. Box 2713, Qatar; (A.-A.A.-S.); (R.E.); (M.M.); (M.R.); (D.A.-K.)
- Biomedical and Pharmaceutical Research Unit, QU Health, Qatar University, Doha P.O. Box 2713, Qatar
| | - Meram Mohamed
- Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, Doha P.O. Box 2713, Qatar; (A.-A.A.-S.); (R.E.); (M.M.); (M.R.); (D.A.-K.)
- Biomedical and Pharmaceutical Research Unit, QU Health, Qatar University, Doha P.O. Box 2713, Qatar
| | - Menatallah Rayan
- Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, Doha P.O. Box 2713, Qatar; (A.-A.A.-S.); (R.E.); (M.M.); (M.R.); (D.A.-K.)
- Biomedical and Pharmaceutical Research Unit, QU Health, Qatar University, Doha P.O. Box 2713, Qatar
| | - Dhabya Al-Khater
- Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, Doha P.O. Box 2713, Qatar; (A.-A.A.-S.); (R.E.); (M.M.); (M.R.); (D.A.-K.)
- Biomedical and Pharmaceutical Research Unit, QU Health, Qatar University, Doha P.O. Box 2713, Qatar
| | - Alain-Pierre Gadeau
- INSERM, Biology of Cardiovascular Disease, University of Bordeaux, U1034 Pessac, France;
| | - Rashid Ahmed
- Department of Mechanical and Chemical Engineering, College of Engineering, Qatar University, Doha P.O. Box 2713, Qatar; (R.A.); (A.H.)
- Biomedical Research Centre (BRC), Qatar University, Doha P.O. Box 2713, Qatar;
| | - Anwarul Hasan
- Department of Mechanical and Chemical Engineering, College of Engineering, Qatar University, Doha P.O. Box 2713, Qatar; (R.A.); (A.H.)
- Biomedical Research Centre (BRC), Qatar University, Doha P.O. Box 2713, Qatar;
| | - Hussein Eldassouki
- College of Kinesiology, University of Saskatchewan, Saskatoon, SK S7N 5B5, Canada;
| | | | - Muhammad Abdul-Ghani
- Division of Diabetes, University of Texas Health Science Center at San Antonio, Floyd Curl Drive, San Antonio, TX 7703, USA;
| | - Fatima Mraiche
- Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, Doha P.O. Box 2713, Qatar; (A.-A.A.-S.); (R.E.); (M.M.); (M.R.); (D.A.-K.)
- Biomedical and Pharmaceutical Research Unit, QU Health, Qatar University, Doha P.O. Box 2713, Qatar
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11
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Insulin-Induced Cardiomyocytes Hypertrophy That Is Prevented by Taurine via β-alanine-Sensitive Na +-Taurine Symporter. Nutrients 2021; 13:nu13113686. [PMID: 34835942 PMCID: PMC8623107 DOI: 10.3390/nu13113686] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 09/30/2021] [Accepted: 10/15/2021] [Indexed: 01/12/2023] Open
Abstract
Although insulin-induced cardiac hypertrophy is reported, very little information is available on the hypertrophic effect of insulin on ventricular cardiomyocytes and the regulation of sodium and calcium homeostasis. Taurine is a non-essential amino acid synthesized by cardiomyocytes and the brain and is present in low quantities in many foods, particularly seafood. The purpose of this study was to investigate whether chronic exposure to insulin induces hypertrophy of ventricular cardiomyocytes that are associated with changes in Na+ and Ca2+ homeostasis and whether taurine pre-treatment prevents these effects. Our results showed that chronic treatment with insulin leads to cardiomyocyte hypertrophy that is associated with an increase in basal intracellular Na+ and Ca2+ levels. Furthermore, long-term taurine treatment prevents morphological and ionic remodeling induced by insulin. In addition, blocking the Na+-taurine co-transporter prevented the taurine antihypertrophic effect. Finally, the insulin-induced remodeling of cardiomyocytes was associated with a decrease in the ratio of phospho-CREB (pCREB) to total cAMP response element binding protein (CREB); taurine prevented this effect. In conclusion, our results show that insulin induces ventricular cardiomyocyte hypertrophy via downregulation of the pCREB/tCREB level and that chronic taurine treatment prevents this effect.
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12
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High Na + Salt Diet and Remodeling of Vascular Smooth Muscle and Endothelial Cells. Biomedicines 2021; 9:biomedicines9080883. [PMID: 34440087 PMCID: PMC8389691 DOI: 10.3390/biomedicines9080883] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 07/19/2021] [Accepted: 07/21/2021] [Indexed: 12/12/2022] Open
Abstract
Our knowledge on essential hypertension is vast, and its treatment is well known. Not all hypertensives are salt-sensitive. The available evidence suggests that even normotensive individuals are at high cardiovascular risk and lower survival rate, as blood pressure eventually rises later in life with a high salt diet. In addition, little is known about high sodium (Na+) salt diet-sensitive hypertension. There is no doubt that direct and indirect Na+ transporters, such as the Na/Ca exchanger and the Na/H exchanger, and the Na/K pump could be implicated in the development of high salt-induced hypertension in humans. These mechanisms could be involved following the destruction of the cell membrane glycocalyx and changes in vascular endothelial and smooth muscle cells membranes’ permeability and osmolarity. Thus, it is vital to determine the membrane and intracellular mechanisms implicated in this type of hypertension and its treatment.
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13
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Zeng Q, Zhou Q, Liu W, Wang Y, Xu X, Xu D. Mechanisms and Perspectives of Sodium-Glucose Co-transporter 2 Inhibitors in Heart Failure. Front Cardiovasc Med 2021; 8:636152. [PMID: 33644138 PMCID: PMC7902509 DOI: 10.3389/fcvm.2021.636152] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Accepted: 01/18/2021] [Indexed: 12/12/2022] Open
Abstract
Heart failure (HF) is a common complication or late-stage manifestation of various heart diseases. Numerous risk factors and underlying causes may contribute to the occurrence and progression of HF. The pathophysiological mechanisms of HF are very complicated. Despite accumulating advances in treatment for HF during recent decades, it remains an intractable clinical syndrome with poor outcomes, significantly reducing the quality of life and expectancy of patients, and imposing a heavy economic burden on society and families. Although initially classified as antidiabetic agents, sodium-glucose co-transporter 2 (SGLT2) inhibitors have demonstrated reduced the prevalence of hospitalization for HF, cardiovascular death, and all-cause death in several large-scale randomized controlled clinical trials. These beneficial effects of SGLT-2 inhibitors can be attributed to multiple hemodynamic, inflammatory and metabolic mechanisms, not only reducing the serum glucose level. SGLT2 inhibitors have been used increasingly in treatment for patients with HF with reduced ejection fraction due to their surprising performance in improving the prognosis. In addition, their roles and mechanisms in patients with HF with preserved ejection fraction or acute HF have also attracted attention. In this review article, we discuss the possible mechanisms and applications of SGLT2 inhibitors in HF.
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Affiliation(s)
- Qingchun Zeng
- State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Shock and Microcirculation, Southern Medical University, Guangzhou, China.,Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, China
| | - Qing Zhou
- State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Department of Cardiology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, China
| | - Weitao Liu
- State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yutong Wang
- State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xingbo Xu
- Department of Cardiology and Pneumology, University Medical Center of Göttingen, Georg-August-University, Göttingen, Germany
| | - Dingli Xu
- State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Shock and Microcirculation, Southern Medical University, Guangzhou, China.,Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, China
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14
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Wang J, Wang W, Wang H, Tuo B. Physiological and Pathological Functions of SLC26A6. Front Med (Lausanne) 2021; 7:618256. [PMID: 33553213 PMCID: PMC7859274 DOI: 10.3389/fmed.2020.618256] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Accepted: 12/30/2020] [Indexed: 12/26/2022] Open
Abstract
Solute Carrier Family 26 (SLC26) is a conserved anion transporter family with 10 members in human (SLC26A1-A11, A10 being a pseudogene). All SLC26 genes except for SLC26A5 (prestin) are versatile anion exchangers with notable ability to transport a variety of anions. SLC26A6 has the most extensive exchange functions in the SLC26 family and is widely expressed in various organs and tissues of mammals. SLC26A6 has some special properties that make it play a particularly important role in ion homeostasis and acid-base balance. In the past few years, the function of SLC26A6 in the diseases has received increasing attention. SLC26A6 not only participates in the development of intestinal and pancreatic diseases but also serves a significant role in mediating nephrolithiasis, fetal skeletal dysplasia and arrhythmia. This review aims to explore the role of SLC26A6 in physiology and pathophysiology of relative mammalian organs to guide in-depth studies about related diseases of human.
