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1
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Bajaj G, Singh V, Sagar P, Gupta R, Singhal NK. Phosphoenolpyruvate carboxykinase-1 targeted siRNA promotes wound healing in type 2 diabetic mice by restoring glucose homeostasis. Int J Biol Macromol 2024; 270:132504. [PMID: 38772464 DOI: 10.1016/j.ijbiomac.2024.132504] [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: 02/24/2024] [Revised: 05/02/2024] [Accepted: 05/17/2024] [Indexed: 05/23/2024]
Abstract
It is well-accepted that the liver plays a vital role in the metabolism of glucose and its homeostasis. Dysregulated hepatic glucose production and utilization, leads to type 2 diabetes (T2DM). In the current study, RNA sequencing and qRT-PCR analysis of nanoformulation-treated T2DM mice (TGthr group) revealed beneficial crosstalk of PCK-1 silencing with other pathways involved in T2DM. The comparison of precise genetic expression profiles of the different experimental groups showed significantly improved hepatic glucose, fatty acid metabolism and several other T2DM-associated crucial markers after the nanoformulation treatment. As a result of these improvements, we observed a significant acceleration in wound healing and improved insulin signaling in vascular endothelial cells in the TGthr group as compared to the T2DM group. Enhanced phosphorylation of PI3K/Akt pathway proteins in the TGthr group resulted in increased angiogenesis as observed by the increased expression of endothelial cell markers (CD31, CD34) thereby improving endothelial dysfunctions in the TGthr group. Additionally, therapeutic nanoformulation has been observed to improve the inflammatory cytokine profile in the TGthr group. Overall, our results demonstrated that the synthesized therapeutic nanoformulation referred to as GPR8:PCK-1siRNA holds the potential in ameliorating hyperglycemia-associated complications such as delayed wound healing in diabetes.
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Affiliation(s)
- Geetika Bajaj
- National Agri-Food Biotechnology Institute (NABI), Sector-81, S.A.S Nagar, Mohali 140306, Punjab, India; Department of Biotechnology, Panjab University, Sector 25, Chandigarh 160014, India
| | - Vishal Singh
- National Institute for Implementation Research on Non-Communicable Diseases, Jodhpur 342005, India
| | - Poonam Sagar
- National Agri-Food Biotechnology Institute (NABI), Sector-81, S.A.S Nagar, Mohali 140306, Punjab, India
| | - Ritika Gupta
- National Agri-Food Biotechnology Institute (NABI), Sector-81, S.A.S Nagar, Mohali 140306, Punjab, India
| | - Nitin Kumar Singhal
- National Agri-Food Biotechnology Institute (NABI), Sector-81, S.A.S Nagar, Mohali 140306, Punjab, India.
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2
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Wang D, Li J, Luo G, Zhou J, Wang N, Wang S, Zhao R, Cao X, Ma Y, Liu G, Hao L. Nox4 as a novel therapeutic target for diabetic vascular complications. Redox Biol 2023; 64:102781. [PMID: 37321060 PMCID: PMC10363438 DOI: 10.1016/j.redox.2023.102781] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Revised: 06/03/2023] [Accepted: 06/08/2023] [Indexed: 06/17/2023] Open
Abstract
Diabetic vascular complications can affect both microvascular and macrovascular. Diabetic microvascular complications, such as diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, and diabetic cardiomyopathy, are believed to be caused by oxidative stress. The Nox family of NADPH oxidases is a significant source of reactive oxygen species and plays a crucial role in regulating redox signaling, particularly in response to high glucose and diabetes mellitus. This review aims to provide an overview of the current knowledge about the role of Nox4 and its regulatory mechanisms in diabetic microangiopathies. Especially, the latest novel advances in the upregulation of Nox4 that aggravate various cell types within diabetic kidney disease will be highlighted. Interestingly, this review also presents the mechanisms by which Nox4 regulates diabetic microangiopathy from novel perspectives such as epigenetics. Besides, we emphasize Nox4 as a therapeutic target for treating microvascular complications of diabetes and summarize drugs, inhibitors, and dietary components targeting Nox4 as important therapeutic measures in preventing and treating diabetic microangiopathy. Additionally, this review also sums up the evidence related to Nox4 and diabetic macroangiopathy.
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Affiliation(s)
- Dongxia Wang
- Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment, Wuhan, 430030, China; Department of Nutrition and Food Hygiene, School of Public Health, Hebei Medical University, Hebei Key Laboratory of Environment and Human Health, Shijiazhuang, 050017, China
| | - Jiaying Li
- Department of Nutrition and Food Hygiene, School of Public Health, Hebei Medical University, Hebei Key Laboratory of Environment and Human Health, Shijiazhuang, 050017, China
| | - Gang Luo
- Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment, Wuhan, 430030, China
| | - Juan Zhou
- Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment, Wuhan, 430030, China
| | - Ning Wang
- Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment, Wuhan, 430030, China
| | - Shanshan Wang
- Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment, Wuhan, 430030, China
| | - Rui Zhao
- Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment, Wuhan, 430030, China
| | - Xin Cao
- Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment, Wuhan, 430030, China
| | - Yuxia Ma
- Department of Nutrition and Food Hygiene, School of Public Health, Hebei Medical University, Hebei Key Laboratory of Environment and Human Health, Shijiazhuang, 050017, China
| | - Gang Liu
- Department of Cardiology, The First Hospital of Hebei Medical University, Hebei International Joint Research Center for Structural Heart Disease, Hebei Key Laboratory of Cardiac Injury Repair Mechanism Study, Shijiazhuang, 050000, China.
| | - Liping Hao
- Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment, Wuhan, 430030, China.
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3
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Role of AMPK in Myocardial Ischemia-Reperfusion Injury-Induced Cell Death in the Presence and Absence of Diabetes. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:7346699. [PMID: 36267813 PMCID: PMC9578802 DOI: 10.1155/2022/7346699] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 09/29/2022] [Indexed: 11/26/2022]
Abstract
Recent studies indicate cell death is the hallmark of cardiac pathology in myocardial infarction and diabetes. The AMP-activated protein kinase (AMPK) signalling pathway is considered a putative salvaging phenomenon, plays a decisive role in almost all cellular, metabolic, and survival functions, and therefore entails precise regulation of its activity. AMPK regulates various programmed cell death depending on the stimuli and context, including autophagy, apoptosis, necroptosis, and ferroptosis. There is substantial evidence suggesting that AMPK is down-regulated in cardiac tissues of animals and humans with type 2 diabetes or metabolic syndrome compared to non-diabetic control and that stimulation of AMPK (physiological or pharmacological) can ameliorate diabetes-associated cardiovascular complications, such as myocardial ischemia-reperfusion injury. Furthermore, AMPK is an exciting therapeutic target for developing novel drug candidates to treat cell death in diabetes-associated myocardial ischemia-reperfusion injury. Therefore, in this review, we summarized how AMPK regulates autophagic, apoptotic, necroptotic, and ferroptosis pathways in the context of myocardial ischemia-reperfusion injury in the presence and absence of diabetes.
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4
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Heather LC, Hafstad AD, Halade GV, Harmancey R, Mellor KM, Mishra PK, Mulvihill EE, Nabben M, Nakamura M, Rider OJ, Ruiz M, Wende AR, Ussher JR. Guidelines on Models of Diabetic Heart Disease. Am J Physiol Heart Circ Physiol 2022; 323:H176-H200. [PMID: 35657616 PMCID: PMC9273269 DOI: 10.1152/ajpheart.00058.2022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Diabetes is a major risk factor for cardiovascular diseases, including diabetic cardiomyopathy, atherosclerosis, myocardial infarction, and heart failure. As cardiovascular disease represents the number one cause of death in people with diabetes, there has been a major emphasis on understanding the mechanisms by which diabetes promotes cardiovascular disease, and how antidiabetic therapies impact diabetic heart disease. With a wide array of models to study diabetes (both type 1 and type 2), the field has made major progress in answering these questions. However, each model has its own inherent limitations. Therefore, the purpose of this guidelines document is to provide the field with information on which aspects of cardiovascular disease in the human diabetic population are most accurately reproduced by the available models. This review aims to emphasize the advantages and disadvantages of each model, and to highlight the practical challenges and technical considerations involved. We will review the preclinical animal models of diabetes (based on their method of induction), appraise models of diabetes-related atherosclerosis and heart failure, and discuss in vitro models of diabetic heart disease. These guidelines will allow researchers to select the appropriate model of diabetic heart disease, depending on the specific research question being addressed.
