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Bhullar SK, Shah AK, Dhalla NS. Role of angiotensin II in the development of subcellular remodeling
in heart failure. EXPLORATION OF MEDICINE 2021. [DOI: 10.37349/emed.2021.00054] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
The development of heart failure under various pathological conditions such as myocardial infarction (MI), hypertension and diabetes are accompanied by adverse cardiac remodeling and cardiac dysfunction. Since heart function is mainly determined by coordinated activities of different subcellular organelles including sarcolemma, sarcoplasmic reticulum, mitochondria and myofibrils for regulating the intracellular concentration of Ca2+, it has been suggested that the occurrence of heart failure is a consequence of subcellular remodeling, metabolic alterations and Ca2+-handling abnormalities in cardiomyocytes. Because of the elevated plasma levels of angiotensin II (ANG II) due to activation of the renin-angiotensin system (RAS) in heart failure, we have evaluated the effectiveness of treatments with angiotensin converting enzyme (ACE) inhibitors and ANG II type 1 receptor (AT1R) antagonists in different experimental models of heart failure. Attenuation of marked alterations in subcellular activities, protein content and gene expression were associated with improvement in cardiac function in MI-induced heart failure by treatment with enalapril (an ACE inhibitor) or losartan (an AT1R antagonist). Similar beneficial effects of ANG II blockade on subcellular remodeling and cardiac performance were also observed in failing hearts due to pressure overload, volume overload or chronic diabetes. Treatments with enalapril and losartan were seen to reduce the degree of RAS activation as well as the level of oxidative stress in failing hearts. These observations provide evidence which further substantiate to support the view that activation of RAS and high level of plasma ANG II play a critical role in inducing subcellular defects and cardiac dys-function during the progression of heart failure.
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Affiliation(s)
- Sukhwinder K. Bhullar
- Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, University of Manitoba, Winnipeg, Manitoba R2H 2A6, Canada
| | - Anureet K. Shah
- School of Kinesiology, Nutrition and Food Science, California State University, Los Angeles, CA 90032, USA
| | - Naranjan S. Dhalla
- Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, University of Manitoba, Winnipeg, Manitoba R2H 2A6, Canada; Department of Physiology and Pathophysiology, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba R3E 3P5, Canada
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Role of Oxidative Stress in Metabolic and Subcellular Abnormalities in Diabetic Cardiomyopathy. Int J Mol Sci 2020; 21:ijms21072413. [PMID: 32244448 PMCID: PMC7177292 DOI: 10.3390/ijms21072413] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Revised: 03/17/2020] [Accepted: 03/29/2020] [Indexed: 01/16/2023] Open
Abstract
Although the presence of cardiac dysfunction and cardiomyopathy in chronic diabetes has been recognized, the pathophysiology of diabetes-induced metabolic and subcellular changes as well as the therapeutic approaches for the prevention of diabetic cardiomyopathy are not fully understood. Cardiac dysfunction in chronic diabetes has been shown to be associated with Ca2+-handling abnormalities, increase in the availability of intracellular free Ca2+ and impaired sensitivity of myofibrils to Ca2+. Metabolic derangements, including depressed high-energy phosphate stores due to insulin deficiency or insulin resistance, as well as hormone imbalance and ultrastructural alterations, are also known to occur in the diabetic heart. It is pointed out that the activation of the sympathetic nervous system and renin-angiotensin system generates oxidative stress, which produces defects in subcellular organelles including sarcolemma, sarcoplasmic reticulum and myofibrils. Such subcellular remodeling plays a critical role in the pathogenesis of diabetic cardiomyopathy. In fact, blockade of the effects of neurohormonal systems has been observed to attenuate oxidative stress and occurrence of subcellular remodeling as well as metabolic abnormalities in the diabetic heart. This review is intended to describe some of the subcellular and metabolic changes that result in cardiac dysfunction in chronic diabetes. In addition, the therapeutic values of some pharmacological, metabolic and antioxidant interventions will be discussed. It is proposed that a combination therapy employing some metabolic agents or antioxidants with insulin may constitute an efficacious approach for the prevention of diabetic cardiomyopathy.