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Affiliation(s)
- Juan Wang
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Wenkang Wang
- Department of Critical Care Medicine of the Third Affiliated Hospital (The First People's Hospital of Zunyi City), Zunyi Medical University, Zunyi, China
| | - Hui Wang
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Biguang Tuo
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
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15
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Medina AJ, Ibáñez AM, Diaz-Zegarra LA, Portiansky EL, Blanco PG, Pereyra EV, de Giusti VC, Aiello EA, Yeves AM, Ennis IL. Cardiac up-regulation of NBCe1 emerges as a beneficial consequence of voluntary wheel running in mice. Arch Biochem Biophys 2020; 694:108600. [PMID: 33007282 DOI: 10.1016/j.abb.2020.108600] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 09/17/2020] [Accepted: 09/23/2020] [Indexed: 11/30/2022]
Abstract
Physical training stimulates the development of physiologic cardiac hypertrophy (CH), being a key event in this process the inhibition of the Na+/H+ exchanger. However, the role of the sodium bicarbonate cotransporter (NBC) has not been explored yet under this circumstance. C57/Bl6 mice were allowed to voluntary exercise (wheel running) for five weeks. Cardiac mass was evaluated by echocardiography and histomorphometry detecting that training promoted the development of physiological CH (heart weight/tibia length ratio, mg/mm: 6.54 ± 0.20 vs 8.81 ± 0.24; interstitial collagen content, %: 3.14 ± 0.63 vs. 1.57 ± 0.27; and cross-sectional area of cardiomyocytes, μm2: 200.6 ± 8.92 vs. 281.9 ± 24.05; sedentary (Sed) and exercised (Ex) mice, respectively). The activity of the electrogenic isoform of the cardiac NBC (NBCe1) was estimated by recording intracellular pH under high potassium concentration and by measuring action potential duration (APD). NBCe1 activity was significantly increased in isolated cardiomyocytes of trained mice. Additionally, the APD was shorter and the alkalization due to high extracellular potassium-induced depolarization was greater in this group, indicating that the NBCe1 was hyperactive. These results are online with the observed myocardial up-regulation of the NBCe1 (Western Blot, %: 100 ± 13.86 vs. 202 ± 29.98; Sed vs. Ex, n = 6 each group). In addition, we detected a reduction in H2O2 production in the myocardium of trained mice. These results support that voluntary training induces the development of physiologic CH with up-regulation of the cardiac NBCe1 in mice. Furthermore, the improvement in the antioxidant capacity contributes to the beneficial cardiovascular consequences of physical training.
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Affiliation(s)
- Andrés J Medina
- Centro de Investigaciones Cardiovasculares "Dr. Horacio E, Cingolani" Facultad de Ciencias Médicas UNLP-CONICET, Argentina
| | - Alejandro M Ibáñez
- Centro de Investigaciones Cardiovasculares "Dr. Horacio E, Cingolani" Facultad de Ciencias Médicas UNLP-CONICET, Argentina
| | - Leandro A Diaz-Zegarra
- Centro de Investigaciones Cardiovasculares "Dr. Horacio E, Cingolani" Facultad de Ciencias Médicas UNLP-CONICET, Argentina
| | - Enrique L Portiansky
- Laboratorio de Análisis de Imágenes, Facultad de Ciencias Veterinarias UNLP-CONICET, Argentina
| | - Paula G Blanco
- Servicio de Cardiología, Facultad de Ciencias Veterinarias, UNLP-CONICET, Argentina
| | - Erica V Pereyra
- Centro de Investigaciones Cardiovasculares "Dr. Horacio E, Cingolani" Facultad de Ciencias Médicas UNLP-CONICET, Argentina
| | - Verónica C de Giusti
- Centro de Investigaciones Cardiovasculares "Dr. Horacio E, Cingolani" Facultad de Ciencias Médicas UNLP-CONICET, Argentina
| | - Ernesto A Aiello
- Centro de Investigaciones Cardiovasculares "Dr. Horacio E, Cingolani" Facultad de Ciencias Médicas UNLP-CONICET, Argentina
| | - Alejandra M Yeves
- Centro de Investigaciones Cardiovasculares "Dr. Horacio E, Cingolani" Facultad de Ciencias Médicas UNLP-CONICET, Argentina
| | - Irene L Ennis
- Centro de Investigaciones Cardiovasculares "Dr. Horacio E, Cingolani" Facultad de Ciencias Médicas UNLP-CONICET, Argentina.
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16
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Peng X, Li L, Zhang M, Zhao Q, Wu K, Bai R, Ruan Y, Liu N. Sodium-Glucose Cotransporter 2 Inhibitors Potentially Prevent Atrial Fibrillation by Ameliorating Ion Handling and Mitochondrial Dysfunction. Front Physiol 2020; 11:912. [PMID: 32848857 PMCID: PMC7417344 DOI: 10.3389/fphys.2020.00912] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Accepted: 07/08/2020] [Indexed: 12/14/2022] Open
Abstract
Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a novel class of glucose-lowering agents that significantly improve the prognosis of patients with type 2 diabetes (T2D) and heart failure. SGLT2i has recently been implicated in the treatment of atrial fibrillation (AF) with clinical data demonstrating that these agents decrease the incidence of AF events in patients with T2D. Fundamental findings have suggested that SGLT2i may alleviate atrial electrical and structural remodeling. The underlying mechanisms of SGLT2i are likely associated with balancing the sodium and calcium handling disorders and mitigating the mitochondrial dysfunction in atrial myocytes. This review illustrates the advances in understanding the underlying mechanisms of SGLT2i as an evolving treatment modality for AF.
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Affiliation(s)
| | | | | | | | | | | | | | - Nian Liu
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
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17
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Long-term administration of recombinant canstatin prevents adverse cardiac remodeling after myocardial infarction. Sci Rep 2020; 10:12881. [PMID: 32732948 PMCID: PMC7393096 DOI: 10.1038/s41598-020-69736-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Accepted: 07/15/2020] [Indexed: 11/08/2022] Open
Abstract
Myocardial infarction (MI) still remains a leading cause of mortality throughout the world. An adverse cardiac remodeling, such as hypertrophy and fibrosis, in non-infarcted area leads to uncompensated heart failure with cardiac dysfunction. We previously demonstrated that canstatin, a C-terminus fragment of type IV collagen α2 chain, exerted anti-remodeling effect against isoproterenol-induced cardiac hypertrophy model rats. In the present study, we examined whether a long-term administration of recombinant canstatin exhibits a cardioprotective effect against the adverse cardiac remodeling in MI model rats. Left anterior descending artery of male Wistar rats was ligated and recombinant mouse canstatin (20 μg/kg/day) was intraperitoneally injected for 28 days. Long-term administration of canstatin improved survival rate and significantly inhibited left ventricular dilatation and dysfunction after MI. Canstatin significantly inhibited scar thinning in the infarcted area and significantly suppressed cardiac hypertrophy, nuclear translocation of nuclear factor of activated T-cells, interstitial fibrosis and increase of myofibroblasts in the non-infarcted area. Canstatin significantly inhibited transforming growth factor-β1-induced differentiation of rat cardiac fibroblasts into myofibroblasts. The present study for the first time demonstrated that long-term administration of recombinant canstatin exerts cardioprotective effects against adverse cardiac remodeling in MI model rats.
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18
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Brea MS, Díaz RG, Escudero DS, Zavala MR, Portiansky EL, Villa-Abrille MC, Caldiz CI, Pérez NG, Morgan PE. Silencing of epidermal growth factor receptor reduces Na+/H+ exchanger 1 activity and hypertensive cardiac hypertrophy. Biochem Pharmacol 2019; 170:113667. [DOI: 10.1016/j.bcp.2019.113667] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Accepted: 10/11/2019] [Indexed: 02/06/2023]
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19
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Richards MA, Simon JN, Ma R, Loonat AA, Crabtree MJ, Paterson DJ, Fahlman RP, Casadei B, Fliegel L, Swietach P. Nitric oxide modulates cardiomyocyte pH control through a biphasic effect on sodium/hydrogen exchanger-1. Cardiovasc Res 2019; 116:1958-1971. [PMID: 31742355 PMCID: PMC7567331 DOI: 10.1093/cvr/cvz311] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Revised: 10/31/2019] [Accepted: 11/16/2019] [Indexed: 11/14/2022] Open
Abstract
AIMS When activated, Na+/H+ exchanger-1 (NHE1) produces some of the largest ionic fluxes in the heart. NHE1-dependent H+ extrusion and Na+ entry strongly modulate cardiac physiology through the direct effects of pH on proteins and by influencing intracellular Ca2+ handling. To attain an appropriate level of activation, cardiac NHE1 must respond to myocyte-derived cues. Among physiologically important cues is nitric oxide (NO), which regulates a myriad of cardiac functions, but its actions on NHE1 are unclear. METHODS AND RESULTS NHE1 activity was measured using pH-sensitive cSNARF1 fluorescence after acid-loading adult ventricular myocytes by an ammonium prepulse solution manoeuvre. NO signalling was manipulated by knockout of its major constitutive synthase nNOS, adenoviral nNOS gene delivery, nNOS inhibition, and application of NO-donors. NHE1 flux was found to be activated by low [NO], but inhibited at high [NO]. These responses involved cGMP-dependent signalling, rather than S-nitros(yl)ation. Stronger cGMP signals, that can inhibit phosphodiesterase enzymes, allowed [cAMP] to rise, as demonstrated by a FRET-based sensor. Inferring from the actions of membrane-permeant analogues, cGMP was determined to activate NHE1, whereas cAMP was inhibitory, which explains the biphasic regulation by NO. Activation of NHE1-dependent Na+ influx by low [NO] also increased the frequency of spontaneous Ca2+ waves, whereas high [NO] suppressed these aberrant forms of Ca2+ signalling. CONCLUSIONS Physiological levels of NO stimulation increase NHE1 activity, which boosts pH control during acid-disturbances and results in Na+-driven cellular Ca2+ loading. These responses are positively inotropic but also increase the likelihood of aberrant Ca2+ signals, and hence arrhythmia. Stronger NO signals inhibit NHE1, leading to a reversal of the aforementioned effects, ostensibly as a potential cardioprotective intervention to curtail NHE1 overdrive.