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Affiliation(s)
- Lisa C Heather
- Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom
| | - Anne D Hafstad
- Department of Medical Biology, Faculty of Health Sciences, UiT-The Arctic University of Norway, Tromsø, Norway
| | - Ganesh V Halade
- Department of Medicine, The University of Alabama at Birmingham, Tampa, Florida, United States
| | - Romain Harmancey
- Department of Internal Medicine, Division of Cardiology, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, TX, United States
| | | | - Paras K Mishra
- Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, United States
| | - Erin E Mulvihill
- University of Ottawa Heart Institute, Ottawa, ON, Canada.,Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
| | - Miranda Nabben
- Departments of Genetics and Cell Biology, and Clinical Genetics, Maastricht University Medical Center, CARIM School of Cardiovascular Diseases, Maastricht, the Netherlands
| | - Michinari Nakamura
- Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark, NJ, United States
| | - Oliver J Rider
- University of Oxford Centre for Clinical Magnetic Resonance Research, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Matthieu Ruiz
- Montreal Heart Institute, Montreal, Quebec, Canada.,Department of Nutrition, Université de Montréal, Montreal, Quebec, Canada
| | - Adam R Wende
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - John R Ussher
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada.,Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada.,Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada
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5
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Dugbartey GJ, Wonje QL, Alornyo KK, Robertson L, Adams I, Boima V, Mensah SD. Combination Therapy of Alpha-Lipoic Acid, Gliclazide and Ramipril Protects Against Development of Diabetic Cardiomyopathy via Inhibition of TGF-β/Smad Pathway. Front Pharmacol 2022; 13:850542. [PMID: 35401218 PMCID: PMC8988231 DOI: 10.3389/fphar.2022.850542] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Accepted: 02/21/2022] [Indexed: 12/17/2022] Open
Abstract
Background: Diabetic cardiomyopathy (DCM) is a major long-term complication of diabetes mellitus, accounting for over 20% of annual mortality rate of diabetic patients globally. Although several existing anti-diabetic drugs have improved glycemic status in diabetic patients, prevalence of DCM is still high. This study investigates cardiac effect of alpha-lipoic acid (ALA) supplementation of anti-diabetic therapy in experimental DCM. Methods: Following 12 h of overnight fasting, 44 male Sprague Dawley rats were randomly assigned to two groups of healthy control (n = 7) and diabetic (n = 37) groups, and fasting blood glucose was measured. Type 2 diabetes mellitus (T2DM) was induced in diabetic group by intraperitoneal (i.p.) administration of nicotinamide (110 mg/kg) and streptozotocin (55 mg/kg). After confirmation of T2DM on day 3, diabetic rats received monotherapies with ALA (60 mg/kg; n = 7), gliclazide (15 mg/kg; n = 7), ramipril (10 mg/kg; n = 7) or combination of the three drugs (n = 7) for 6 weeks while untreated diabetic rats received distilled water and were used as diabetic control (n = 9). Rats were then sacrificed, and blood, pancreas and heart tissues were harvested for analyses using standard methods. Results: T2DM induction caused pancreatic islet destruction, hyperglycemia, weight loss, high relative heart weight, and development of DCM, which was characterized by myocardial degeneration and vacuolation, cardiac fibrosis, elevated cardiac damage markers (plasma and cardiac creatine kinase-myocardial band, brain natriuretic peptide and cardiac troponin I). Triple combination therapy of ALA, gliclazide and ramipril preserved islet structure, maintained body weight and blood glucose level, and prevented DCM development compared to diabetic control (p < 0.001). In addition, the combination therapy markedly reduced plasma levels of inflammatory markers (IL-1β, IL-6 and TNF-α), plasma and cardiac tissue malondialdehyde, triglycerides and total cholesterol while significantly increasing cardiac glutathione and superoxide dismutase activity and high-density lipoprotein-cholesterol compared to diabetic control (p < 0.001). Mechanistically, induction of T2DM upregulated cardiac expression of TGF-β1, phosphorylated Smad2 and Smad3 proteins, which were downregulated following triple combination therapy (p < 0.001). Conclusion: Triple combination therapy of ALA, gliclazide and ramipril prevented DCM development by inhibiting TGF-β1/Smad pathway. Our findings can be extrapolated to the human heart, which would provide effective additional pharmacological therapy against DCM in T2DM patients.
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Affiliation(s)
- George J Dugbartey
- Department of Pharmacology and Toxicology, School of Pharmacy, College of Health Sciences, University of Ghana, Accra, Ghana
| | - Quinsker L Wonje
- Department of Pharmacology and Toxicology, School of Pharmacy, College of Health Sciences, University of Ghana, Accra, Ghana
| | - Karl K Alornyo
- Department of Pharmacology and Toxicology, School of Pharmacy, College of Health Sciences, University of Ghana, Accra, Ghana
| | - Louis Robertson
- Department of Pharmacology and Toxicology, School of Pharmacy, College of Health Sciences, University of Ghana, Accra, Ghana
| | - Ismaila Adams
- Department of Pharmacology and Toxicology, School of Pharmacy, College of Health Sciences, University of Ghana, Accra, Ghana
| | - Vincent Boima
- Department of Medicine and Therapeutics, University of Ghana Medical School, College of Health Sciences, University of Ghana, Accra, Ghana
| | - Samuel D Mensah
- Department of Pharmacology and Toxicology, School of Pharmacy, College of Health Sciences, University of Ghana, Accra, Ghana
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6
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Wenzl FA, Ambrosini S, Mohammed SA, Kraler S, Lüscher TF, Costantino S, Paneni F. Inflammation in Metabolic Cardiomyopathy. Front Cardiovasc Med 2021; 8:742178. [PMID: 34671656 PMCID: PMC8520939 DOI: 10.3389/fcvm.2021.742178] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Accepted: 08/31/2021] [Indexed: 12/24/2022] Open
Abstract
Overlapping pandemics of lifestyle-related diseases pose a substantial threat to cardiovascular health. Apart from coronary artery disease, metabolic disturbances linked to obesity, insulin resistance and diabetes directly compromise myocardial structure and function through independent and shared mechanisms heavily involving inflammatory signals. Accumulating evidence indicates that metabolic dysregulation causes systemic inflammation, which in turn aggravates cardiovascular disease. Indeed, elevated systemic levels of pro-inflammatory cytokines and metabolic substrates induce an inflammatory state in different cardiac cells and lead to subcellular alterations thereby promoting maladaptive myocardial remodeling. At the cellular level, inflammation-induced oxidative stress, mitochondrial dysfunction, impaired calcium handling, and lipotoxicity contribute to cardiomyocyte hypertrophy and dysfunction, extracellular matrix accumulation and microvascular disease. In cardiometabolic patients, myocardial inflammation is maintained by innate immune cell activation mediated by pattern recognition receptors such as Toll-like receptor 4 (TLR4) and downstream activation of the NLRP3 inflammasome and NF-κB-dependent pathways. Chronic low-grade inflammation progressively alters metabolic processes in the heart, leading to a metabolic cardiomyopathy (MC) phenotype and eventually to heart failure with preserved ejection fraction (HFpEF). In accordance with preclinical data, observational studies consistently showed increased inflammatory markers and cardiometabolic features in patients with HFpEF. Future treatment approaches of MC may target inflammatory mediators as they are closely intertwined with cardiac nutrient metabolism. Here, we review current evidence on inflammatory processes involved in the development of MC and provide an overview of nutrient and cytokine-driven pro-inflammatory effects stratified by cell type.
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Affiliation(s)
- Florian A Wenzl
- Center for Molecular Cardiology, University of Zurich, Zurich, Switzerland
| | - Samuele Ambrosini
- Center for Molecular Cardiology, University of Zurich, Zurich, Switzerland
| | - Shafeeq A Mohammed
- Center for Molecular Cardiology, University of Zurich, Zurich, Switzerland
| | - Simon Kraler
- Center for Molecular Cardiology, University of Zurich, Zurich, Switzerland
| | - Thomas F Lüscher
- Center for Molecular Cardiology, University of Zurich, Zurich, Switzerland.,Royal Brompton and Harefield Hospitals and Imperial College, London, United Kingdom
| | - Sarah Costantino
- Center for Molecular Cardiology, University of Zurich, Zurich, Switzerland
| | - Francesco Paneni
- Center for Molecular Cardiology, University of Zurich, Zurich, Switzerland.,University Heart Center, Cardiology, University Hospital Zurich, Zurich, Switzerland.,Department of Research and Education, University Hospital Zurich, Zurich, Switzerland
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7
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Tuleta I, Frangogiannis NG. Fibrosis of the diabetic heart: Clinical significance, molecular mechanisms, and therapeutic opportunities. Adv Drug Deliv Rev 2021; 176:113904. [PMID: 34331987 PMCID: PMC8444077 DOI: 10.1016/j.addr.2021.113904] [Citation(s) in RCA: 75] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 07/19/2021] [Accepted: 07/24/2021] [Indexed: 01/02/2023]
Abstract
In patients with diabetes, myocardial fibrosis may contribute to the pathogenesis of heart failure and arrhythmogenesis, increasing ventricular stiffness and delaying conduction. Diabetic myocardial fibrosis involves effects of hyperglycemia, lipotoxicity and insulin resistance on cardiac fibroblasts, directly resulting in increased matrix secretion, and activation of paracrine signaling in cardiomyocytes, immune and vascular cells, that release fibroblast-activating mediators. Neurohumoral pathways, cytokines, growth factors, oxidative stress, advanced glycation end-products (AGEs), and matricellular proteins have been implicated in diabetic fibrosis; however, the molecular links between the metabolic perturbations and activation of a fibrogenic program remain poorly understood. Although existing therapies using glucose- and lipid-lowering agents and neurohumoral inhibition may act in part by attenuating myocardial collagen deposition, specific therapies targeting the fibrotic response are lacking. This review manuscript discusses the clinical significance, molecular mechanisms and cell biology of diabetic cardiac fibrosis and proposes therapeutic targets that may attenuate the fibrotic response, preventing heart failure progression.
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Affiliation(s)
- Izabela Tuleta
- The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx NY, USA
| | - Nikolaos G Frangogiannis
- The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx NY, USA.