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Vijayakumar S, Vaduganathan M, Butler J. Exploring heart failure events in contemporary cardiovascular outcomes trials in type 2 diabetes mellitus. Expert Rev Cardiovasc Ther 2018; 16:123-131. [PMID: 29298108 DOI: 10.1080/14779072.2018.1423962] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
INTRODUCTION Type 2 diabetes mellitus (DM) and heart failure (HF) are closely related, with the onset of one serving as an independent risk factor for the development or progression of the other. The true impact of their relationship is poorly understood. Since various classes of glucose-lowering therapies have been shown to have differing impact on cardiovascular outcomes, cardiovascular effects of such therapies have been increasingly formally evaluated. Areas covered: With the increasing prevalence of concomitant HF and type 2 DM, HF outcomes serve as important endpoints in trials of glucose-lowering therapies. A thorough literature search of recent cardiovascular outcome trials of glucose-lowering therapies was performed. The authors focus on the availability and extent of ascertainment of data related to HF outcomes in these contemporary clinical trial experiences. Expert commentary: Although early cardiovascular outcome trials did not focus on HF events, these outcomes have been increasingly recognized as meaningful end points in cardiovascular outcome trials. The ascertainment of HF end point data needs to become routine and standardized.
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Affiliation(s)
- Shilpa Vijayakumar
- a Department of Medicine , Stony Brook University , Stony Brook , NY , USA
| | - Muthiah Vaduganathan
- b Brigham and Women's Hospital Heart & Vascular Center, Harvard Medical School , Boston , MA , USA
| | - Javed Butler
- c Division of Cardiology , Stony Brook University , Stony Brook , NY , USA
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Liu JH, Chen Y, Zhen Z, Ho LM, Tsang A, Yuen M, Lam K, Tse HF, Yiu KH. Relationship of biomarkers of extracellular matrix with myocardial function in Type 2 diabetes mellitus. Biomark Med 2017; 11:569-578. [PMID: 28685602 DOI: 10.2217/bmm-2017-0044] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
AIM The study evaluated the relationship of extracellular matrix and renin angiotensin system with myocardial dysfunction in Type 2 diabetes mellitus. METHODS All patients underwent resting and exercise echocardiography, including conventional parameters, E/E' ratio, global longitudinal strain and diastolic function reserve index. Plasma matrix metalloproteinase-1, TIMP-1, amino-terminal propeptide of type I and type III procollagen and renin angiotensin system activity were measured. RESULTS As patients with diastolic dysfunction had a higher plasma level of TIMP-1 and propeptide of type III procollagen than those with no diastolic dysfunction. After multivariate adjustment, TIMP-1 associated with E/E' (both at rest and stress) and diastolic function reserve index. CONCLUSION TIMP-1 is independently associated with myocardial diastolic dysfunction in patients with Type 2 diabetes mellitus.
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Affiliation(s)
- Ju-Hua Liu
- Division of Cardiology, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China.,Department of Medicine, Affiliated Hospital of North Sichuan Medical College, Nanchong City, Sichuan Province, China
| | - Yan Chen
- Division of Cardiology, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | - Zhe Zhen
- Division of Cardiology, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | - Lai-Ming Ho
- School of Public Health, The University of Hong Kong, Hong Kong, China
| | - Anita Tsang
- Division of Cardiology, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | - Michele Yuen
- Division of Endocrinology, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | - Karen Lam
- Division of Endocrinology, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China.,Research Centre of Heart, Brain, Hormone & Healthy Aging, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Hung-Fat Tse
- Division of Cardiology, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China.,Research Centre of Heart, Brain, Hormone & Healthy Aging, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Kai-Hang Yiu
- Division of Cardiology, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China.,Research Centre of Heart, Brain, Hormone & Healthy Aging, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
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5
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Kain V, Halade GV. Metabolic and Biochemical Stressors in Diabetic Cardiomyopathy. Front Cardiovasc Med 2017; 4:31. [PMID: 28620607 PMCID: PMC5449449 DOI: 10.3389/fcvm.2017.00031] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2017] [Accepted: 04/28/2017] [Indexed: 12/18/2022] Open
Abstract
Diabetic cardiomyopathy (DCM) or diabetes-induced cardiac dysfunction is a direct consequence of uncontrolled metabolic syndrome and is widespread in US population and worldwide. Despite of the heterogeneous and distinct features of DCM, the clinical relevance of DCM is now becoming established. DCM progresses to pathological cardiac remodeling with the higher risk of heart attack and subsequent heart failure in diabetic patients. In this review, we emphasize lipid substrate quality and the phenotypic, metabolic, and biochemical stressors of DCM in the rodent and human pathophysiology. We discuss lipoxygenase signaling in the inflammatory pathway with multiple contributing and confounding factors leading to DCM. Additionally, emerging biochemical pathways are emphasized to make progress toward therapeutic advancement to treat DCM.