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Affiliation(s)
- Mark A Richards
- Department of Physiology, Anatomy and Genetics, Parks Road, Oxford OX1 3PT, UK
| | - Jillian N Simon
- Division of Cardiovascular Medicine, Radcliffe Department of Medicine, British Heart Foundation Centre for Research Excellence, John Radcliffe Hospital, Oxford OX3 9DU, UK
| | - Ruichong Ma
- Department of Physiology, Anatomy and Genetics, Parks Road, Oxford OX1 3PT, UK
| | - Aminah A Loonat
- Department of Physiology, Anatomy and Genetics, Parks Road, Oxford OX1 3PT, UK
| | - Mark J Crabtree
- Division of Cardiovascular Medicine, Radcliffe Department of Medicine, British Heart Foundation Centre for Research Excellence, John Radcliffe Hospital, Oxford OX3 9DU, UK
| | - David J Paterson
- Department of Physiology, Anatomy and Genetics, Parks Road, Oxford OX1 3PT, UK
| | - Richard P Fahlman
- Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2H7, Canada
| | - Barbara Casadei
- Division of Cardiovascular Medicine, Radcliffe Department of Medicine, British Heart Foundation Centre for Research Excellence, John Radcliffe Hospital, Oxford OX3 9DU, UK
| | - Larry Fliegel
- Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2H7, Canada
| | - Pawel Swietach
- Department of Physiology, Anatomy and Genetics, Parks Road, Oxford OX1 3PT, UK
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20
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Cardioprotection Conferred by Sitagliptin Is Associated with Reduced Cardiac Angiotensin II/Angiotensin-(1-7) Balance in Experimental Chronic Kidney Disease. Int J Mol Sci 2019; 20:ijms20081940. [PMID: 31010001 PMCID: PMC6515057 DOI: 10.3390/ijms20081940] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Revised: 04/15/2019] [Accepted: 04/18/2019] [Indexed: 12/17/2022] Open
Abstract
Dipeptidyl peptidase IV (DPPIV) inhibitors are antidiabetic agents that exert renoprotective actions independently of glucose lowering. Cardiac dysfunction is one of the main outcomes of chronic kidney disease (CKD); however, the effects of DPPIV inhibition on cardiac impairment during CKD progression remain elusive. This study investigated whether DPPIV inhibition mitigates cardiac dysfunction and remodeling in rats with a 5/6 renal ablation and evaluated if these effects are associated with changes in the cardiac renin-angiotensin system (RAS). To this end, male Wistar rats underwent a 5/6 nephrectomy (Nx) or sham operation, followed by an 8-week treatment period with the DPPIV inhibitor sitagliptin (IDPPIV) or vehicle. Nx rats had lower glomerular filtration rate, overt albuminuria and higher blood pressure compared to sham rats, whereas CKD progression was attenuated in Nx + IDPPIV rats. Additionally, Nx rats exhibited cardiac hypertrophy and fibrosis, which were associated with higher cardiac DPPIV activity and expression. The sitagliptin treatment prevented cardiac fibrosis and mitigated cardiac hypertrophy. The isovolumic relaxation time (IRVT) was higher in Nx than in sham rats, which was suggestive of CKD-associated-diastolic dysfunction. Sitagliptin significantly attenuated the increase in IRVT. Levels of angiotensin II (Ang II) in the heart tissue from Nx rats were higher while those of angiotensin-(1-7) Ang-(1-7) were lower than that in sham rats. This cardiac hormonal imbalance was completely prevented by sitagliptin. Collectively, these results suggest that DPPIV inhibition may delay the onset of cardiovascular impairment in CKD. Furthermore, these findings strengthen the hypothesis that a crosstalk between DPPIV and the renin-angiotensin system plays a role in the pathophysiology of cardiorenal syndromes.
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21
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Silencing of the Na+/H+ exchanger 1(NHE-1) prevents cardiac structural and functional remodeling induced by angiotensin II. Exp Mol Pathol 2019; 107:1-9. [DOI: 10.1016/j.yexmp.2019.01.007] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Revised: 01/08/2019] [Accepted: 01/16/2019] [Indexed: 12/30/2022]
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Davis MP, Behm B. Ginseng: A Qualitative Review of Benefits for Palliative Clinicians. Am J Hosp Palliat Care 2019; 36:630-659. [PMID: 30686023 DOI: 10.1177/1049909118822704] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Ginseng has been used for centuries to treat various diseases and has been commercially developed and cultivated in the past 300 years. Ginseng products may be fresh, dried (white), or dried and steamed (red). Extracts may be made using water or alcohol. There are over 50 different ginsenosides identified by chromatography. We did an informal systematic qualitative review that centered on fatigue, cancer, dementia, respiratory diseases, and heart failure, and we review 113 studies in 6 tables. There are multiple potential benefits to ginseng in cancer. Ginseng, in certain circumstances, has been shown to improve dementia, chronic obstructive pulmonary disease, and heart failure through randomized trials. Most trials had biases or unknown biases and so most evidence is of low quality. We review the gaps in the evidence and make some recommendations regarding future studies.
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Affiliation(s)
- Mellar P Davis
- 1 Palliative Care Department, Knapper Cancer Center, Geisinger Medical Center, Danville, PA, USA
| | - Bertrand Behm
- 1 Palliative Care Department, Knapper Cancer Center, Geisinger Medical Center, Danville, PA, USA
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Baartscheer A, Veldkamp MW. Is IGF-1 a useful inhibitor of Na + /H + -exchanger activity? Acta Physiol (Oxf) 2018; 224:e13164. [PMID: 30039514 DOI: 10.1111/apha.13164] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Revised: 07/12/2018] [Accepted: 07/17/2018] [Indexed: 01/02/2023]
Affiliation(s)
- Antonius Baartscheer
- Department of Clinical and Experimental Cardiology; Heart Center, Academic Medical Center; University of Amsterdam; Amsterdam The Netherlands
| | - Marieke W. Veldkamp
- Department of Clinical and Experimental Cardiology; Heart Center, Academic Medical Center; University of Amsterdam; Amsterdam The Netherlands
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Tian G, Sun Y, Liu S, Li C, Chen S, Qiu R, Zhang X, Li Y, Li M, Shang H. Therapeutic Effects of Wenxin Keli in Cardiovascular Diseases: An Experimental and Mechanism Overview. Front Pharmacol 2018; 9:1005. [PMID: 30233380 PMCID: PMC6134428 DOI: 10.3389/fphar.2018.01005] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2018] [Accepted: 08/16/2018] [Indexed: 02/05/2023] Open
Abstract
Cardiovascular diseases (CVDs) are the major public health problem and a leading cause of morbidity and mortality on a global basis. Wenxin Keli (WXKL), a formally classical Chinese patent medicine with obvious efficacy and favorable safety, plays a great role in the management of patients with CVDs. Accumulating evidence from various animal and cell studies has showed that WXKL could protect myocardium and anti-arrhythmia against CVDs. WXKL exhibited its cardioprotective roles by inhibiting inflammatory reaction, decreasing oxidative stress, regulating vasomotor disorders, lowering cell apoptosis, and protection against endothelial injure, myocardial ischemia, cardiac fibrosis, and cardiac hypertrophy. Besides, WXKL could effectively shorten the QRS and Q-T intervals, decrease the incidence of atrial/ventricular fibrillation and the number of ventricular tachycardia episodes, improve the severity of arrhythmias by regulating various ion channels with different potencies, mainly comprising peak sodium current (INa), late sodium current (INaL), transient outward potassium current (Ito), L-type calcium current (ICaL), and pacemaker current (If).
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Affiliation(s)
- Guihua Tian
- Chinese Cochrane Center, West China Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Yang Sun
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Shuo Liu
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Chengyu Li
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Shiqi Chen
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Ruijin Qiu
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Xiaoyu Zhang
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Youping Li
- Chinese Cochrane Center, West China Hospital, Sichuan University, Chengdu, China
| | - Min Li
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Hongcai Shang
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Institute of Integration of Traditional Chinese and Western Medicine, Guangzhou Medical University, Guangzhou, China
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The role of CD44, hyaluronan and NHE1 in cardiac remodeling. Life Sci 2018; 209:197-201. [PMID: 30089233 DOI: 10.1016/j.lfs.2018.08.009] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2018] [Revised: 07/16/2018] [Accepted: 08/04/2018] [Indexed: 12/12/2022]
Abstract
Cardiac remodeling, characterized by excessive extracellular matrix (ECM) remodeling, predisposes the heart to failure if left unresolved. Understanding the signaling mechanisms involved in excessive extracellular matrix (ECM) remodeling is necessary to identify the means to regress the development of cardiac remodeling and heart failure. Recently, hyaluronan (HA), a ubiquitously expressed glycosaminoglycan in the ECM, was shown to participate in tissue fibrosis and myofibroblast proliferation through interacting with its ubiquitously expressed cell-surface receptor, CD44. CD44 is a multifunctional transmembrane glycoprotein that serves as a cell-surface receptor for a number of ECM proteins. The mechanism by which the interaction between CD44-HA contributes to ECM and cardiac remodeling remains unknown. A previous study performed on a non-cardiac model showed that CD44-HA enhances Na+/H+ exchanger isoform-1 (NHE1) activity, causing ECM remodeling, HA metabolism and tumor invasion. Interestingly, NHE1 has been demonstrated to be involved in cardiac remodeling and myocardial fibrosis. In addition, it has previously been demonstrated that CD44 is upregulated in transgenic mouse hearts expressing active NHE-1. The role of CD44, HA and NHE1 and the cellular interplay of these factors in the ECM and cardiac remodeling is the focus of this review.