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8
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Byrne NJ, Rajasekaran NS, Abel ED, Bugger H. Therapeutic potential of targeting oxidative stress in diabetic cardiomyopathy. Free Radic Biol Med 2021; 169:317-342. [PMID: 33910093 PMCID: PMC8285002 DOI: 10.1016/j.freeradbiomed.2021.03.046] [Citation(s) in RCA: 91] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 02/24/2021] [Accepted: 03/25/2021] [Indexed: 02/07/2023]
Abstract
Even in the absence of coronary artery disease and hypertension, diabetes mellitus (DM) may increase the risk for heart failure development. This risk evolves from functional and structural alterations induced by diabetes in the heart, a cardiac entity termed diabetic cardiomyopathy (DbCM). Oxidative stress, defined as the imbalance of reactive oxygen species (ROS) has been increasingly proposed to contribute to the development of DbCM. There are several sources of ROS production including the mitochondria, NAD(P)H oxidase, xanthine oxidase, and uncoupled nitric oxide synthase. Overproduction of ROS in DbCM is thought to be counterbalanced by elevated antioxidant defense enzymes such as catalase and superoxide dismutase. Excess ROS in the cardiomyocyte results in further ROS production, mitochondrial DNA damage, lipid peroxidation, post-translational modifications of proteins and ultimately cell death and cardiac dysfunction. Furthermore, ROS modulates transcription factors responsible for expression of antioxidant enzymes. Lastly, evidence exists that several pharmacological agents may convey cardiovascular benefit by antioxidant mechanisms. As such, increasing our understanding of the pathways that lead to increased ROS production and impaired antioxidant defense may enable the development of therapeutic strategies against the progression of DbCM. Herein, we review the current knowledge about causes and consequences of ROS in DbCM, as well as the therapeutic potential and strategies of targeting oxidative stress in the diabetic heart.
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Affiliation(s)
- Nikole J Byrne
- Division of Cardiology, Medical University of Graz, Graz, Austria
| | - Namakkal S Rajasekaran
- Cardiac Aging & Redox Signaling Laboratory, Molecular and Cellular Pathology, Department of Pathology, Birmingham, AL, USA; Division of Cardiovascular Medicine, Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA; Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - E Dale Abel
- Fraternal Order of Eagles Diabetes Research Center, Division of Endocrinology and Metabolism, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, USA
| | - Heiko Bugger
- Division of Cardiology, Medical University of Graz, Graz, Austria.
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9
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Ren J, Wu NN, Wang S, Sowers JR, Zhang Y. Obesity cardiomyopathy: evidence, mechanisms, and therapeutic implications. Physiol Rev 2021; 101:1745-1807. [PMID: 33949876 PMCID: PMC8422427 DOI: 10.1152/physrev.00030.2020] [Citation(s) in RCA: 197] [Impact Index Per Article: 49.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The prevalence of heart failure is on the rise and imposes a major health threat, in part, due to the rapidly increased prevalence of overweight and obesity. To this point, epidemiological, clinical, and experimental evidence supports the existence of a unique disease entity termed “obesity cardiomyopathy,” which develops independent of hypertension, coronary heart disease, and other heart diseases. Our contemporary review evaluates the evidence for this pathological condition, examines putative responsible mechanisms, and discusses therapeutic options for this disorder. Clinical findings have consolidated the presence of left ventricular dysfunction in obesity. Experimental investigations have uncovered pathophysiological changes in myocardial structure and function in genetically predisposed and diet-induced obesity. Indeed, contemporary evidence consolidates a wide array of cellular and molecular mechanisms underlying the etiology of obesity cardiomyopathy including adipose tissue dysfunction, systemic inflammation, metabolic disturbances (insulin resistance, abnormal glucose transport, spillover of free fatty acids, lipotoxicity, and amino acid derangement), altered intracellular especially mitochondrial Ca2+ homeostasis, oxidative stress, autophagy/mitophagy defect, myocardial fibrosis, dampened coronary flow reserve, coronary microvascular disease (microangiopathy), and endothelial impairment. Given the important role of obesity in the increased risk of heart failure, especially that with preserved systolic function and the recent rises in COVID-19-associated cardiovascular mortality, this review should provide compelling evidence for the presence of obesity cardiomyopathy, independent of various comorbid conditions, underlying mechanisms, and offer new insights into potential therapeutic approaches (pharmacological and lifestyle modification) for the clinical management of obesity cardiomyopathy.
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Affiliation(s)
- Jun Ren
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital Fudan University, Shanghai, China.,Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington
| | - Ne N Wu
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital Fudan University, Shanghai, China
| | - Shuyi Wang
- School of Medicine, Shanghai University, Shanghai, China.,University of Wyoming College of Health Sciences, Laramie, Wyoming
| | - James R Sowers
- Dalton Cardiovascular Research Center, Diabetes and Cardiovascular Research Center, University of Missouri-Columbia, Columbia, Missouri
| | - Yingmei Zhang
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital Fudan University, Shanghai, China
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10
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Tuleta I, Frangogiannis NG. Diabetic fibrosis. Biochim Biophys Acta Mol Basis Dis 2021; 1867:166044. [PMID: 33378699 PMCID: PMC7867637 DOI: 10.1016/j.bbadis.2020.166044] [Citation(s) in RCA: 114] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 11/25/2020] [Accepted: 12/07/2020] [Indexed: 12/13/2022]
Abstract
Diabetes-associated morbidity and mortality is predominantly due to complications of the disease that may cause debilitating conditions, such as heart and renal failure, hepatic insufficiency, retinopathy or peripheral neuropathy. Fibrosis, the excessive and inappropriate deposition of extracellular matrix in various tissues, is commonly found in patients with advanced type 1 or type 2 diabetes, and may contribute to organ dysfunction. Hyperglycemia, lipotoxic injury and insulin resistance activate a fibrotic response, not only through direct stimulation of matrix synthesis by fibroblasts, but also by promoting a fibrogenic phenotype in immune and vascular cells, and possibly also by triggering epithelial and endothelial cell conversion to a fibroblast-like phenotype. High glucose stimulates several fibrogenic pathways, triggering reactive oxygen species generation, stimulating neurohumoral responses, activating growth factor cascades (such as TGF-β/Smad3 and PDGFs), inducing pro-inflammatory cytokines and chemokines, generating advanced glycation end-products (AGEs) and stimulating the AGE-RAGE axis, and upregulating fibrogenic matricellular proteins. Although diabetes-activated fibrogenic signaling has common characteristics in various tissues, some organs, such as the heart, kidney and liver develop more pronounced and clinically significant fibrosis. This review manuscript summarizes current knowledge on the cellular and molecular pathways involved in diabetic fibrosis, discussing the fundamental links between metabolic perturbations and fibrogenic activation, the basis for organ-specific differences, and the promises and challenges of anti-fibrotic therapies for diabetic patients.
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Affiliation(s)
- Izabela Tuleta
- The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx, NY, USA
| | - Nikolaos G Frangogiannis
- The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx, NY, USA.
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11
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NADPH Oxidase 2 Mediates Myocardial Oxygen Wasting in Obesity. Antioxidants (Basel) 2020; 9:antiox9020171. [PMID: 32093119 PMCID: PMC7070669 DOI: 10.3390/antiox9020171] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Revised: 02/03/2020] [Accepted: 02/17/2020] [Indexed: 12/17/2022] Open
Abstract
Obesity and diabetes are independent risk factors for cardiovascular diseases, and they are associated with the development of a specific cardiomyopathy with elevated myocardial oxygen consumption (MVO2) and impaired cardiac efficiency. Although the pathophysiology of this cardiomyopathy is multifactorial and complex, reactive oxygen species (ROS) may play an important role. One of the major ROS-generating enzymes in the cardiomyocytes is nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2), and many potential systemic activators of NOX2 are elevated in obesity and diabetes. We hypothesized that NOX2 activity would influence cardiac energetics and/or the progression of ventricular dysfunction following obesity. Myocardial ROS content and mechanoenergetics were measured in the hearts from diet-induced-obese wild type (DIOWT) and global NOK2 knock-out mice (DIOKO) and in diet-induced obese C57BL/6J mice given normal water (DIO) or water supplemented with the NOX2-inhibitor apocynin (DIOAPO). Mitochondrial function and ROS production were also assessed in DIO and DIOAPO mice. This study demonstrated that ablation and pharmacological inhibition of NOX2 both improved mechanical efficiency and reduced MVO2 for non-mechanical cardiac work. Mitochondrial ROS production was also reduced following NOX2 inhibition, while cardiac mitochondrial function was not markedly altered by apocynin-treatment. Therefore, these results indicate a link between obesity-induced myocardial oxygen wasting, NOX2 activation, and mitochondrial ROS.
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12
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Kolovou GD, Watts GF, Mikhailidis DP, Pérez-Martínez P, Mora S, Bilianou H, Panotopoulos G, Katsiki N, Ooi TC, Lopez-Miranda J, Tybjærg-Hansen A, Tentolouris N, Nordestgaard BG. Postprandial Hypertriglyceridaemia Revisited in the Era of Non-Fasting Lipid Profile Testing: A 2019 Expert Panel Statement, Narrative Review. Curr Vasc Pharmacol 2019; 17:515-537. [DOI: 10.2174/1570161117666190503123911] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Revised: 04/01/2019] [Accepted: 04/11/2019] [Indexed: 12/17/2022]
Abstract
Postprandial hypertriglyceridaemia, defined as an increase in plasma triglyceride-containing
lipoproteins following a fat meal, is a potential risk predictor of atherosclerotic cardiovascular disease
and other chronic diseases. Several non-modifiable factors (genetics, age, sex and menopausal status)
and lifestyle factors (diet, physical activity, smoking status, obesity, alcohol and medication use) may
influence postprandial hypertriglyceridaemia. This narrative review considers the studies published over
the last decade that evaluated postprandial hypertriglyceridaemia. Additionally, the genetic determinants
of postprandial plasma triglyceride levels, the types of meals for studying postprandial triglyceride response,
and underlying conditions (e.g. familial dyslipidaemias, diabetes mellitus, metabolic syndrome,
non-alcoholic fatty liver and chronic kidney disease) that are associated with postprandial hypertriglyceridaemia
are reviewed; therapeutic aspects are also considered.