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Affiliation(s)
- Vasundhara Kain
- Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Ganesh V Halade
- Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
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Properties of Na,K-ATPase in cerebellum of male and female rats: effects of acute and prolonged diabetes. Mol Cell Biochem 2016; 425:25-36. [DOI: 10.1007/s11010-016-2859-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Accepted: 10/22/2016] [Indexed: 02/07/2023]
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Xiang L, Mittwede PN, Clemmer JS. Glucose Homeostasis and Cardiovascular Alterations in Diabetes. Compr Physiol 2015; 5:1815-39. [PMID: 26426468 DOI: 10.1002/cphy.c150001] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Waddingham MT, Edgley AJ, Tsuchimochi H, Kelly DJ, Shirai M, Pearson JT. Contractile apparatus dysfunction early in the pathophysiology of diabetic cardiomyopathy. World J Diabetes 2015; 6:943-960. [PMID: 26185602 PMCID: PMC4499528 DOI: 10.4239/wjd.v6.i7.943] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2014] [Revised: 12/30/2014] [Accepted: 03/09/2015] [Indexed: 02/05/2023] Open
Abstract
Diabetes mellitus significantly increases the risk of cardiovascular disease and heart failure in patients. Independent of hypertension and coronary artery disease, diabetes is associated with a specific cardiomyopathy, known as diabetic cardiomyopathy (DCM). Four decades of research in experimental animal models and advances in clinical imaging techniques suggest that DCM is a progressive disease, beginning early after the onset of type 1 and type 2 diabetes, ahead of left ventricular remodeling and overt diastolic dysfunction. Although the molecular pathogenesis of early DCM still remains largely unclear, activation of protein kinase C appears to be central in driving the oxidative stress dependent and independent pathways in the development of contractile dysfunction. Multiple subcellular alterations to the cardiomyocyte are now being highlighted as critical events in the early changes to the rate of force development, relaxation and stability under pathophysiological stresses. These changes include perturbed calcium handling, suppressed activity of aerobic energy producing enzymes, altered transcriptional and posttranslational modification of membrane and sarcomeric cytoskeletal proteins, reduced actin-myosin cross-bridge cycling and dynamics, and changed myofilament calcium sensitivity. In this review, we will present and discuss novel aspects of the molecular pathogenesis of early DCM, with a special focus on the sarcomeric contractile apparatus.