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Xue J, Zhou D, Poulsen O, Hartley I, Imamura T, Xie EX, Haddad GG. Exploring miRNA-mRNA regulatory network in cardiac pathology in Na +/H + exchanger isoform 1 transgenic mice. Physiol Genomics 2018; 50:846-861. [PMID: 30029588 DOI: 10.1152/physiolgenomics.00048.2018] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Numerous studies have demonstrated that Na+/H+ exchanger isoform 1 (NHE1) is elevated in myocardial diseases and its effect is detrimental. To better understand the involvement of NHE1, we have previously studied cardiac-specific NHE1 transgenic mice and shown that these mice develop cardiac hypertrophy, interstitial fibrosis, and cardiac dysfunction. The purpose of current study was to identify microRNAs and their mRNA targets involved in NHE1-mediated cardiac injury. An unbiased high-throughput sequencing study was performed on both microRNAs and mRNAs. RNA sequencing showed that differentially expressed genes were enriched in hypertrophic cardiomyopathy pathway by Kyoto Encyclopedia of Genes and Genomes annotation in NHE1 transgenic hearts. These genes were classified as contraction defects (e.g., Myl2, Myh6, Mybpc3, and Actb), impaired intracellular Ca2+ homeostasis (e.g., SERCA2a, Ryr2, Rcan1, and CaMKII delta), and signaling molecules for hypertrophic cardiomyopathy (e.g., Itga/b, IGF-1, Tgfb2/3, and Prkaa1/2). microRNA sequencing revealed that 15 microRNAs were differentially expressed (2-fold, P < 0.05). Six of them (miR-1, miR-208a-3p, miR-199a-5p, miR-21-5p, miR-146a-5p, and miR-30c-5p) were reported to be related to cardiac pathological functions. The integrative analysis of microRNA and RNA sequencing data identified several crucial microRNAs including miR-30c-5p, miR-199a-5p, miR-21-5p, and miR-34a-5p as well as 10 of their mRNA targets that may affect the heart via NFAT hypertrophy and cardiac hypertrophy signaling. Furthermore, important microRNAs and mRNA targets were validated by quantitative PCR. Our study comprehensively characterizes the expression patterns of microRNAs and mRNAs, establishes functional microRNA-mRNA pairs, elucidates the potential signaling pathways, and provides novel insights on the mechanisms underlying NHE1-medicated cardiac injury.
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Affiliation(s)
- Jin Xue
- Department of Pediatrics, University of California San Diego , La Jolla, California
| | - Dan Zhou
- Department of Pediatrics, University of California San Diego , La Jolla, California
| | - Orit Poulsen
- Department of Pediatrics, University of California San Diego , La Jolla, California
| | - Iain Hartley
- Department of Pediatrics, University of California San Diego , La Jolla, California
| | - Toshihiro Imamura
- Department of Pediatrics, University of California San Diego , La Jolla, California
| | - Edward X Xie
- Department of Pediatrics, University of California San Diego , La Jolla, California
| | - Gabriel G Haddad
- Department of Pediatrics, University of California San Diego , La Jolla, California.,Departments of Neurosciences, University of California San Diego , La Jolla, California.,The Rady Children's Hospital , San Diego, California
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Meng W, Zhou D, Li C, Wang G, Huang L, Cheng Z. A polyclonal antibody against extracellular loops 1 of chNHE1 blocks avian leukosis virus subgroup J infection. Res Vet Sci 2018; 118:477-483. [PMID: 29747134 DOI: 10.1016/j.rvsc.2018.04.014] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Revised: 04/27/2018] [Accepted: 04/30/2018] [Indexed: 11/16/2022]
Abstract
Avian leukosis virus subgroup J (ALV-J), an oncogenic retrovirus, induces myelocytomas and other various tumors, leading to great economical losses in poultry industry. It is a great challenge to develop effective preventive methods for ALV-J control due to its antigenic variations in the variable regions of envelope. In present study, we generated a mouse polyclonal antibody targeting the first extracellular loop (ECL1) of chicken Na+/H+ exchanger isoform 1 (chNHE1), the receptor of ALV-J, to block ALV-J infection in vitro and in vivo. In ALV-J infected DF-1 cells, chNHE1 expression and the intracellular pH (pHi) were up-regulated with "wave" pattern, indicating that the disequilibrium of ALV-J infected cells associated with chNHE1. Next, we validated that ALV-J infection was significantly blocked with time dependent after treating with anti-ECL1 antibody and accordingly the pHi value were recovered, indicating the blockage of ALV-J infection did not affect Na+/H+ exchange. Furthermore, in anti-ECL1 antibody treatment chickens that infected by ALV-J, weight gain and immune organs were recovered, and viral loads were significantly decreased, and the tissue injury and inflammation were reduced significantly from 21 to 35 days of age. The study demonstrated that anti-ECL1 antibody effectively blocks ALV-J infection without affecting Na+/H+ exchange, and sheds light on a novel strategy for retroviruses control.
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Affiliation(s)
- Wei Meng
- College of Veterinary Medicine, Shandong Agricultural University, Tai'an 271018, China
| | - Defang Zhou
- College of Veterinary Medicine, Shandong Agricultural University, Tai'an 271018, China
| | - Chengui Li
- College of Veterinary Medicine, Shandong Agricultural University, Tai'an 271018, China
| | - Guihua Wang
- College of Veterinary Medicine, Shandong Agricultural University, Tai'an 271018, China
| | - Libo Huang
- College of Veterinary Medicine, Shandong Agricultural University, Tai'an 271018, China
| | - Ziqiang Cheng
- College of Veterinary Medicine, Shandong Agricultural University, Tai'an 271018, China.
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Yim J, Cho H, Rabkin SW. Gene expression and gene associations during the development of heart failure with preserved ejection fraction in the Dahl salt sensitive model of hypertension. Clin Exp Hypertens 2017; 40:155-166. [DOI: 10.1080/10641963.2017.1346113] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Affiliation(s)
- Jeffrey Yim
- Department of Medicine (Cardiology), University of British Columbia, Vancouver, BC, Canada
| | - Hyokeun Cho
- Department of Medicine (Cardiology), University of British Columbia, Vancouver, BC, Canada
| | - Simon W. Rabkin
- Department of Medicine (Cardiology), University of British Columbia, Vancouver, BC, Canada
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Karmazyn M, Gan XT. Treatment of the cardiac hypertrophic response and heart failure with ginseng, ginsenosides, and ginseng-related products. Can J Physiol Pharmacol 2017; 95:1170-1176. [DOI: 10.1139/cjpp-2017-0092] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Heart failure is a major medical and economic burden throughout the world. Although various treatment options are available to treat heart failure, death rates in both men and women remain high. Potential adjunctive therapies may lie with use of herbal medications, many of which possess potent pharmacological properties. Among the most widely studied is ginseng, a member of the genus Panax that is grown in many parts of the world and that has been used as a medical treatment for a variety of conditions for thousands of years, particularly in Asian societies. There are a number of ginseng species, each possessing distinct pharmacological effects due primarily to differences in their bioactive components including saponin ginsenosides and polysaccharides. While experimental evidence for salutary effects of ginseng on heart failure is robust, clinical evidence is less so, primarily due to a paucity of large-scale well-controlled clinical trials. However, there is evidence from small trials that ginseng-containing Chinese medications such as Shenmai can offer benefit when administered as adjunctive therapy to heart failure patients. Substantial additional studies are required, particularly in the clinical arena, to provide evidence for a favourable effect of ginseng in heart failure patients.
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30
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Bkaily G, Jacques D. Na +-H + exchanger and proton channel in heart failure associated with Becker and Duchenne muscular dystrophies. Can J Physiol Pharmacol 2017; 95:1213-1223. [PMID: 28727929 DOI: 10.1139/cjpp-2017-0265] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Cardiomyopathy is found in patients with Duchenne (DMD) and Becker (BMD) muscular dystrophies, which are linked muscle diseases caused by mutations in the dystrophin gene. Dystrophin defects are not limited to DMD but are also present in mild BMD. The hereditary cardiomyopathic hamster of the UM-X7.1 strain is a particular experimental model of heart failure (HF) leading to early death in muscular dystrophy (dystrophin deficiency and sarcoglycan mutation) and heart disease (δ-sarcoglycan deficiency and dystrophin mutation) in human DMD. Using this model, our previous work showed a defect in intracellular sodium homeostasis before the appearance of any apparent biochemical and histological defects. This was attributed to the continual presence of the fetal slow sodium channel, which was also found to be active in human DMD. Due to muscular intracellular acidosis, the intracellular sodium overload in DMD and BMD was also due to sodium influx through the sodium-hydrogen exchanger NHE-1. Lifetime treatment with an NHE-1 inhibitor prevented intracellular Na+ overload and early death due to HF. Our previous work also showed that another proton transporter, the voltage-gated proton channel (Hv1), exists in many cell types including heart cells and skeletal muscle fibers. The Hv1 could be indirectly implicated in the beneficial effect of blocking NHE-1.