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Affiliation(s)
- Genovefa D. Kolovou
- Cardiology Department and LDL-Apheresis Unit, Onassis Cardiac Surgery Center, Athens, Greece
| | - Gerald F. Watts
- Lipid Disorders Clinic, Department of Cardiology, Royal Perth Hospital, School of Medicine, Faculty of Health and Medical Sciences, University of Western Australia, Crawley, Australia
| | - Dimitri P. Mikhailidis
- Department of Clinical Biochemistry, Royal Free Hospital Campus, University College London Medical School, University College London (UCL), London, United Kingdom
| | - Pablo Pérez-Martínez
- Lipid and Atherosclerosis Unit, IMIBIC/Reina Sofia University Hospital/University of Cordoba, and CIBER Fisiopatologia Obesidad y Nutricion (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
| | - Samia Mora
- Center for Lipid Metabolomics, Divisions of Preventive and Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
| | - Helen Bilianou
- Department of Cardiology, Tzanio Hospital, Piraeus, Greece
| | | | - Niki Katsiki
- First Department of Internal Medicine, Division of Endocrinology-Metabolism, Diabetes Center, AHEPA University Hospital, Thessaloniki, Greece
| | - Teik C. Ooi
- Department of Medicine, Division of Endocrinology and Metabolism, University of Ottawa, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - José Lopez-Miranda
- Lipid and Atherosclerosis Unit, IMIBIC/Reina Sofia University Hospital/University of Cordoba, and CIBER Fisiopatologia Obesidad y Nutricion (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
| | - Anne Tybjærg-Hansen
- Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Nicholas Tentolouris
- First Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Børge G. Nordestgaard
- Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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13
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The role of NADPH oxidases in diabetic cardiomyopathy. Biochim Biophys Acta Mol Basis Dis 2018; 1864:1908-1913. [DOI: 10.1016/j.bbadis.2017.07.025] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2017] [Revised: 07/19/2017] [Accepted: 07/21/2017] [Indexed: 12/14/2022]
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14
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Nox4 genetic inhibition in experimental hypertension and metabolic syndrome. Arch Cardiovasc Dis 2018; 111:41-52. [DOI: 10.1016/j.acvd.2017.03.011] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Revised: 12/28/2016] [Accepted: 03/22/2017] [Indexed: 02/07/2023]
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15
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Pro-inflammatory hepatic macrophages generate ROS through NADPH oxidase 2 via endocytosis of monomeric TLR4-MD2 complex. Nat Commun 2017; 8:2247. [PMID: 29269727 PMCID: PMC5740170 DOI: 10.1038/s41467-017-02325-2] [Citation(s) in RCA: 181] [Impact Index Per Article: 22.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2017] [Accepted: 11/21/2017] [Indexed: 12/12/2022] Open
Abstract
Reactive oxygen species (ROS) contribute to the development of non-alcoholic fatty liver disease. ROS generation by infiltrating macrophages involves multiple mechanisms, including Toll-like receptor 4 (TLR4)-mediated NADPH oxidase (NOX) activation. Here, we show that palmitate-stimulated CD11b+F4/80low hepatic infiltrating macrophages, but not CD11b+F4/80high Kupffer cells, generate ROS via dynamin-mediated endocytosis of TLR4 and NOX2, independently from MyD88 and TRIF. We demonstrate that differently from LPS-mediated dimerization of the TLR4–MD2 complex, palmitate binds a monomeric TLR4–MD2 complex that triggers endocytosis, ROS generation and increases pro-interleukin-1β expression in macrophages. Palmitate-induced ROS generation in human CD68lowCD14high macrophages is strongly suppressed by inhibition of dynamin. Furthermore, Nox2-deficient mice are protected against high-fat diet-induced hepatic steatosis and insulin resistance. Therefore, endocytosis of TLR4 and NOX2 into macrophages might be a novel therapeutic target for non-alcoholic fatty liver disease. Reactive species of oxygen promote the development of hepatic steatosis. Here, Kim et al. demonstrate that palmitate stimulates macrophage infiltration and increases oxidative stress during steatosis by binding to the TLR4–MD2 complex, which results in the activation of NOX2.
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16
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Huang T, Fu J, Zhang Z, Zhang Y, Liang Y, Ge C, Qin X. Pancreatic islet regeneration through PDX-1/Notch-1/Ngn3 signaling after gastric bypass surgery in db/db mice. Exp Ther Med 2017; 14:2831-2838. [PMID: 28966671 PMCID: PMC5613180 DOI: 10.3892/etm.2017.4896] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2016] [Accepted: 04/11/2017] [Indexed: 01/27/2023] Open
Abstract
In view of the compelling anti-diabetic effects of gastric bypass surgery (GBS) in the treatment of morbid obesity, it is important to clarify its enhancing effect on pancreatic islets, which is closely linked with diabetes remission in obese patients, as well as the underlying mechanisms. The present study evaluated the effects of GBS on glycemic control and other pancreatic changes in db/db mice. The db/db mice were divided into Control, Sham and GBS group. A significant improvement in fasting plasma glucose levels and glucose intolerance were observed post-surgery. At 4 weeks after surgery, further noteworthy changes were observed in the GBS group, including improved islet structure (revealed by immunohistochemical analysis), enhanced insulin secretion, pancreatic hyperplasia and a marked increase in the ratio of β-cells to non-β endocrine cells. Furthermore, notable changes in the levels of Notch-1, pancreatic and duodenal homeobox 1 (PDX-1) and neurogenin 3 (Ngn3) were observed in the GBS group, indicating a potential role of Notch signaling in pancreatic islet regeneration after surgery. In addition, results obtained in PDX-1 knockout (KO), Notch-1 KO and Ngn3 KO mouse models with GBS suggested that elevated PDX-1 resulted in the inhibition of Notch-1, further facilitated Ngn3 and thus promoted pancreatic β-cell regeneration after GBS. The present findings demonstrated that GBS in db/db mice resulted in pancreatic islet regeneration through the PDX-1/Notch-1/Ngn3 signaling pathway, which also reflected the important role of the gastrointestinal system in metabolism control.
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Affiliation(s)
- Tao Huang
- Department of General Surgery, Shanghai Eighth People's Hospital, Shanghai 200235, P.R. China
| | - Jun Fu
- Department of General Surgery, Shanghai Eighth People's Hospital, Shanghai 200235, P.R. China
| | - Zhijing Zhang
- Department of General Surgery, Shanghai Eighth People's Hospital, Shanghai 200235, P.R. China
| | - Yuhao Zhang
- Department of General Surgery, Shanghai Eighth People's Hospital, Shanghai 200235, P.R. China
| | - Yunjia Liang
- Department of General Surgery, Shanghai Eighth People's Hospital, Shanghai 200235, P.R. China
| | - Cuicui Ge
- Department of General Surgery, Shanghai Eighth People's Hospital, Shanghai 200235, P.R. China
| | - Xianju Qin
- Department of General Surgery, Shanghai Eighth People's Hospital, Shanghai 200235, P.R. China
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17
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Yan J, Wang C, Jin Y, Meng Q, Liu Q, Liu Z, Liu K, Sun H. Catalpol prevents alteration of cholesterol homeostasis in non-alcoholic fatty liver disease via attenuating endoplasmic reticulum stress and NOX4 over-expression. RSC Adv 2017. [DOI: 10.1039/c6ra26046b] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Catalpol has protective effects against hepatic lipid accumulation and alteration of cholesterol homeostasis in HFD- and PA-induced NAFLDviainhibiting ER stress and NOX4 over-expression.
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Affiliation(s)
- Jiting Yan
- Department of Clinical Pharmacology
- College of Pharmacy
- Dalian Medical University
- Dalian 116044
- China
| | - Changyuan Wang
- Department of Clinical Pharmacology
- College of Pharmacy
- Dalian Medical University
- Dalian 116044
- China
| | - Yue Jin
- Department of Clinical Pharmacology
- College of Pharmacy
- Dalian Medical University
- Dalian 116044
- China
| | - Qiang Meng
- Department of Clinical Pharmacology
- College of Pharmacy
- Dalian Medical University
- Dalian 116044
- China
| | - Qi Liu
- Department of Clinical Pharmacology
- College of Pharmacy
- Dalian Medical University
- Dalian 116044
- China
| | - Zhihao Liu
- Department of Clinical Pharmacology
- College of Pharmacy
- Dalian Medical University
- Dalian 116044
- China
| | - Kexin Liu
- Department of Clinical Pharmacology
- College of Pharmacy
- Dalian Medical University
- Dalian 116044
- China
| | - Huijun Sun
- Department of Clinical Pharmacology
- College of Pharmacy
- Dalian Medical University
- Dalian 116044
- China
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18
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Russo I, Frangogiannis NG. Diabetes-associated cardiac fibrosis: Cellular effectors, molecular mechanisms and therapeutic opportunities. J Mol Cell Cardiol 2015; 90:84-93. [PMID: 26705059 DOI: 10.1016/j.yjmcc.2015.12.011] [Citation(s) in RCA: 341] [Impact Index Per Article: 34.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2015] [Revised: 12/13/2015] [Accepted: 12/14/2015] [Indexed: 02/07/2023]
Abstract
Both type 1 and type 2 diabetes are associated with cardiac fibrosis that may reduce myocardial compliance, contribute to the pathogenesis of heart failure, and trigger arrhythmic events. Diabetes-associated fibrosis is mediated by activated cardiac fibroblasts, but may also involve fibrogenic actions of macrophages, cardiomyocytes and vascular cells. The molecular basis responsible for cardiac fibrosis in diabetes remains poorly understood. Hyperglycemia directly activates a fibrogenic program, leading to accumulation of advanced glycation end-products (AGEs) that crosslink extracellular matrix proteins, and transduce fibrogenic signals through reactive oxygen species generation, or through activation of Receptor for AGEs (RAGE)-mediated pathways. Pro-inflammatory cytokines and chemokines may recruit fibrogenic leukocyte subsets in the cardiac interstitium. Activation of transforming growth factor-β/Smad signaling may activate fibroblasts inducing deposition of structural extracellular matrix proteins and matricellular macromolecules. Adipokines, endothelin-1 and the renin-angiotensin-aldosterone system have also been implicated in the diabetic myocardium. This manuscript reviews our current understanding of the cellular effectors and molecular pathways that mediate fibrosis in diabetes. Based on the pathophysiologic mechanism, we propose therapeutic interventions that may attenuate the diabetes-associated fibrotic response and discuss the challenges that may hamper clinical translation.