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Kaločayová B, Mézešová L, Barteková M, Vlkovičová J, Jendruchová V, Vrbjar N. Effect of duration of diabetes mellitus type 1 on properties of Na, K-ATPase in cerebral cortex. Mol Cell Biochem 2015; 405:41-52. [DOI: 10.1007/s11010-015-2394-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2014] [Accepted: 03/27/2015] [Indexed: 01/28/2023]
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Dhalla NS, Takeda N, Rodriguez-Leyva D, Elimban V. Mechanisms of subcellular remodeling in heart failure due to diabetes. Heart Fail Rev 2014; 19:87-99. [PMID: 23436108 DOI: 10.1007/s10741-013-9385-8] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Diabetic cardiomyopathy is not only associated with heart failure but there also occurs a loss of the positive inotropic effect of different agents. It is now becoming clear that cardiac dysfunction in chronic diabetes is intimately involved with Ca(2+)-handling abnormalities, metabolic defects and impaired sensitivity of myofibrils to Ca(2+) in cardiomyocytes. On the other hand, loss of the inotropic effect in diabetic myocardium is elicited by changes in signal transduction mechanisms involving hormone receptors and depressions in phosphorylation of various membrane proteins. Ca(2+)-handling abnormalities in the diabetic heart occur mainly due to defects in sarcolemmal Na(+)-K(+) ATPase, Na(+)-Ca(2+) exchange, Na(+)-H(+) exchange, Ca(2+)-channels and Ca(2+)-pump activities as well as changes in sarcoplasmic reticular Ca(2+)-uptake and Ca(2+)-release processes; these alterations may lead to the occurrence of intracellular Ca(2+) overload. Metabolic defects due to insulin deficiency or ineffectiveness as well as hormone imbalance in diabetes are primarily associated with a shift in substrate utilization and changes in the oxidation of fatty acids in cardiomyocytes. Mitochondria initially seem to play an adaptive role in serving as a Ca(2+) sink, but the excessive utilization of long-chain fatty acids for a prolonged period results in the generation of oxidative stress and impairment of their function in the diabetic heart. In view of the activation of sympathetic nervous system and renin-angiotensin system as well as platelet aggregation, endothelial dysfunction and generation of oxidative stress in diabetes and blockade of their effects have been shown to attenuate subcellular remodeling, metabolic derangements and signal transduction abnormalities in the diabetic heart. On the basis of these observations, it is suggested that oxidative stress and subcellular remodeling due to hormonal imbalance and metabolic defects play a critical role in the genesis of heart failure during the development of diabetic cardiomyopathy.
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Affiliation(s)
- Naranjan S Dhalla
- Department of Physiology, Faculty of Medicine, Institute of Cardiovascular Sciences, St. Boniface Hospital Research, University of Manitoba, 351 Tache Avenue, Winnipeg, MB, R2H 2A6, Canada,
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Abstract
Although heart disease due to diabetes is mainly associated with complications of the large vessels, microvascular abnormalities are also considered to be involved in altering cardiac structure and function. Three major defects, such as endothelial dysfunction, alteration in the production/release of hormones, and shift in metabolism of smooth muscle cells, have been suggested to produce damage to the small arteries and capillaries (microangiopathy) due to hyperglycemia, and promote the development of diabetic cardiomyopathy. These factors may either act alone or in combination to produce oxidative stress as well as changes in cellular signaling and gene transcription, which in turn cause vasoconstriction and structural remodeling of the coronary vessels. Such alterations in microvasculature produce hypoperfusion of the myocardium and thereby lower the energy status resulting in changes in Ca(2+)-handling, apoptosis, and decreased cardiac contractile force. This article discusses diabetes-induced mechanisms of microvascular damage leading to cardiac dysfunction that is characterized by myocardial dilatation, cardiac hypertrophy as well as early diastolic and late systolic defects. Metabolic defects and changes in neurohumoral system due to diabetes, which promote disturbances in vascular homeostasis, are highlighted. In addition, increase in the vulnerability of the diabetic heart to the development of heart failure and the signaling pathways integrating nuclear factor κB and protein kinase C in diabetic cardiomyopathy are also described for comparison.
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Affiliation(s)
- Adriana Adameova
- Institute of Cardiovascular Sciences, Department of Physiology, Faculty of Medicine, University of Manitoba, St. Boniface Hospital Research, 351 Tache Avenue, Winnipeg, MB, R2H 2A6, Canada
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Dei Cas A, Fonarow GC, Gheorghiade M, Butler J. Concomitant diabetes mellitus and heart failure. Curr Probl Cardiol 2014; 40:7-43. [PMID: 25499908 DOI: 10.1016/j.cpcardiol.2014.09.002] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The prevalence of patients with concomitant diabetes mellitus (DM) and heart failure (HF) is growing exponentially. Patients with HF and DM show specific metabolic, neurohormonal, and structural heart abnormalities, which potentially contribute to worse HF outcomes than seen in patients without comorbid DM. Subgroup analysis of recent trials suggest that patients with HF and DM may respond differently to standard therapy, and data are emerging on the possible increase in the risk of hospitalizations for HF in patients with DM treated with specific class of antidiabetic agents, pointing to the need of developing specific medications to be tested in dedicated future studies to address the unique metabolic and hemodynamic alterations seen in these patients.