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Affiliation(s)
- Ghassan Bkaily
- Department of Anatomy and Cell Biology, Faculty of Medicine, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada.,Department of Anatomy and Cell Biology, Faculty of Medicine, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada
| | - Danielle Jacques
- Department of Anatomy and Cell Biology, Faculty of Medicine, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada.,Department of Anatomy and Cell Biology, Faculty of Medicine, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada
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31
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Maarman GJ, Schulz R, Sliwa K, Schermuly RT, Lecour S. Novel putative pharmacological therapies to protect the right ventricle in pulmonary hypertension: a review of current literature. Br J Pharmacol 2017; 174:497-511. [PMID: 28099680 DOI: 10.1111/bph.13721] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Revised: 09/06/2016] [Accepted: 09/27/2016] [Indexed: 12/15/2022] Open
Abstract
Pulmonary hypertension (PH) is defined by elevated mean pulmonary artery pressure following the pathological remodelling of small pulmonary arteries. An increase in right ventricular (RV) afterload results in RV hypertrophy and RV failure. The pathophysiology of PH, and RV remodelling in particular, is not well understood, thus explaining, at least in part, why current PH therapies have a limited effect. Existing therapies mostly target the pulmonary circulation. Because the remodelled RV fails to support normal cardiac function, patients eventually succumb from RV failure. Developing novel therapies that directly target the function of the RV may therefore benefit patients with PH. In the past decade, several promising studies have investigated novel cardioprotective strategies in experimental models of PH. This review aims to comprehensively discuss and highlight these novel experimental approaches to confer, in the long-term, greater health benefit in patients with PH.
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Affiliation(s)
- Gerald J Maarman
- Hatter Institute for Cardiovascular Research in Africa (HICRA) and MRC Inter-University Cape Heart Group, Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Rainer Schulz
- Institute of Physiology, Justus Liebig University Giessen, Giessen, Germany
| | - Karen Sliwa
- Hatter Institute for Cardiovascular Research in Africa (HICRA) and MRC Inter-University Cape Heart Group, Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Ralph Theo Schermuly
- Universities of Giessen and Marburg Lung Centre, Member of the German Lung Centre (DZL), Justus Liebig University Giessen, Giessen, Germany
| | - Sandrine Lecour
- Hatter Institute for Cardiovascular Research in Africa (HICRA) and MRC Inter-University Cape Heart Group, Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
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LASHEEN NN, MOHAMED GF. Possible Mechanisms of Cardiac Contractile Dysfunction and Electrical Changes in Ammonium Chloride Induced Chronic Metabolic Acidosis in Wistar Rats. Physiol Res 2016; 65:927-940. [DOI: 10.33549/physiolres.933171] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Metabolic acidosis could occur due to either endogenous acids accumulation or bicarbonate loss from the gastrointestinal tract or commonly from the kidney. This study aimed to investigate the possible underlying mechanism(s) of chronic acidosis-induced cardiac contractile and electrical changes in rats. Twenty four adult Wistar rats, of both sexes, were randomly divided into control group and chronic metabolic acidosis group, which received orally 0.28 M NH4Cl in the drinking water for 2 weeks. At the end of experimental period, systolic and diastolic blood pressure values were measured. On the day of sacrifice, rats were anesthetized by i.p. pentobarbitone (40 mg/kg b.w.), transthoracic echocardiography and ECG were performed. Blood samples were obtained from abdominal aorta for complete blood count and determination of pH, bicarbonate, chloride, sodium, potassium, troponin I, CK-MB, IL-6, renin and aldosterone levels. Hearts from both groups were studied for cardiac tissue IL-6 and aldosterone in addition to histopathological examination. Compared to control group, chronic metabolic acidosis group showed anemia, significant systolic and diastolic hypotension accompanied by significant reduction of ejection fraction and fraction of shortening, significant bradycardia, prolonged QTc interval and higher widened T wave as well as significantly elevated plasma levels of renin, aldosterone, troponin I, CK-MB and IL-6, and cardiac tissue aldosterone and IL-6. The left ventricular wall of the acidosis group showed degenerated myocytes with fibrosis and apoptosis. Thus, chronic metabolic acidosis induced negative inotropic and chronotropic effects and cardiomyopathy, possibly by elevated aldosterone and IL-6 levels released from the cardiac tissue.
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Affiliation(s)
- N. N. LASHEEN
- Department of Physiology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
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De Oliveira Moreira D, Santo Neto H, Marques MJ. P2Y 2 purinergic receptors are highly expressed in cardiac and diaphragm muscles of mdx mice, and their expression is decreased by suramin. Muscle Nerve 2016; 55:116-121. [PMID: 27220808 DOI: 10.1002/mus.25199] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2015] [Revised: 05/16/2016] [Accepted: 05/23/2016] [Indexed: 12/31/2022]
Abstract
INTRODUCTION In Duchenne muscular dystrophy (DMD) and in the mdx mouse model of DMD, the lack of dystrophin leads to increased calcium influx and muscle necrosis. Patients suffer progressive muscle loss, and cardiomyopathy is an important determinant of morbidity. P2 purinergic receptors participate in the increased calcium levels in dystrophic skeletal muscles. METHODS In this study, we evaluated whether P2 receptors are involved in cardiomyopathy in mdx mice at later stages of the disease. RESULTS Western blotting revealed that P2Y2 receptor levels were upregulated (54%) in dystrophic heart compared with a normal heart. Suramin reduced the levels of P2Y2 to almost normal values. Suramin also decreased heart necrosis (reduced CK-MB) and the expression of the stretch-activated calcium channel TRPC1. CONCLUSIONS This study suggests that P2Y2 may participate in cardiomyopathy in mdx mice. P2-selective drugs with specific actions in the dystrophic heart may ameliorate cardiomyopathy in dystrophinopathies. Muscle Nerve 55: 116-121, 2017.
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Affiliation(s)
- Drielen De Oliveira Moreira
- Departamento de Biologia Estrutural e Funcional, Instituto de Biologia, Universidade Estadual de Campinas (UNICAMP), Campinas, São Paulo, 13083-970, Brazil
| | - Humberto Santo Neto
- Departamento de Biologia Estrutural e Funcional, Instituto de Biologia, Universidade Estadual de Campinas (UNICAMP), Campinas, São Paulo, 13083-970, Brazil
| | - Maria Julia Marques
- Departamento de Biologia Estrutural e Funcional, Instituto de Biologia, Universidade Estadual de Campinas (UNICAMP), Campinas, São Paulo, 13083-970, Brazil
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Chen TI, Tu WC. Exercise Attenuates Intermittent Hypoxia-Induced Cardiac Fibrosis Associated with Sodium-Hydrogen Exchanger-1 in Rats. Front Physiol 2016; 7:462. [PMID: 27790155 PMCID: PMC5064604 DOI: 10.3389/fphys.2016.00462] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2016] [Accepted: 09/26/2016] [Indexed: 12/22/2022] Open
Abstract
Purpose: To investigate the role of sodium–hydrogen exchanger-1 (NHE-1) and exercise training on intermittent hypoxia-induced cardiac fibrosis in obstructive sleep apnea (OSA), using an animal model mimicking the intermittent hypoxia of OSA. Methods: Eight-week-old male Sprague–Dawley rats were randomly assigned to control (CON), intermittent hypoxia (IH), exercise (EXE), or IH combined with exercise (IHEXE) groups. These groups were randomly assigned to subgroups receiving either a vehicle or the NHE-1 inhibitor cariporide. The EXE and IHEXE rats underwent exercise training on an animal treadmill for 10 weeks (5 days/week, 60 min/day, 24–30 m/min, 2–10% grade). The IH and IHEXE rats were exposed to 14 days of IH (30 s of hypoxia—nadir of 2–6% O2—followed by 45 s of normoxia) for 8 h/day. At the end of 10 weeks, rats were sacrificed and then hearts were removed to determine the myocardial levels of fibrosis index, oxidative stress, antioxidant capacity, and NHE-1 activation. Results: Compared to the CON rats, IH induced higher cardiac fibrosis, lower myocardial catalase, and superoxidative dismutase activities, higher myocardial lipid and protein peroxidation and higher NHE-1 activation (p < 0.05 for each), which were all abolished by cariporide. Compared to the IH rats, lower cardiac fibrosis, higher myocardial antioxidant capacity, lower myocardial lipid, and protein peroxidation and lower NHE-1 activation were found in the IHEXE rats (p < 0.05 for each). Conclusion: IH-induced cardiac fibrosis was associated with NHE-1 hyperactivity. However, exercise training and cariporide exerted an inhibitory effect to prevent myocardial NHE-1 hyperactivity, which contributed to reduced IH-induced cardiac fibrosis. Therefore, NHE-1 plays a critical role in the effect of exercise on IH-induced increased cardiac fibrosis.