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Affiliation(s)
- Ilaria Russo
- The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx, NY, USA
| | - Nikolaos G Frangogiannis
- The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx, NY, USA.
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19
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Kato R, Nishioka S, Nomura A, Ijiri Y, Miyamura M, Ukimura A, Okada Y, Kitaura Y, Hayashi T. Cardiovascular protection by ezetimibe and influence on oxidative stress in mice exposed to intermittent hypoxia. Eur J Pharmacol 2015; 765:7-14. [PMID: 26276396 DOI: 10.1016/j.ejphar.2015.08.013] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 07/03/2015] [Accepted: 08/10/2015] [Indexed: 01/03/2023]
Abstract
Ezetimibe is as an inhibitor of NPC1L1 protein, which has a key role in cholesterol absorption. The aim of this study was to evaluate the influence of ezetimibe on the plasma lipid profile, atherosclerotic lesions, and cardiomyocyte ultrastructure in an animal model of atherosclerosis with intermittent hypoxia. Apolipoprotein E-knockout mice received a high-fat diet for 30 days. Then animals were exposed to intermittent hypoxia for 10 days or were maintained under normoxic conditions. In the ezetimibe group, ezetimibe (5 mg/kg/day) was added to the diet. Under normoxic conditions, the total cholesterol level was significantly lower in the ezetimibe group (63.6±6.6 mg/dl) than in the control group (116.3±16.9 mg/dl, P<0.001). Intermittent hypoxia accelerated atherosclerosis associated with increased superoxide production, which also caused degeneration of cardiomyocytes, mitochondrial abnormalities, and interstitial fibrosis. Compared with the control group, the ezetimibe group showed significantly less advanced atherosclerotic lesions and lower superoxide production in the thoracic aorta, as well as reduced oxidative stress, preservation of cardiomyocyte ultrastructure, and reduced interstitial fibrosis in the left ventricular myocardium. In conclusion, ezetimibe not only reduces total cholesterol, but also prevents the development of atherosclerosis and cardiovascular events due to intermittent hypoxia at least partly through suppression of oxidative stress.
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Affiliation(s)
- Ryuji Kato
- Laboratory of Cardiovascular Pharmacotherapy and Toxicology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan
| | - Satoshi Nishioka
- Laboratory of Pathological and Molecular Pharmacology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan
| | - Atsuo Nomura
- Laboratory of Cardiovascular Pharmacotherapy and Toxicology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan
| | - Yoshio Ijiri
- Laboratory of Cardiovascular Pharmacotherapy and Toxicology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan
| | - Masatoshi Miyamura
- Department of Internal Medicine III, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, Japan
| | - Akira Ukimura
- Department of Internal Medicine III, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, Japan
| | - Yoshikatsu Okada
- Department of Pathology, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, Japan
| | - Yasushi Kitaura
- Department of Internal Medicine III, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, Japan
| | - Tetsuya Hayashi
- Laboratory of Cardiovascular Pharmacotherapy and Toxicology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan.
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20
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Chang E, Kim L, Park SE, Rhee EJ, Lee WY, Oh KW, Park SW, Park CY. Ezetimibe improves hepatic steatosis in relation to autophagy in obese and diabetic rats. World J Gastroenterol 2015; 21:7754-7763. [PMID: 26167075 PMCID: PMC4491962 DOI: 10.3748/wjg.v21.i25.7754] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2014] [Revised: 11/18/2014] [Accepted: 01/08/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate whether ezetimibe ameliorates hepatic steatosis and induces autophagy in a rat model of obesity and type 2 diabetes.
METHODS: Male age-matched lean control LETO and obese and diabetic OLETF rats were administered either PBS or ezetimibe (10 mg/kg per day) via stomach gavage for 20 wk. Changes in weight gain and energy intake were regularly monitored. Blood and liver tissue were harvested after overnight fasting at the end of study. Histological assessment was performed in liver tissue. The concentrations of glucose, insulin, triglycerides (TG), free fatty acids (FFA), and total cholesterol (TC) in blood and TG, FFA, and TG in liver tissue were measured. mRNA and protein abundance involved in autophagy was analyzed in the liver. To investigate the effect of ezetimibe on autophagy and reduction in hepatic fat accumulation, human Huh7 hepatocytes were incubated with ezetimibe (10 μmol/L) together with or without palmitic acid (PA, 0.5 mmol/L, 24 h). Transmission electron microscopy (TEM) was employed to demonstrate effect of ezetimibe on autophagy formation. Autophagic flux was measured with bafilomycin A1, an inhibitor of autophagy and following immunoblotting for autophagy-related protein expression.
RESULTS: In the OLETF rats that received ezetimibe (10 mg/kg per day), liver weight were significantly decreased by 20% compared to OLETF control rats without changes in food intake and body weight (P < 0.05). Lipid parameters including TG, FFA, and TC in liver tissue of ezetimibe-administrated OLETF rats were dramatically decreased at least by 30% compared to OLETF controls (P < 0.01). The serum glucose, insulin, HOMA-IR, and lipid profiles were also improved by ezetimibe (P < 0.05). In addition, autophagy-related mRNA expression including ATG5, ATG6, and ATG7 and the protein level of microtubule-associated protein light chain 3 (LC3) were significantly increased in the liver in rats that received ezetimibe (P < 0.05). Likewise, for hepatocytes cultured in vitro, ezetimibe treatment significantly decreased PA-induced fat accumulation and increased PA-reduced mRNA and protein expression involved in autophagy (P < 0.05). Ezetimibe-increased autophagosomes was observed in TEM analysis. Immunoblotting analysis of autophagy formation with an inhibitor of autophagy demonstrated that ezetimibe-increased autophagy resulted from increased autophagic flux.
CONCLUSION: The present study demonstrates that ezetimibe-mediated improvement in hepatic steatosis might involve the induction of autophagy.
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21
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A newly designed curcumin analog Y20 mitigates cardiac injury via anti-inflammatory and anti-oxidant actions in obese rats. PLoS One 2015; 10:e0120215. [PMID: 25786209 PMCID: PMC4364772 DOI: 10.1371/journal.pone.0120215] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2014] [Accepted: 01/20/2015] [Indexed: 12/23/2022] Open
Abstract
Obesity is strongly associated with the cause of structural and functional changes of the heart in both human and animal models. Oxidative stress and inflammation play a critical role in the development of obesity-induced cardiac disorders. Curcumin is a natural product from Curcuma Longa with multiple bioactivities. In our previous study, in order to reach better anti-inflammatory and anti-oxidant dual activities, we designed a new mono-carbonyl curcumin analog, Y20, via the structural modification with both trifluoromethyl and bromine. This study was designed to investigate the protective effects of Y20 on obesity-induced cardiac injury and its underlying mechanisms. In high fat diet–fed rats, oral administration of Y20 at 20 mg/kg or curcumin at 50 mg/kg significantly decreased the cardiac inflammation and oxidative stress and eventually improved the cardiac remodeling by mitigating cardiac disorganization, hypertrophy, fibrosis and apoptosis. Y20 at 20 mg/kg showed comparable and even stronger bioactivities than curcumin at 50 mg/kg. The beneficial actions of Y20 are closely associated with its ability to increase Nrf2 expression and inhibit NF-κB activation. Taken together, these results suggest that Y20 may have a great therapeutic potential in the treatment of obesity-induced cardiac injury using Nrf2 and NF-κB as the therapeutic targets for treating obesity-related disorders.
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22
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Pechánová O, Varga ZV, Cebová M, Giricz Z, Pacher P, Ferdinandy P. Cardiac NO signalling in the metabolic syndrome. Br J Pharmacol 2015; 172:1415-33. [PMID: 25297560 PMCID: PMC4369254 DOI: 10.1111/bph.12960] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2014] [Revised: 09/09/2014] [Accepted: 09/28/2014] [Indexed: 02/06/2023] Open
Abstract
It is well documented that metabolic syndrome (i.e. a group of risk factors, such as abdominal obesity, elevated blood pressure, elevated fasting plasma glucose, high serum triglycerides and low cholesterol level in high-density lipoprotein), which raises the risk for heart disease and diabetes, is associated with increased reactive oxygen and nitrogen species (ROS/RNS) generation. ROS/RNS can modulate cardiac NO signalling and trigger various adaptive changes in NOS and antioxidant enzyme expressions/activities. While initially these changes may represent protective mechanisms in metabolic syndrome, later with more prolonged oxidative, nitrosative and nitrative stress, these are often exhausted, eventually favouring myocardial RNS generation and decreased NO bioavailability. The increased oxidative and nitrative stress also impairs the NO-soluble guanylate cyclase (sGC) signalling pathway, limiting the ability of NO to exert its fundamental signalling roles in the heart. Enhanced ROS/RNS generation in the presence of risk factors also facilitates activation of redox-dependent transcriptional factors such as NF-κB, promoting myocardial expression of various pro-inflammatory mediators, and eventually the development of cardiac dysfunction and remodelling. While the dysregulation of NO signalling may interfere with the therapeutic efficacy of conventional drugs used in the management of metabolic syndrome, the modulation of NO signalling may also be responsible for the therapeutic benefits of already proven or recently developed treatment approaches, such as ACE inhibitors, certain β-blockers, and sGC activators. Better understanding of the above-mentioned pathological processes may ultimately lead to more successful therapeutic approaches to overcome metabolic syndrome and its pathological consequences in cardiac NO signalling.