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Falcão-Pires I, Leite-Moreira AF. Diabetic cardiomyopathy: understanding the molecular and cellular basis to progress in diagnosis and treatment. Heart Fail Rev 2013; 17:325-44. [PMID: 21626163 DOI: 10.1007/s10741-011-9257-z] [Citation(s) in RCA: 267] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Diabetes mellitus is an important and prevalent risk factor for congestive heart failure. Diabetic cardiomyopathy has been defined as ventricular dysfunction that occurs in diabetic patients independent of a recognized cause such as coronary artery disease or hypertension. The disease course consists of a hidden subclinical period, during which cellular structural insults and abnormalities lead initially to diastolic dysfunction, later to systolic dysfunction, and eventually to heart failure. Left ventricular hypertrophy, metabolic abnormalities, extracellular matrix changes, small vessel disease, cardiac autonomic neuropathy, insulin resistance, oxidative stress, and apoptosis are the most important contributors to diabetic cardiomyopathy onset and progression. Hyperglycemia is a major etiological factor in the development of diabetic cardiomyopathy. It increases the levels of free fatty acids and growth factors and causes abnormalities in substrate supply and utilization, calcium homeostasis, and lipid metabolism. Furthermore, it promotes excessive production and release of reactive oxygen species, which induces oxidative stress leading to abnormal gene expression, faulty signal transduction, and cardiomyocytes apoptosis. Stimulation of connective tissue growth factor, fibrosis, and the formation of advanced glycation end-products increase the stiffness of the diabetic hearts. Despite all the current information on diabetic cardiomyopathy, translational research is still scarce due to limited human myocardial tissue and most of our knowledge is extrapolated from animals. This paper aims to elucidate some of the molecular and cellular pathophysiologic mechanisms, structural changes, and therapeutic strategies that may help struggle against diabetic cardiomyopathy.
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Affiliation(s)
- Inês Falcão-Pires
- Department of Physiology and Cardiothoracic Surgery, Cardiovascular R&D Unit, University of Porto, Porto, Portugal
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14
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Interaction of diabetes and ACE2 in the pathogenesis of cardiovascular disease in experimental diabetes. Clin Sci (Lond) 2012; 123:519-29. [DOI: 10.1042/cs20110668] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Local and systemic AngII (angiotensin II) levels are regulated by ACE2 (angiotensin-converting enzyme 2), which is reduced in diabetic tissues. In the present study, we examine the effect of ACE2 deficiency on the early cardiac and vascular changes associated with experimental diabetes. Streptozotocin diabetes was induced in male C57BL6 mice and Ace2-KO (knockout) mice, and markers of RAS (renin–angiotensin system) activity, cardiac function and injury were assessed after 10 weeks. In a second protocol, diabetes was induced in male ApoE (apolipoprotein E)-KO mice and ApoE/Ace2-double-KO mice, and plaque accumulation and markers of atherogenesis assessed after 20 weeks. The induction of diabetes in wild-type mice led to reduced ACE2 expression and activity in the heart, elevated circulating AngII levels and reduced cardiac Ang-(1–7) [angiotensin-(1–7)] levels. This was associated structurally with thinning of the LV (left ventricular) wall and mild ventricular dilatation, and histologically with increased cardiomyocyte apoptosis on TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling) staining and compensatory hypertrophy denoted by an increased cardiomyocyte cross-sectional area. By contrast Ace2-KO mice failed to increase circulating AngII concentration, experienced a paradoxical fall in cardiac AngII levels and no change in Ang-(1–7) following the onset of diabetes. At the same time the major phenotypic differences between Ace2-deficient and Ace2-replete mice with respect to BP (blood pressure) and cardiac hypertrophy were eliminated following the induction of diabetes. Consistent with findings in the heart, the accelerated atherosclerosis that was observed in diabetic ApoE-KO mice was not seen in diabetic ApoE/Ace2-KO mice, which experienced no further increase in plaque accumulation or expression in key adhesion molecules beyond that seen in ApoE/Ace2-KO mice. These results point to the potential role of ACE2 deficiency in regulating the tissue and circulating levels of AngII and their sequelae in the context of diabetes, as well as the preservation or augmentation of ACE2 expression or activity as a potential therapeutic target for the prevention of CVD (cardiovascular disease) in diabetes.