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Affiliation(s)
- Tsung-I Chen
- Center of Physical Education, Office of General and Basic Education, Tzu Chi University Hualien, Taiwan
| | - Wei-Chia Tu
- Master program in Physiological and Anatomical Medicine, School of Medicine, Tzu Chi University Hualien, Taiwan
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Li X, Augustine A, Chen S, Fliegel L. Stop Codon Polymorphisms in the Human SLC9A1 Gene Disrupt or Compromise Na+/H+ Exchanger Function. PLoS One 2016; 11:e0162902. [PMID: 27636896 PMCID: PMC5026351 DOI: 10.1371/journal.pone.0162902] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2016] [Accepted: 08/30/2016] [Indexed: 11/18/2022] Open
Abstract
The NHE1 isoform of the mammalian Na+/H+ exchanger is a ubiquitous plasma membrane protein that regulates intracellular pH in mammalian cells by removing one intracellular proton in exchange for one extracellular sodium. Deletion of the NHE1 gene (SLC9A1) affects the growth and motor ability of mice and humans but mutations and polymorphisms of the gene are only beginning to be characterized. NHE1 has a cytosolic C-terminal regulatory tail of approximately 315 amino acids and a 500 amino acid membrane domain. We examined the functional effects of three human stop codon mutations at amino acids 321, 449 and 735 in comparison with a mutant that had a shortened tail region (543 stop codon). The short mutants, 321, 449 and 543 stop codon mutant proteins, lost NHE1 activity and expression, and did not target to the plasma membrane. Protein for these short mutants was more rapidly degraded than the wild type and 735 ending proteins. The 735 terminating mutant, with the membrane domain and much of the cytosolic tail, had reduced protein expression and activity. The results demonstrate that early stop codon polymorphisms have significant and deleterious effects on the activity of the SLC9A1 protein product. The 735-NHE1 mutant, without the last 80 amino acids, had more minor defects. Surprisingly, retention of a proximal 43 amino acids adjacent to the membrane domain did little to maintain NHE1 expression, targeting and activity.
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Affiliation(s)
- Xiuju Li
- Department of Biochemistry, University Alberta, Edmonton, AB T6G 2H7, Canada
| | - Aruna Augustine
- Department of Biochemistry, University Alberta, Edmonton, AB T6G 2H7, Canada
| | - Shuo Chen
- Department of Biochemistry, University Alberta, Edmonton, AB T6G 2H7, Canada
| | - Larry Fliegel
- Department of Biochemistry, University Alberta, Edmonton, AB T6G 2H7, Canada
- * E-mail:
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Kawase H, Bando YK, Nishimura K, Aoyama M, Monji A, Murohara T. A dipeptidyl peptidase-4 inhibitor ameliorates hypertensive cardiac remodeling via angiotensin-II/sodium-proton pump exchanger-1 axis. J Mol Cell Cardiol 2016; 98:37-47. [DOI: 10.1016/j.yjmcc.2016.06.066] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2016] [Revised: 06/26/2016] [Accepted: 06/28/2016] [Indexed: 10/21/2022]
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Li X, Augustine A, Sun D, Li L, Fliegel L. Activation of the Na +/H + exchanger in isolated cardiomyocytes through β-Raf dependent pathways. Role of Thr 653 of the cytosolic tail. J Mol Cell Cardiol 2016; 99:65-75. [PMID: 27555478 DOI: 10.1016/j.yjmcc.2016.08.014] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Revised: 08/04/2016] [Accepted: 08/19/2016] [Indexed: 10/21/2022]
Abstract
The mammalian Na+/H+ exchanger isoform 1 (NHE1) is a ubiquitous plasma membrane protein that is a key regulator of intracellular pH in isolated cardiomyocytes. A 500 amino acid membrane domain removes protons and is regulated by a 315 amino acid cytosolic domain. In the myocardium, aberrant regulation of NHE1 contributes to ischemia reperfusion damage and to heart hypertrophy. We examined mechanisms of regulation of NHE1 in the myocardium by endothelin and β-Raf. Endothelin stimulated NHE1 activity and activated Erk-dependent pathways. Inhibition of β-Raf reduced NHE1 activity and Erk-pathway activation. We demonstrated that myocardial β-Raf binds to the C-terminal 182 amino acids of the NHE1 protein and that β-Raf is associated with NHE1 in intact cardiomyocytes. NHE1 was phosphorylated in vivo and the protein kinase inhibitor sorafenib reduced NHE1 phosphorylation levels. Immunoprecipitates of β-Raf from cardiomyocytes phosphorylated the C-terminal 182 amino acids of NHE1 and mass spectrometry analysis showed that amino acid Thr653 was phosphorylated. Mutation of this amino acid to Ala resulted in defective activity while mutation to Asp restored the activity. The results demonstrate that Thr653 is an important regulatory amino acid of NHE1 that is activated through β-Raf dependent pathways by phosphorylation either directly or indirectly by β-Raf, and this affects NHE1 activity.
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Affiliation(s)
- Xiuju Li
- Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2H7, Canada.
| | - Aruna Augustine
- Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2H7, Canada.
| | - Difei Sun
- Department of Chemistry, University of Alberta, Edmonton, AB T6G 2G2, Canada.
| | - Liang Li
- Department of Chemistry, University of Alberta, Edmonton, AB T6G 2G2, Canada.
| | - Larry Fliegel
- Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2H7, Canada.
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Blaustein MP, Chen L, Hamlyn JM, Leenen FHH, Lingrel JB, Wier WG, Zhang J. Pivotal role of α2 Na + pumps and their high affinity ouabain binding site in cardiovascular health and disease. J Physiol 2016; 594:6079-6103. [PMID: 27350568 DOI: 10.1113/jp272419] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2016] [Accepted: 06/18/2016] [Indexed: 12/13/2022] Open
Abstract
Reduced smooth muscle (SM)-specific α2 Na+ pump expression elevates basal blood pressure (BP) and increases BP sensitivity to angiotensin II (Ang II) and dietary NaCl, whilst SM-α2 overexpression lowers basal BP and decreases Ang II/salt sensitivity. Prolonged ouabain infusion induces hypertension in rodents, and ouabain-resistant mutation of the α2 ouabain binding site (α2R/R mice) confers resistance to several forms of hypertension. Pressure overload-induced heart hypertrophy and failure are attenuated in cardio-specific α2 knockout, cardio-specific α2 overexpression and α2R/R mice. We propose a unifying hypothesis that reconciles these apparently disparate findings: brain mechanisms, activated by Ang II and high NaCl, regulate sympathetic drive and a novel neurohumoral pathway mediated by both brain and circulating endogenous ouabain (EO). Circulating EO modulates ouabain-sensitive α2 Na+ pump activity and Ca2+ transporter expression and, via Na+ /Ca2+ exchange, Ca2+ homeostasis. This regulates sensitivity to sympathetic activity, Ca2+ signalling and arterial and cardiac contraction.
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Affiliation(s)
- Mordecai P Blaustein
- Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA. .,Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
| | - Ling Chen
- Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.,Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, 21201, USA
| | - John M Hamlyn
- Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA
| | - Frans H H Leenen
- Hypertension Unit, University of Ottawa Heart Institute, Ottawa, ON, Canada, K1Y 4W7
| | - Jerry B Lingrel
- Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH, 45267-0524, USA
| | - W Gil Wier
- Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA
| | - Jin Zhang
- Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA
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Bkaily G, Chahine M, Al-Khoury J, Avedanian L, Beier N, Scholz W, Jacques D. Na+–H+ exchanger inhibitor prevents early death in hereditary cardiomyopathy. Can J Physiol Pharmacol 2015; 93:923-34. [DOI: 10.1139/cjpp-2015-0107] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Using the UM-X7.1 hereditary cardiomyopathic and muscular dystrophy hamsters (HCMH), we tested the effects of lifelong preventive or curative treatments during the heart failure phase with the NHE-1 inhibitor EMD 87580 (EMD) or with the angiotensin-converting enzyme inhibitor cilazapril on the intracellular Na+ and Ca2+ overloads, elevated level of NHE-1, necrosis, hypertrophy, heart failure, and early death. Our results showed that 310-day pretreatment of 30-day-old HCMHs with EMD significantly prevented cardiac necrosis, cardiomyocyte hypertrophy, and reduced the heart to body mass ratio. This treatment significantly prevented Na+ and Ca2+ overloads and the increase in NHE-1 protein level observed in HCMHs. Importantly, this lifelong preventive treatment significantly decreased the levels of creatine kinase and prevented early death of HCMHs. Curative treatment of hypertrophic 275-day-old HCMHs for 85 days with EMD significantly prevented hypertrophy and early death of HCMHs. However, treatments with cilazapril did not have any significant effects on the cardiac parameters studied or on early death of HCMHs. Our results suggest that the increase in the NHE-1 level and the consequent Na+ and Ca2+ overloads are implicated in the pathological process leading to heart failure and early death in HCMHs, and treatment with the NHE-1 inhibitor is promising for preventing early death in hereditary cardiomyopathy.