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Affiliation(s)
- O Pechánová
- Institute of Normal and Pathological Physiology and Centre of Excellence for Regulatory Role of Nitric Oxide in Civilization Diseases, Slovak Academy of SciencesBratislava, Slovak Republic
- Faculty of Natural Sciences, Comenius UniversityBratislava, Slovak Republic
| | - Z V Varga
- Cardiometabolic Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis UniversityBudapest, Hungary
| | - M Cebová
- Institute of Normal and Pathological Physiology and Centre of Excellence for Regulatory Role of Nitric Oxide in Civilization Diseases, Slovak Academy of SciencesBratislava, Slovak Republic
| | - Z Giricz
- Cardiometabolic Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis UniversityBudapest, Hungary
| | - P Pacher
- Laboratory of Physiological Studies, National Institutes of Health/NIAAABethesda, MD, USA
| | - P Ferdinandy
- Cardiometabolic Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis UniversityBudapest, Hungary
- Pharmahungary GroupSzeged, Hungary
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23
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Cavalera M, Wang J, Frangogiannis NG. Obesity, metabolic dysfunction, and cardiac fibrosis: pathophysiological pathways, molecular mechanisms, and therapeutic opportunities. Transl Res 2014; 164:323-35. [PMID: 24880146 PMCID: PMC4180761 DOI: 10.1016/j.trsl.2014.05.001] [Citation(s) in RCA: 187] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2014] [Revised: 04/28/2014] [Accepted: 05/03/2014] [Indexed: 02/09/2023]
Abstract
Cardiac fibrosis is strongly associated with obesity and metabolic dysfunction and may contribute to the increased incidence of heart failure, atrial arrhythmias, and sudden cardiac death in obese subjects. This review discusses the evidence linking obesity and myocardial fibrosis in animal models and human patients, focusing on the fundamental pathophysiological alterations that may trigger fibrogenic signaling, the cellular effectors of fibrosis, and the molecular signals that may regulate the fibrotic response. Obesity is associated with a wide range of pathophysiological alterations (such as pressure and volume overload, metabolic dysregulation, neurohumoral activation, and systemic inflammation); their relative role in mediating cardiac fibrosis is poorly defined. Activation of fibroblasts likely plays a major role in obesity-associated fibrosis; however, inflammatory cells, cardiomyocytes, and vascular cells may also contribute to fibrogenic signaling. Several molecular processes have been implicated in regulation of the fibrotic response in obesity. Activation of the renin-angiotensin-aldosterone system, induction of transforming growth factor β, oxidative stress, advanced glycation end-products, endothelin 1, Rho-kinase signaling, leptin-mediated actions, and upregulation of matricellular proteins (such as thrombospondin 1) may play a role in the development of fibrosis in models of obesity and metabolic dysfunction. Moreover, experimental evidence suggests that obesity and insulin resistance profoundly affect the fibrotic and remodeling response after cardiac injury. Understanding the pathways implicated in obesity-associated fibrosis may lead to the development of novel therapies to prevent heart failure and attenuate postinfarction cardiac remodeling in patients with obesity.
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Affiliation(s)
- Michele Cavalera
- Division of Cardiology, Department of Medicine, The Wilf Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, New York
| | - Junhong Wang
- Division of Cardiology, Department of Medicine, The Wilf Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, New York
| | - Nikolaos G Frangogiannis
- Division of Cardiology, Department of Medicine, The Wilf Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, New York.
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24
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Alleman RJ, Katunga LA, Nelson MAM, Brown DA, Anderson EJ. The "Goldilocks Zone" from a redox perspective-Adaptive vs. deleterious responses to oxidative stress in striated muscle. Front Physiol 2014; 5:358. [PMID: 25278906 PMCID: PMC4166897 DOI: 10.3389/fphys.2014.00358] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2014] [Accepted: 09/02/2014] [Indexed: 01/17/2023] Open
Abstract
Consequences of oxidative stress may be beneficial or detrimental in physiological systems. An organ system's position on the “hormetic curve” is governed by the source and temporality of reactive oxygen species (ROS) production, proximity of ROS to moieties most susceptible to damage, and the capacity of the endogenous cellular ROS scavenging mechanisms. Most importantly, the resilience of the tissue (the capacity to recover from damage) is a decisive factor, and this is reflected in the disparate response to ROS in cardiac and skeletal muscle. In myocytes, a high oxidative capacity invariably results in a significant ROS burden which in homeostasis, is rapidly neutralized by the robust antioxidant network. The up-regulation of key pathways in the antioxidant network is a central component of the hormetic response to ROS. Despite such adaptations, persistent oxidative stress over an extended time-frame (e.g., months to years) inevitably leads to cumulative damages, maladaptation and ultimately the pathogenesis of chronic diseases. Indeed, persistent oxidative stress in heart and skeletal muscle has been repeatedly demonstrated to have causal roles in the etiology of heart disease and insulin resistance, respectively. Deciphering the mechanisms that underlie the divergence between adaptive and maladaptive responses to oxidative stress remains an active area of research for basic scientists and clinicians alike, as this would undoubtedly lead to novel therapeutic approaches. Here, we provide an overview of major types of ROS in striated muscle and the divergent adaptations that occur in response to them. Emphasis is placed on highlighting newly uncovered areas of research on this topic, with particular focus on the mitochondria, and the diverging roles that ROS play in muscle health (e.g., exercise or preconditioning) and disease (e.g., cardiomyopathy, ischemia, metabolic syndrome).
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Affiliation(s)
- Rick J Alleman
- Departments of Physiology, East Carolina University Greenville, NC, USA ; East Carolina Diabetes and Obesity Institute, East Carolina University Greenville, NC, USA
| | - Lalage A Katunga
- East Carolina Diabetes and Obesity Institute, East Carolina University Greenville, NC, USA ; Pharmacology and Toxicology, Brody School of Medicine, East Carolina University Greenville, NC, USA
| | - Margaret A M Nelson
- East Carolina Diabetes and Obesity Institute, East Carolina University Greenville, NC, USA ; Pharmacology and Toxicology, Brody School of Medicine, East Carolina University Greenville, NC, USA
| | - David A Brown
- Departments of Physiology, East Carolina University Greenville, NC, USA ; East Carolina Diabetes and Obesity Institute, East Carolina University Greenville, NC, USA
| | - Ethan J Anderson
- East Carolina Diabetes and Obesity Institute, East Carolina University Greenville, NC, USA ; Pharmacology and Toxicology, Brody School of Medicine, East Carolina University Greenville, NC, USA
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Trocha M, Merwid-Ląd A, Chlebda E, Sozański T, Pieśniewska M, Gliniak H, Szeląg A. Influence of ezetimibe on selected parameters of oxidative stress in rat liver subjected to ischemia/reperfusion. Arch Med Sci 2014; 10:817-24. [PMID: 25276169 PMCID: PMC4175761 DOI: 10.5114/aoms.2013.38087] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2011] [Revised: 02/21/2012] [Accepted: 04/01/2012] [Indexed: 12/21/2022] Open
Abstract
INTRODUCTION Ischemia/reperfusion (I/R) is considered to be one of the main causes of liver damage after transplantation. The authors evaluated the effect of ezetimibe on selected oxidative stress parameters in ischemic/reperfused (I/R) rat liver. MATERIAL AND METHODS Rats were administered ezetimibe (5 mg/kg) (groups E and E-I/R) or saline solution (groups C and C-I/R) intragastrically for 21 days. Livers of animals in groups C-I/R and E-I/R were subjected to 60 min of partial ischemia (left lateral and median lobes) followed by 4 h of reperfusion. Alanine and asparagine aminotransferase (ALT, AST) activity was determined in blood before I/R and during reperfusion (at 15 and 240 min). After the reperfusion period, malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH) and glutathione peroxidase (GPx) were determined in liver homogenates using colorimetric methods. RESULTS Ezetimibe caused a significant increase in GSH level in groups subjected to I/R (E-I/R (99.91 ±9.01) vs. C-I/R (90.51 ±8.87), p < 0.05). Additionally, under I/R the decrease of GPx activity in the drug-treated group was lower compared to the non-treated group (E-I/R (3.88 ±1.11) vs. E (5.31 ±1.83), p = 0.076). Neither ezetimibe nor I/R affected SOD or MDA levels. I/R produced a significant increase in aminotransferase levels (ALT240-0: C-I/R (42.23 ±43.56) vs. C (9.75 ±11.09), and E-I/R (39.85 ±26.53) vs. E (4.38 ±1.36), p < 0.05 in both cases; AST 240-0: E-I/R (53.87 ±17.23) vs. E (24.10 ±9.66), p < 0.05) but no effect of ezetimibe on those enzymes was found. CONCLUSIONS Ezetimibe demonstrates antioxidant properties in rat livers subjected to I/R. However, neither a hepatoprotective nor a hepatotoxic effect of ezetimibe was demonstrated, regardless of I/R.