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Zhang X, Chen C. A new insight of mechanisms, diagnosis and treatment of diabetic cardiomyopathy. Endocrine 2012; 41:398-409. [PMID: 22322947 DOI: 10.1007/s12020-012-9623-1] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2011] [Accepted: 01/28/2012] [Indexed: 12/25/2022]
Abstract
Diabetes mellitus is one of the most common chronic diseases across the world. Cardiovascular complication is the major morbidity and mortality among the diabetic patients. Diabetic cardiomyopathy, a new entity independent of coronary artery disease or hypertension, has been increasingly recognized by clinicians and epidemiologists. Cardiac dysfunction is the major characteristic of diabetic cardiomyopathy. For a better understanding of diabetic cardiomyopathy and necessary treatment strategy, several pathological mechanisms such as impaired calcium handling and increased oxidative stress, have been proposed through clinical and experimental observations. In this review, we will discuss the development of cardiac dysfunction, the mechanisms underlying diabetic cardiomyopathy, diagnostic methods, and treatment options.
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Affiliation(s)
- Xinli Zhang
- School of Biomedical Sciences, University of Queensland, Room 409A, Sir William MacGregor Building (64), St Lucia Campus, Brisbane, QLD 4072, Australia
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Tarquini R, Lazzeri C, Pala L, Rotella CM, Gensini GF. The diabetic cardiomyopathy. Acta Diabetol 2011; 48:173-81. [PMID: 20198391 DOI: 10.1007/s00592-010-0180-x] [Citation(s) in RCA: 120] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2009] [Accepted: 02/11/2010] [Indexed: 12/11/2022]
Abstract
Diabetic cardiomyopathy has been defined as "a distinct entity characterized by the presence of abnormal myocardial performance or structure in the absence of epicardial coronary artery disease, hypertension, and significant valvular disease". The diagnosis stems from the detection of myocardial abnormalities and the exclusion of other contributory causes of cardiomyopathy. It rests on non-invasive imaging techniques which can demonstrate myocardial dysfunction across the spectra of clinical presentation. The presence of diabetes is associated with an increased risk of developing heart failure, and the 75% of patients with unexplained idiopathic dilated cardiomyopathy were found to be diabetic. Diabetic patients with microvascular complications show the strongest association between diabetes and cardiomyopathy, an association that parallels the duration and severity of hyperglycemia. Metabolic abnormalities (that is hyperglycemia, hyperinsulinemia, and hyperlipemia) can lead to the cellular alterations characterizing diabetic cardiomyopathy (that is myocardial fibrosis and/or myocardial hypertrophy) directly or indirectly (that is by means of renin-angiotensin system activation, cardiac autonomic neuropathy, alterations in calcium homeostasis). Moreover, metabolic abnormalities represent, on a clinical ground, the main therapeutic target in the patients with diabetes since the diagnosis of diabetes is made. Since diabetic cardiomyopathy is highly prevalent in the asymptomatic type 2 diabetic patients, screening for its presence at the earliest stage of development can lead to prevent the progression to chronic heart failure. The most sensitive test is standard echocardiogram, while a less expensive pre-screening method is the detection of microalbuminuria.
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Affiliation(s)
- Roberto Tarquini
- Department of Internal Medicine, Azienda Ospedaliero-Universitaria Careggi, University of Florence, Italy.