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Affiliation(s)
- Ghassan Bkaily
- Department of Anatomy and Cell Biology, Faculty of Medicine, Université de Sherbrooke, 3001 12th Avenue North, Sherbrooke, QC J1H 5N4, Canada
| | - Mirna Chahine
- Department of Anatomy and Cell Biology, Faculty of Medicine, Université de Sherbrooke, 3001 12th Avenue North, Sherbrooke, QC J1H 5N4, Canada
| | - Johny Al-Khoury
- Department of Anatomy and Cell Biology, Faculty of Medicine, Université de Sherbrooke, 3001 12th Avenue North, Sherbrooke, QC J1H 5N4, Canada
| | - Levon Avedanian
- Department of Anatomy and Cell Biology, Faculty of Medicine, Université de Sherbrooke, 3001 12th Avenue North, Sherbrooke, QC J1H 5N4, Canada
| | - Norbert Beier
- Diabetes and Complication Research, Merck KGaA, D-64293 Darmstadt, Germany
| | - Wolfgang Scholz
- Diabetes and Complication Research, Merck KGaA, D-64293 Darmstadt, Germany
| | - Danielle Jacques
- Department of Anatomy and Cell Biology, Faculty of Medicine, Université de Sherbrooke, 3001 12th Avenue North, Sherbrooke, QC J1H 5N4, Canada
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Liu Y, Basu A, Li X, Fliegel L. Topological analysis of the Na+/H+ exchanger. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2015. [DOI: 10.1016/j.bbamem.2015.07.011] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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41
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Mohamed IA, Mraiche F. Targeting osteopontin, the silent partner of Na+/H+ exchanger isoform 1 in cardiac remodeling. J Cell Physiol 2015; 230:2006-18. [PMID: 25677682 DOI: 10.1002/jcp.24958] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2014] [Accepted: 02/06/2015] [Indexed: 12/11/2022]
Abstract
Cardiac hypertrophy (CH), characterized by the enlargement of cardiomyocytes, fibrosis and apoptosis, contributes to cardiac remodeling, which if left unresolved results in heart failure. Understanding the signaling pathways underlying CH is necessary to identify potential therapeutic targets. The Na(+) /H(+) -exchanger isoform I (NHE1), a ubiquitously expressed glycoprotein and cardiac specific isoform, regulates intracellular pH. Recent studies have demonstrated that enhanced expression/activity of NHE1 contributes to cardiac remodeling and CH. Inhibition of NHE1 in both in vitro and in vivo models have suggested that inhibition of NHE1 protects against hypertrophy. However, clinical trials using NHE1 inhibitors have proven to be unsuccessful, suggesting that additional factors maybe contributing to cardiac remodeling. Recent studies have indicated that the upregulation of NHE1 is associated with enhanced levels of osteopontin (OPN) in the setting of CH. OPN has been demonstrated to be upregulated in left ventricular hypertrophy, dilated cardiomyopathy and in diabetic cardiomyopathy. The cellular interplay between OPN and NHE1 in the setting of CH remains unknown. This review focuses on the role of NHE1 and OPN in cardiac remodeling and emphasizes the signaling pathways implicating OPN in the NHE1-induced hypertrophic response.
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Jinadasa T, Josephson CB, Boucher A, Orlowski J. Determinants of Cation Permeation and Drug Sensitivity in Predicted Transmembrane Helix 9 and Adjoining Exofacial Re-entrant Loop 5 of Na+/H+ Exchanger NHE1. J Biol Chem 2015; 290:18173-18186. [PMID: 26063808 DOI: 10.1074/jbc.m115.642199] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2015] [Indexed: 12/25/2022] Open
Abstract
Mammalian Na(+)/H(+) exchangers (NHEs) regulate numerous physiological processes and are involved in the pathogenesis of several diseases, including tissue ischemia and reperfusion injuries, cardiac hypertrophy and failure, and cancer progression. Hence, NHEs are being targeted for pharmaceutical-based clinical therapies, but pertinent information regarding the structural elements involved in cation translocation and drug binding remains incomplete. Molecular manipulations of the prototypical NHE1 isoform have implicated several predicted membrane-spanning (M) helices, most notably M4, M9, and M11, as important determinants of cation permeation and drug sensitivity. Here, we have used substituted-cysteine accessibility mutagenesis and thiol-modifying methanethiosulfonate (MTS) reagents to further probe the involvement of evolutionarily conserved sites within M9 (residues 342-363) and the adjacent exofacial re-entrant loop 5 between M9 and M10 (EL5; residues 364-415) of a cysteine-less variant of rat NHE1 on its kinetic and pharmacological properties. MTS treatment significantly reduced the activity of mutants containing substitutions within M9 (H353C, S355C, and G356C) and EL5 (G403C and S405C). In the absence of MTS, mutants S355C, G403C, and S405C showed modest to significant decreases in their apparent affinities for Na(+) o and/or H(+) i. In addition, mutations Y370C and E395C within EL5, whereas failing to confer sensitivity to MTS, nevertheless, reduced the affinity for Na(+) o, but not for H(+) i. The Y370C mutant also exhibited higher affinity for ethylisopropylamiloride, a competitive antagonist of Na(+) o transport. Collectively, these results further implicate helix M9 and EL5 of NHE1 as important elements involved in cation transport and inhibitor sensitivity, which may inform rational drug design.
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Affiliation(s)
- Tushare Jinadasa
- Department of Physiology, McGill University, Montréal, Québec H3G 1Y6
| | - Colin B Josephson
- Department of Physiology, McGill University, Montréal, Québec H3G 1Y6; Division of Clinical Neurosciences, University of Calgary Foothills Medical Centre, Calgary, Alberta T2N 2T9, Canada
| | - Annie Boucher
- Department of Physiology, McGill University, Montréal, Québec H3G 1Y6
| | - John Orlowski
- Department of Physiology, McGill University, Montréal, Québec H3G 1Y6.
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Nolly MB, Pinilla AO, Ennis IL, Cingolani HE, Morgan PE. Cardiac hypertrophy reduction in SHR by specific silencing of myocardial Na+/H+ exchanger. J Appl Physiol (1985) 2015; 118:1154-60. [DOI: 10.1152/japplphysiol.00996.2014] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2014] [Accepted: 02/26/2015] [Indexed: 12/13/2022] Open
Abstract
We examined the effect of specific and local silencing of sodium/hydrogen exchanger isoform 1 (NHE1) with a small hairpin RNA delivered by lentivirus (L-shNHE1) in the cardiac left ventricle (LV) wall of spontaneously hypertensive rats, to reduce cardiac hypertrophy. Thirty days after the lentivirus was injected, NHE1 protein expression was reduced 53.3 ± 3% in the LV of the L-shNHE1 compared with the control group injected with L-shSCR (NHE1 scrambled sequence), without affecting its expression in other organs, such as liver and lung. Hypertrophic parameters as LV weight-to-body weight and LV weight-to-tibia length ratio were significantly reduced in animals injected with L-shNHE1 (2.32 ± 0.5 and 19.30 ± 0.42 mg/mm, respectively) compared with L-shSCR-injected rats (2.68 ± 0.06 and 21.53 ± 0.64 mg/mm, respectively). Histochemical analysis demonstrated a reduction of cardiomyocytes cross-sectional area in animals treated with L-shNHE1 compared with L-shSCR (309,81 ± 20,86 vs. 424,52 ± 21 μm2, P < 0.05). Echocardiography at the beginning and at the end of the treatment showed that shNHE1 expression for 30 days induced 9% reduction of LV mass. Also, animals treated with L-shNHE1 exhibited a reduced LV wall thickness without changing LV diastolic dimension and arterial pressure, indicating an increased parietal stress. In addition, midwall shortening was not modified, despite the increased wall tension, suggesting an improvement of cardiac function. Chronic shNHE1 expression in the heart emerges as a possible methodology to reduce pathological cardiac hypertrophy, avoiding potentially undesired effects caused from a body-wide inhibition of NHE1.
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Affiliation(s)
- Mariela B. Nolly
- Centro de Investigaciones Cardiovasculares, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, La Plata, Argentina
| | - Andrés O. Pinilla
- Centro de Investigaciones Cardiovasculares, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, La Plata, Argentina
| | - Irene L. Ennis
- Centro de Investigaciones Cardiovasculares, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, La Plata, Argentina
| | - Horacio E. Cingolani
- Centro de Investigaciones Cardiovasculares, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, La Plata, Argentina
| | - Patricio E. Morgan
- Centro de Investigaciones Cardiovasculares, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, La Plata, Argentina
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Weeks KL, Avkiran M. Exchanging cardiac phenotype: Is AKT-mediated NHE1 inhibition a permissive switch in physiological hypertrophy? J Mol Cell Cardiol 2014; 77:175-7. [PMID: 25451172 DOI: 10.1016/j.yjmcc.2014.10.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2014] [Revised: 10/14/2014] [Accepted: 10/15/2014] [Indexed: 11/26/2022]
Affiliation(s)
- Kate L Weeks
- Cardiovascular Division, King's College London British Heart Foundation Centre, London SE1 7EH, UK
| | - Metin Avkiran
- Cardiovascular Division, King's College London British Heart Foundation Centre, London SE1 7EH, UK.