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Affiliation(s)
| | - Anna Merwid-Ląd
- Department of Pharmacology, Wroclaw Medical University, Poland
| | - Ewa Chlebda
- Department of Pharmacology, Wroclaw Medical University, Poland
| | - Tomasz Sozański
- Department of Pharmacology, Wroclaw Medical University, Poland
| | | | - Halina Gliniak
- Department of Pharmacology, Wroclaw Medical University, Poland
| | - Adam Szeląg
- Department of Pharmacology, Wroclaw Medical University, Poland
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Influence of ezetimibe on ADMA-DDAH-NO pathway in rat liver subjected to partial ischemia followed by global reperfusion. Pharmacol Rep 2013; 65:122-33. [PMID: 23563030 DOI: 10.1016/s1734-1140(13)70970-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2011] [Revised: 10/02/2012] [Indexed: 02/04/2023]
Abstract
BACKGROUND We evaluated effect of ezetimibe on selected parameters determining NO level in rat liver subjected to ischemia reperfusion (IR). METHODS Rats received ezetimibe (5 mg/kg) (groups E0 and EIR) or saline solution (groups C0 and CIR) intragastrically for 21 days. Then, the livers of CIR and EIR underwent ischemia (60 min) and reperfusion (4 h). Blood samples were obtained before surgery to estimate activities of aminotransferases, and just before ischemia and during reperfusion to estimate asymmetric and symmetric dimethylarginine (ADMA, SDMA) and arginine (Arg) levels. After IR, dimethylarginine dimethylaminohydrolase (DDAH) activity and endothelial nitric oxide synthase (eNOS) protein concentration were measured in liver homogenates. DDAH and protein arginine methyltransferase (PRMT) mRNA were quantified by real-time PCR in liver tissue samples. RESULTS In CIR, the ADMA level was significantly higher compared to all other groups in 30 min and to E0 group in 120 min of reperfusion. In EIR, ADMA was low, compared to non-ischemic groups. At 30 and 120 min of reperfusion, in non-ischemic groups the level of Arg and Arg/ADMA ratio were significantly higher than in ischemic groups and E0 was the group with the highest levels of those parameters of all. In CIR, eNOS protein concentration was significantly lower than in ezetimibe-treated groups. Activity of DDAH was significantly higher in E0 than in non-treated groups. In ischemic groups, DDAH mRNA expression was significantly higher than in non-ischemic ones and PRMT mRNA expression was significantly higher in C0 than in all other groups. CONCLUSIONS Influence of ezetimibe on ADMA/DDAH/NO pathway demonstrated in this work may suggest protective properties of this drug on rat livers injured by IR and, to a lower extent, on livers non-subjected to IR.
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Abstract
Polytopic transmembrane protein, Niemann-Pick C1-Like 1 (NPC1L1) is localized at the apical membrane of enterocytes and the canalicular membrane of hepatocytes. It mediates intestinal cholesterol absorption and prevents extensive loss of cholesterol by transporting biliary cholesterol into hepatocytes. NPC1L1 is a molecular target of ezetimibe, an agent for hypercholesterolemia. Recently, NPC1L1 inhibition has been shown to prevent metabolic disorders such as fatty liver disease, obesity, diabetes, and atherosclerosis. In this review, the identification and characterization of NPC1L1, NPC1L1-dependent cholesterol transport, the relationship with pathogenesis of metabolic disease and its newly introduced function for virus entry are discussed.
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Affiliation(s)
- Sung-Woo Park
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
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Koka S, Das A, Salloum FN, Kukreja RC. Phosphodiesterase-5 inhibitor tadalafil attenuates oxidative stress and protects against myocardial ischemia/reperfusion injury in type 2 diabetic mice. Free Radic Biol Med 2013; 60:80-8. [PMID: 23385031 DOI: 10.1016/j.freeradbiomed.2013.01.031] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2012] [Revised: 01/04/2013] [Accepted: 01/29/2013] [Indexed: 12/21/2022]
Abstract
Diabetic patients exhibit increased risk for the development of cardiovascular diseases primarily because of impaired nitric oxide (NO) bioavailability. The phosphodiesterase-5 (PDE-5) inhibitor sildenafil restores NO signaling and protects against ischemia/reperfusion (I/R) injury. In this study, we determined the effect of the long-acting PDE-5 inhibitor tadalafil on diabetes-associated complications and its role in attenuating oxidative stress after I/R injury in type 2 diabetic db/db mice. Adult male db/db mice (n=40/group) were randomized to receive dimethyl sulfoxide (10% DMSO, 0.2ml, ip) or tadalafil (1mg/kg in 10% DMSO, ip) for 28 days. After 28 days treatment, the hearts were isolated and subjected to 30min global ischemia followed by 60min reperfusion in the Langendorff mode. Infarct size was measured using computer morphometry of tetrazolium-stained sections. Cardiomyocytes were isolated from a subset of hearts and subjected to 40min simulated ischemia followed by 1h of reoxygenation (SI/RO). Dichlorodihydrofluorescein diacetate and JC-1 staining was used to measure reactive oxygen species (ROS) generation and mitochondrial membrane potential (Δψm), respectively. Another subset of hearts was used for the estimation of lipid peroxidation, glutathione, and the expression of myocardial pRac1, Rac1, gp91(phox), p47(phox), and p67(phox) by Western blot. Tadalafil treatment improved the metabolic status and reduced infarct size compared to the untreated db/db mice (21.2±1.8% vs 45.8±2.8%; p<0.01). The db/db mice showed enhanced oxidative stress in cardiomyocytes as indicated by a significant increase in ROS production. Cardiac NAD(P)H oxidase activity, lipid peroxidation, and oxidized glutathione were also increased in db/db mice compared to nondiabetic control animals. Tadalafil treatment in db/db mice suppressed oxidative stress, attenuated myocardial expression of pRac1 and gp91(phox), and also preserved the loss of Δψm in cardiomyocytes after SI/RO. In conclusion, these results demonstrate that chronic treatment with tadalafil attenuates oxidative stress and improves mitochondrial integrity while providing powerful cardioprotective effects in type 2 diabetes.
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MESH Headings
- Animals
- Apoptosis/drug effects
- Carbolines/administration & dosage
- Cardiotonic Agents/administration & dosage
- Cyclic Nucleotide Phosphodiesterases, Type 5/metabolism
- Diabetes Mellitus, Experimental/drug therapy
- Diabetes Mellitus, Experimental/metabolism
- Diabetes Mellitus, Experimental/pathology
- Diabetes Mellitus, Type 2/drug therapy
- Diabetes Mellitus, Type 2/metabolism
- Diabetes Mellitus, Type 2/physiopathology
- Humans
- Mice
- Mitochondria, Heart/drug effects
- Mitochondria, Heart/pathology
- Myocardial Reperfusion Injury/drug therapy
- Myocardial Reperfusion Injury/pathology
- Myocytes, Cardiac/cytology
- Myocytes, Cardiac/drug effects
- Nitric Oxide/metabolism
- Oxidative Stress/drug effects
- Oxidative Stress/genetics
- Phosphodiesterase 5 Inhibitors/administration & dosage
- Reactive Oxygen Species/metabolism
- Tadalafil
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Affiliation(s)
- Saisudha Koka
- Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University Medical Center, Richmond, VA 23298-0204, USA
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Umemoto T, Subramanian S, Ding Y, Goodspeed L, Wang S, Han CY, Teresa AS, Kim J, O'Brien KD, Chait A. Inhibition of intestinal cholesterol absorption decreases atherosclerosis but not adipose tissue inflammation. J Lipid Res 2012; 53:2380-9. [PMID: 22956784 DOI: 10.1194/jlr.m029264] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Adipose tissue inflammation is associated with insulin resistance and increased cardiovascular disease risk in obesity. We previously showed that addition of cholesterol to a diet rich in saturated fat and refined carbohydrate significantly worsens dyslipidemia, insulin resistance, adipose tissue macrophage accumulation, systemic inflammation, and atherosclerosis in LDL receptor-deficient (Ldlr(-/-)) mice. To test whether inhibition of intestinal cholesterol absorption would improve metabolic abnormalities and adipose tissue inflammation in obesity, we administered ezetimibe, a dietary and endogenous cholesterol absorption inhibitor, to Ldlr(-/-) mice fed chow or high-fat, high-sucrose (HFHS) diets without or with 0.15% cholesterol (HFHS+C). Ezetimibe blunted weight gain and markedly reduced plasma lipids in the HFHS+C group. Ezetimibe had no effect on glucose homeostasis or visceral adipose tissue macrophage gene expression in the HFHS+C fed mice, although circulating inflammatory markers serum amyloid A (SSA) and serum amyloid P (SSP) levels decreased. Nevertheless, ezetimibe treatment led to a striking (>85%) reduction in atherosclerotic lesion area with reduced lesion lipid and macrophage content in the HFHS+C group. Thus, in the presence of dietary cholesterol, ezetimibe did not improve adipose tissue inflammation in obese Ldlr(-/-) mice, but it led to a major reduction in atherosclerotic lesions associated with improved plasma lipids and lipoproteins.
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Affiliation(s)
- Tomio Umemoto
- Division of Metabolism, Endocrinology, and Nutrition, University of Washington, Seattle, WA, USA
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Abstract
Diabetes mellitus is rapidly becoming a global health issue that may overtake cancer during the next two decades as it covertly affects multiple organ systems that goes undiagnosed long after the onset. A number of complications are associated with poorly controlled hyperglycemia. Diabetic nephropathy is one of the most common complications of diabetes mellitus. Other than angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blocker (ARB) there is not much in the armamentarium with which to treat patients with overt diabetic nephropathy. Research points towards a multifactorial etiology and complex interplay of several pathogenic pathways that can contribute to the declining kidney function in diabetes. Patients with diabetic nephropathy (and with any chronic kidney disease) eventually develop kidney fibrosis. Despite the financial and labor investment spent on determining the basic mechanism of fibrosis, not much progress has been made in terms of therapeutic targets available to us today. This may be in part due to paucity in the experimental animal models available. However, there now seems to be a concerted effort from several pharmaceutical companies to develop a drug that would halt/delay the process of fibrosis, if not reverse it. This review discusses the current state of research in the field while staying within the context of diabetic nephropathy.