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Goyal RK, Elimban V, Xu YJ, Kumamoto H, Takeda N, Dhalla NS. Mechanism of sarpogrelate action in improving cardiac function in diabetes. J Cardiovasc Pharmacol Ther 2010; 16:380-7. [PMID: 21183729 DOI: 10.1177/1074248410384708] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Although sarpogrelate, a 5-HT(2A) receptor antagonist, has been reported to exert beneficial effects in diabetes, the mechanisms of its action are not understood. In this study, diabetes was induced in rats by an injection of streptozotocin (65 mg/kg) and the animals were assessed 7 weeks later. Decreased serum insulin as well as increased serum glucose, cholesterol, and triglyceride levels in diabetic animals were associated with increased blood pressure and heart/body weight ratio. Impaired cardiac performance in diabetic animals was evident by decreased heart rate, left ventricular developed pressure, rate of pressure development, and rate of pressure decay. Treatment of diabetic animals with sarpogrelate (5 mg/kg) or insulin (10 units/kg) daily for 6 weeks attenuated the observed changes in serum insulin, glucose, and lipid levels as well as blood pressure and cardiac function by varying degrees. Protein content for membrane glucose transporters (GLUT-1 and GLUT-4) was depressed in diabetic heart; the observed alteration in GLUT-4 was partially prevented by both sarpogrelate and insulin, whereas that in GLUT-1 was attenuated by sarpogrelate only. Incubation of myoblast cells with sarpogrelate and insulin stimulated glucose uptake; these effects were additive. 5-hydroxytryptamine was found to inhibit glucose-induced insulin release from the pancreas; this effect was prevented by sarpogrelate. These results suggest that sarpogrelate may improve cardiac function in chronic diabetes by promoting the expression of membrane glucose transporters as well as by releasing insulin from the pancreas.
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Affiliation(s)
- Ramesh K Goyal
- Institute of Cardiovascular Sciences, St Boniface General Hospital Research Center, University of Manitoba, Winnipeg, Manitoba, Canada
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Prevention of myocardial fibrosis by N-acetyl-seryl-aspartyl-lysyl-proline in diabetic rats. Clin Sci (Lond) 2009; 118:211-20. [PMID: 20310083 DOI: 10.1042/cs20090234] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Ac-SDKP (N-acetyl-seryl-aspartyl-lysyl-proline) is a physiological tetrapeptide hydrolysed by ACE (angiotensin-converting enzyme). In experimental models of hypertension, Ac-SDKP has antifibrotic effects in the heart; however, the role of Ac-SDKP in diabetic cardiomyopathy is currently unknown. The aim of the present study was to evaluate the effect of Ac-SDKP on cardiac systolic and diastolic function, and interstitial and perivascular fibrosis in the heart of diabetic rats.Diabetes was induced in 55 Sprague-Dawley rats by streptozotocin injection. Control rats (n=18)underwent only buffer injection.Out of the 55 diabetic rats, 19 were chronically treated with insulin and 13 with the ACEI (ACE inhibitor) ramipril (3 mg x kg(-1 )of body weight x day(-1)). At 2 months after the onset of diabetes, Ac-SDKP (1 mg x kg(-1) of body weight x day(-1)) was administered by osmotic minipumps for 8 weeks to eight control rats, 13 diabetic rats, seven diabetic rats treated with ramipril and nine insulin-treated diabetic rats. Diabetic rats had a significant increase in blood glucose levels. Left ventricular interstitial and perivascular fibrosis, and TGF-beta1 (transforming growth factor-beta1) protein levels were increased in diabetic rats, but not in insulin-treated diabetic rats and ramipril-treated diabetic rats, compared with control rats. Ac-SDKP administration significantly reduced left ventricular interstitial and perivascular fibrosis in diabetic rats and in diabetic rats treated with ramipril. This was accompanied by a significant reduction in active TGF-beta1 and phospho-Smad2/3 protein levels in myocardial tissue of diabetic rats. Echocardiography showed that diabetes was associated with increased end-systolic diameters, and depressed global systolic function and diastolic dysfunction, as assessed by transmitral Doppler velocity profile. These changes were completely reversed by insulin or ramipril treatment. Ac-SDKP treatment partially restored diastolic function in diabetic rats. In conclusion, Ac-SDKP administration in diabetic rats reduces left ventricular interstitial and perivascular fibrosis, active TGF-beta1 and phospho-Smad2/3levels, and improves diastolic function. Taken together, these findings suggest that, by inhibiting theTGF-beta/Smad pathway, Ac-SDKP protects against the development of diabetic cardiomyopathy
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Abstract
Diabetic cardiomyopathy is a distinct primary disease process, independent of coronary artery disease, which leads to heart failure in diabetic patients. Epidemiological and clinical trial data have confirmed the greater incidence and prevalence of heart failure in diabetes. Novel echocardiographic and MR (magnetic resonance) techniques have enabled a more accurate means of phenotyping diabetic cardiomyopathy. Experimental models of diabetes have provided a range of novel molecular targets for this condition, but none have been substantiated in humans. Similarly, although ultrastructural pathology of the microvessels and cardiomyocytes is well described in animal models, studies in humans are small and limited to light microscopy. With regard to treatment, recent data with thiazoledinediones has generated much controversy in terms of the cardiac safety of both these and other drugs currently in use and under development. Clinical trials are urgently required to establish the efficacy of currently available agents for heart failure, as well as novel therapies in patients specifically with diabetic cardiomyopathy.