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45
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Kilić A, Huang CX, Rajapurohitam V, Madwed JB, Karmazyn M. Early and transient sodium-hydrogen exchanger isoform 1 inhibition attenuates subsequent cardiac hypertrophy and heart failure following coronary artery ligation. J Pharmacol Exp Ther 2014; 351:492-9. [PMID: 25216745 DOI: 10.1124/jpet.114.217091] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/08/2025] Open
Abstract
Na(+)/H(+) exchanger 1 (NHE-1) inhibition attenuates the hypertrophic response and heart failure in various experimental models. As the hypertrophic program is rapidly initiated following insult, we investigated whether early and transient administration of a NHE-1 inhibitor will exert salutary effects on cardiomyocyte hypertrophy or heart failure using both in vitro and in vivo approaches. Neonatal cardiomyocytes were treated with the novel, potent, and highly specific NHE-1 inhibitor BIX (N-[4-(1-acetyl-piperidin-4-yl)-3-trifluoromethyl-benzoyl]-guanidine; 100 nM) for 1 hour in the presence of 10 µM phenylephrine, after which the cells were maintained for a further 23 hours in the absence of NHE-1 inhibition. One-hour treatment with the NHE-1 inhibitor prevented phenylephrine-induced hypertrophy, which was associated with prevention of activation of calcineurin, a key component of the hypertrophic process. Experiments were then performed in rats subjected to coronary artery ligation, in which the NHE-1 inhibitor was administered immediately after infarction for a 1-week period followed by a further 5 weeks of sustained coronary artery occlusion in the absence of drug treatment. This approach significantly attenuated left ventricular hypertrophy and improved both left ventricular systolic and diastolic dysfunction, which was also associated with inhibition of calcineurin activation. Our findings indicate that early and transient administration of an NHE-1 inhibitor bestows subsequent inhibition of cardiomyocyte hypertrophy in culture as well as cardiac hypertrophy and heart failure in vivo, suggesting a critical early NHE-1-dependent initiation of the hypertrophic program. The study also suggests a preconditioning-like phenomenon in preventing hypertrophy and heart failure by early and transient NHE-1 inhibition.
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Affiliation(s)
- Ana Kilić
- Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada (A.K., C.X.H., V.R., M.K.); and Department of Pharmacology, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut (J.B.M.)
| | - Cathy X Huang
- Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada (A.K., C.X.H., V.R., M.K.); and Department of Pharmacology, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut (J.B.M.)
| | - Venkatesh Rajapurohitam
- Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada (A.K., C.X.H., V.R., M.K.); and Department of Pharmacology, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut (J.B.M.)
| | - Jeffrey B Madwed
- Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada (A.K., C.X.H., V.R., M.K.); and Department of Pharmacology, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut (J.B.M.)
| | - Morris Karmazyn
- Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada (A.K., C.X.H., V.R., M.K.); and Department of Pharmacology, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut (J.B.M.)
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Wang HS, Chen Y, Vairamani K, Shull GE. Critical role of bicarbonate and bicarbonate transporters in cardiac function. World J Biol Chem 2014; 5:334-345. [PMID: 25225601 PMCID: PMC4160527 DOI: 10.4331/wjbc.v5.i3.334] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2014] [Revised: 03/06/2014] [Accepted: 05/19/2014] [Indexed: 02/05/2023] Open
Abstract
Bicarbonate is one of the major anions in mammalian tissues and extracellular fluids. Along with accompanying H+, HCO3- is generated from CO2 and H2O, either spontaneously or via the catalytic activity of carbonic anhydrase. It serves as a component of the major buffer system, thereby playing a critical role in pH homeostasis. Bicarbonate can also be utilized by a variety of ion transporters, often working in coupled systems, to transport other ions and organic substrates across cell membranes. The functions of HCO3- and HCO3--transporters in epithelial tissues have been studied extensively, but their functions in heart are less well understood. Here we review studies of the identities and physiological functions of Cl-/HCO3- exchangers and Na+/HCO3- cotransporters of the SLC4A and SLC26A families in heart. We also present RNA Seq analysis of their cardiac mRNA expression levels. These studies indicate that slc4a3 (AE3) is the major Cl-/HCO3- exchanger and plays a protective role in heart failure, and that Slc4a4 (NBCe1) is the major Na+/HCO3- cotransporter and affects action potential duration. In addition, previous studies show that HCO3- has a positive inotropic effect in the perfused heart that is largely independent of effects on intracellular Ca2+. The importance of HCO3- in the regulation of contractility is supported by experiments showing that isolated cardiomyocytes exhibit sharply enhanced contractility, with no change in Ca2+ transients, when switched from Hepes-buffered to HCO3-- buffered solutions. These studies demonstrate that HCO3- and HCO3--handling proteins play important roles in the regulation of cardiac function.
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Wangensteen R, Rodríguez-Gómez I, Perez-Abud R, Quesada A, Montoro-Molina S, Osuna A, Vargas F. Dietary salt restriction in hyperthyroid rats. Differential influence on left and right ventricular mass. Exp Biol Med (Maywood) 2014; 240:113-20. [PMID: 25030483 DOI: 10.1177/1535370214544265] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
This study assessed the impact of salt restriction on cardiac morphology and biochemistry and its effects on hemodynamic and renal variables in experimental hyperthyroidism. Four groups of male Wistar rats were used: control, hyperthyroid, and the same groups under low salt intake. Body weight, blood pressure (BP), and heart rate (HR) were recorded weekly for 4 weeks. Morphologic, metabolic, plasma, cardiac, and renal variables were also measured. Low salt intake decreased BP in T(4)-treated rats but not in controls. Low salt intake reduced relative left ventricular mass but increased absolute right ventricular weight and right ventricular weight/BW ratio in both control and hyperthyroid groups. Low salt intake increased Na(+)/H(+) exchanger-1 (NHE-1) protein abundance in both ventricles in normal rats but not in hyperthyroid rats, independently of its effect on ventricular mass. Mammalian target of rapamycin (mTOR) protein abundance was not related to left or right ventricular mass in hyperthyroid or controls rats under normal or low salt conditions. Proteinuria was increased in hyperthyroid rats and attenuated by low salt intake. In this study, low salt intake produced an increase in right ventricular mass in normal and hyperthyroid rats. Changes in the left or right ventricular mass of control and hyperthyroid rats under low salt intake were not explained by the NHE-1 or mTOR protein abundance values observed. In hyperthyroid rats, low salt intake also slightly reduced BP and decreased HR, proteinuria, and water and sodium balances.
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Affiliation(s)
| | | | - Rocío Perez-Abud
- Servicio de Nefrología, Unidad Experimental, Hospital Virgen de las Nieves, 18014 Granada, Spain
| | - Andrés Quesada
- Servicio de Nefrología, Unidad Experimental, Hospital Virgen de las Nieves, 18014 Granada, Spain
| | | | - Antonio Osuna
- Servicio de Nefrología, Unidad Experimental, Hospital Virgen de las Nieves, 18014 Granada, Spain
| | - Félix Vargas
- Departamento de Fisiología, Facultad de Medicina, 18012 Granada, Spain
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Wagner MA, Siddiqui MAQ. The JAK-STAT pathway in hypertrophic stress signaling and genomic stress response. JAKSTAT 2014; 1:131-41. [PMID: 24058762 PMCID: PMC3670293 DOI: 10.4161/jkst.20702] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The JAK-STAT signaling pathway plays a central role in transducing stress and growth signals in the hypertrophic heart. Unlike most signal transducers, JAKs and STATs signal in a number of different ways, both within the JAK-STAT pathway and in collaboration with other signaling pathways. In this review, we discuss how IL-6 activates cells lacking IL-6 receptors through trans-signaling and examine JAK-STAT pathway interaction with GPCR-linked pathways both within and between cells. Finally, we discuss recent studies showing how the JAK-STAT pathway can intersect with a general transcriptional regulatory mechanism to effect transcription of STAT-dependent stress response genes.
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Affiliation(s)
- Michael A Wagner
- Department of Cell Biology; Center for Cardiovascular and Muscle Research; State University of New York Downstate Medical Center; Brooklyn, NY USA
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50
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Shimada-Shimizu N, Hisamitsu T, Nakamura TY, Hirayama N, Wakabayashi S. Na+/H+ exchanger 1 is regulated via its lipid-interacting domain, which functions as a molecular switch: a pharmacological approach using indolocarbazole compounds. Mol Pharmacol 2014; 85:18-28. [PMID: 24136992 DOI: 10.1124/mol.113.089268] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
The plasma membrane Na(+)/H(+) exchanger 1 (NHE1) is rapidly activated in response to various stimuli. The membrane-proximal cytoplasmic region (∼60 residues), termed the lipid-interacting domain (LID), is an important regulatory domain of NHE1. Here, we used a pharmacological approach to further characterize the role of LID in the regulation of NHE1. Pharmacological analysis using staurosporine-like indolocarbazole and bisindolylmaleimide compounds suggested that the phorbol ester- and receptor agonist-induced activation of NHE1 occurs through a protein kinase C-independent mechanism. In particular, only indolocarbazole compounds that inhibited NHE1 activation were able to interact with the LID, suggesting that the inhibition of NHE1 activation is achieved through the direct action of these compounds on the LID. Furthermore, in addition to phorbol esters and a receptor agonist, okadaic acid and hyperosmotic stress, which are known to activate NHE1 through unknown mechanisms, were found to promote membrane association of the LID concomitant with NHE1 activation; these effects were inhibited by staurosporine, as well as by a mutation in the LID. Binding experiments using the fluorescent ATP analog trinitrophenyl ATP revealed that ATP and the NHE1 activator phosphatidylinositol 4,5-bisphosphate bind competitively to the LID. These findings suggest that modulation of NHE1 activity by various activators and inhibitors occurs through the direct binding of these molecules to the LID, which alters the association of the LID with the plasma membrane.
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Affiliation(s)
- Naoko Shimada-Shimizu
- Department of Molecular Physiology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan (N.S.-S., T.H., T.Y.N., S.W.); and Basic Medical Science & Molecular Medicine, Tokai University School of Medicine, Kanagawa, Japan (N.H.)
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