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Affiliation(s)
- Anil Karihaloo
- Section of Nephrology, Yale University School of Medicine, New Haven, CT 06520, USA.
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Naples M, Baker C, Lino M, Iqbal J, Hussain MM, Adeli K. Ezetimibe ameliorates intestinal chylomicron overproduction and improves glucose tolerance in a diet-induced hamster model of insulin resistance. Am J Physiol Gastrointest Liver Physiol 2012; 302:G1043-52. [PMID: 22345552 PMCID: PMC4380478 DOI: 10.1152/ajpgi.00250.2011] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Ezetimibe is a cholesterol uptake inhibitor that targets the Niemann-Pick C1-like 1 cholesterol transporter. Ezetimibe treatment has been shown to cause significant decreases in plasma cholesterol levels in patients with hypercholesterolemia and familial hypercholesterolemia. A recent study in humans has shown that ezetimibe can decrease the release of atherogenic postprandial intestinal lipoproteins. In the present study, we evaluated the mechanisms by which ezetimibe treatment can lower postprandial apoB48-containing chylomicron particles, using a hyperlipidemic and insulin-resistant hamster model fed a diet rich in fructose and fat (the FF diet) and fructose, fat, and cholesterol (the FFC diet). Male Syrian Golden hamsters were fed either chow or the FF or FFC diet ± ezetimibe for 2 wk. After 2 wk, chylomicron production was assessed following intravenous triton infusion. Tissues were then collected and analyzed for protein and mRNA content. FFC-fed hamsters treated with ezetimibe showed improved glucose tolerance, decreased fasting insulin levels, and markedly reduced circulating levels of TG and cholesterol in both the LDL and VLDL fractions. Examination of triglyceride (TG)-rich lipoprotein (TRL) fractions showed that ezetimibe treatment reduced postprandial cholesterol content in TRL lipoproteins as well as reducing apoB48 content. Although ezetimibe did not decrease TRL-TG levels in FFC hamsters, ezetimibe treatment in FF hamsters resulted in decreases in TRL-TG. Jejunal apoB48 protein expression was lower in ezetimibe-treated hamsters. Reductions in jejunal protein levels of scavenger receptor type B-1 (SRB-1) and fatty acid transport protein 4 were also observed. In addition, ezetimibe-treated hamsters showed significantly lower jejunal mRNA expression of a number of genes involved in lipid synthesis and transport, including srebp-1c, sr-b1, ppar-γ, and abcg1. These data suggest that treatment with ezetimibe not only inhibits cholesterol uptake, but may also alter intestinal function to promote improved handling of dietary lipids and reduced chylomicron production. These, in turn, promote decreases in fasting and postprandial lipid levels and improvements in glucose homeostasis.
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Affiliation(s)
- Mark Naples
- 1Molecular Structure and Function, Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, Canada;
| | - Chris Baker
- 1Molecular Structure and Function, Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, Canada;
| | - Marsel Lino
- 1Molecular Structure and Function, Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, Canada;
| | | | | | - Khosrow Adeli
- 1Molecular Structure and Function, Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, Canada;
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Kotani K, Caccavello R, Sakane N, Miyamoto M, Gugliucci A. Influence of ezetimibe monotherapy on ischemia-modified albumin levels in hypercholesterolemic patients. Pharmacol Rep 2012; 63:1248-51. [PMID: 22180369 DOI: 10.1016/s1734-1140(11)70646-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2011] [Revised: 06/21/2011] [Indexed: 10/25/2022]
Abstract
Ischemia-modified albumin (IMA) is considered to be a novel biochemical marker for ischemic and atherosclerotic conditions. This study aimed to investigate the influence of ezetimibe monotherapy on circulating IMA levels in hypercholesterolemic patients. A total of 31 patients (mean age 65.7 years) received 10 mg of ezetimibe daily during a 12-week treatment period. The levels of low-density lipoprotein cholesterol and IMA were significantly reduced after ezetimibe treatment. The adjusted regression analyses revealed that the changes in the IMA levels were not significantly correlated with those of the other atherosclerotic risk markers, such as body mass index, blood pressure, glucose and lipid panels. The significant reduction of the IMA levels following ezetimibe treatment, which was independent of the reduction of low-density lipoprotein cholesterol levels, suggests that ezetimibe may improve the oxidative stress burden in hypercholesterolemic patients.
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Affiliation(s)
- Kazuhiko Kotani
- Division of Preventive Medicine, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, Kyoto 612-8555, Japan.
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Tamaki N, Ueno H, Morinaga Y, Shiiya T, Nakazato M. Ezetimibe Ameliorates Atherosclerotic and Inflammatory Markers, Atherogenic Lipid Profiles, Insulin Sensitivity, and Liver Dysfunction in Japanese Patients with Hypercholesterolemia. J Atheroscler Thromb 2012; 19:532-8. [DOI: 10.5551/jat.10835] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
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Kotani K, Sakane N, Taniguchi N. Effect of ezetimibe on remnant-like particle cholesterol in subjects with metabolic syndrome. Med Princ Pract 2012; 21:134-8. [PMID: 22024552 DOI: 10.1159/000332436] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2011] [Accepted: 06/22/2011] [Indexed: 11/19/2022] Open
Abstract
OBJECTIVE To investigate the influence of ezetimibe monotherapy on remnant-like particle cholesterol (RLP-C) in subjects with metabolic syndrome (MetS). MATERIALS AND METHODS Ezetimibe (10 mg/daily) was prescribed over a 12-week period for hypercholesterolemic subjects divided into groups with MetS (n = 28; male/female = 13/15; mean age 67 years) and without MetS (n = 22; male/female = 9/13; mean age 66 years). In the pre- and post-treatment phases, BMI, blood pressure and fasting blood levels of glucose, lipid panels and RLP-C were measured. RESULTS The group with MetS showed significantly higher RLP-C levels than the group without MetS [median level: 0.18 vs. 0.12 mmol/l (7.1 vs. 4.4 mg/dl), p < 0.01] in the pre-treatment phase. In the post-treatment phase, the low-density lipoprotein cholesterol levels were significantly reduced in both groups to a similar level (p < 0.001 in both), while there was a significantly greater reduction in RLP-C in the group with MetS than the group without MetS [median level: 0.12 vs. 0.11 mmol/l (4.8 vs. 4.1 mg/dl), p < 0.05]. This difference in RLP-C remained significant after adjusting for confounding factors. CONCLUSION Ezetimibe monotherapy may be associated with a greater reduction in RLP-C levels in subjects with MetS than in those without MetS.
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Affiliation(s)
- Kazuhiko Kotani
- Department of Preventive Medicine and Diabetes Education, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, Kyoto, Japan.
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Current world literature. Curr Opin Lipidol 2011; 22:231-6. [PMID: 21562387 DOI: 10.1097/mol.0b013e328347aeca] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Kurobe H, Aihara KI, Higashida M, Hirata Y, Nishiya M, Matsuoka Y, Kanbara T, Nakayama T, Kinoshita H, Sugano M, Fujimoto E, Kurobe A, Sugasawa N, Kitaichi T, Akaike M, Sata M, Matsumoto T, Kitagawa T. Ezetimibe Monotherapy Ameliorates Vascular Function in Patients with Hypercholesterolemia Through Decreasing Oxidative Stress. J Atheroscler Thromb 2011; 18:1080-9. [DOI: 10.5551/jat.9548] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
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Hur J, Sullivan KA, Schuyler AD, Hong Y, Pande M, States DJ, Jagadish HV, Feldman EL. Literature-based discovery of diabetes- and ROS-related targets. BMC Med Genomics 2010; 3:49. [PMID: 20979611 PMCID: PMC2988702 DOI: 10.1186/1755-8794-3-49] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2010] [Accepted: 10/27/2010] [Indexed: 12/13/2022] Open
Abstract
Background Reactive oxygen species (ROS) are known mediators of cellular damage in multiple diseases including diabetic complications. Despite its importance, no comprehensive database is currently available for the genes associated with ROS. Methods We present ROS- and diabetes-related targets (genes/proteins) collected from the biomedical literature through a text mining technology. A web-based literature mining tool, SciMiner, was applied to 1,154 biomedical papers indexed with diabetes and ROS by PubMed to identify relevant targets. Over-represented targets in the ROS-diabetes literature were obtained through comparisons against randomly selected literature. The expression levels of nine genes, selected from the top ranked ROS-diabetes set, were measured in the dorsal root ganglia (DRG) of diabetic and non-diabetic DBA/2J mice in order to evaluate the biological relevance of literature-derived targets in the pathogenesis of diabetic neuropathy. Results SciMiner identified 1,026 ROS- and diabetes-related targets from the 1,154 biomedical papers (http://jdrf.neurology.med.umich.edu/ROSDiabetes/). Fifty-three targets were significantly over-represented in the ROS-diabetes literature compared to randomly selected literature. These over-represented targets included well-known members of the oxidative stress response including catalase, the NADPH oxidase family, and the superoxide dismutase family of proteins. Eight of the nine selected genes exhibited significant differential expression between diabetic and non-diabetic mice. For six genes, the direction of expression change in diabetes paralleled enhanced oxidative stress in the DRG. Conclusions Literature mining compiled ROS-diabetes related targets from the biomedical literature and led us to evaluate the biological relevance of selected targets in the pathogenesis of diabetic neuropathy.
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Affiliation(s)
- Junguk Hur
- Bioinformatics Program, University of Michigan, Ann Arbor, MI 48109, USA
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