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Khavandi K, Khavandi A, Asghar O, Greenstein A, Withers S, Heagerty AM, Malik RA. Diabetic cardiomyopathy--a distinct disease? Best Pract Res Clin Endocrinol Metab 2009; 23:347-60. [PMID: 19520308 DOI: 10.1016/j.beem.2008.10.016] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Diabetic individuals have a significantly increased likelihood of developing cardiovascular disease. Whilst part of this association is explained by the presence of concomitant risk factors, large epidemiological studies have consistently reported diabetes as a strong risk factor for the development of heart failure after adjusting for such covariates. This has resulted in the notion that there is a distinct cardiomyopathy specific to diabetes, termed 'diabetic cardiomyopathy'. The natural history is characterized by a latent subclinical period, during which there is evidence of diastolic dysfunction and left ventricular hypertrophy, before overt clinical deterioration and systolic failure ensue. These clinical findings have been supported by a growing body of experimental data which support the notion that diabetes inflicts a direct insult to the myocardium, with cellular, structural and functional changes manifest as the diabetic myocardial phenotype. Several of these mechanisms appear to work in unison, forming complicated reciprocal pathways of disease. Reactive oxygen species and alterations in intracellular calcium homeostasis appear to play significant roles in many of these mechanisms. Determining the hierarchy of this cascade of disease will allow identification of the pathological trigger most responsible for disease. Translational research in this field is currently hindered by a lack of clinical studies and intervention trials specifically in patients with diabetic cardiomyopathy. Future clinical and experimental studies of accurate models of diabetic cardiomyopathy should help to define the true aetiology and lead to the development of specific pharmacotherapies for this condition, ultimately reducing the increased cardiovascular morbidity and mortality in diabetic patients.
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Affiliation(s)
- Kaivan Khavandi
- Division of Cardiovascular and Endocrine Sciences, Core Technology Facility, University of Manchester, Manchester, UK
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21
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Flagg TP, Cazorla O, Remedi MS, Haim TE, Tones MA, Bahinski A, Numann RE, Kovacs A, Schaffer JE, Nichols CG, Nerbonne JM. Ca
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-Independent Alterations in Diastolic Sarcomere Length and Relaxation Kinetics in a Mouse Model of Lipotoxic Diabetic Cardiomyopathy. Circ Res 2009; 104:95-103. [DOI: 10.1161/circresaha.108.186809] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Thomas P. Flagg
- From the Departments of Cell Biology and Physiology (T.P.F., M.S.R., C.G.N.), Molecular Biology and Pharmacology (J.M.N.), and Internal Medicine (A.K., J.E.S.), Washington University School of Medicine, St Louis, Mo; Institut National de la Santé et de la Recherche Médicale, U-637 (O.C.), Université Montpellier 1, Unité de Formation et de Recherche de Médecine, Montpellier, France; and Pfizer Global Research & Development (T.E.H., M.A.T., A.B., R.E.N.), Chesterfield, Mo
| | - Olivier Cazorla
- From the Departments of Cell Biology and Physiology (T.P.F., M.S.R., C.G.N.), Molecular Biology and Pharmacology (J.M.N.), and Internal Medicine (A.K., J.E.S.), Washington University School of Medicine, St Louis, Mo; Institut National de la Santé et de la Recherche Médicale, U-637 (O.C.), Université Montpellier 1, Unité de Formation et de Recherche de Médecine, Montpellier, France; and Pfizer Global Research & Development (T.E.H., M.A.T., A.B., R.E.N.), Chesterfield, Mo
| | - Maria S. Remedi
- From the Departments of Cell Biology and Physiology (T.P.F., M.S.R., C.G.N.), Molecular Biology and Pharmacology (J.M.N.), and Internal Medicine (A.K., J.E.S.), Washington University School of Medicine, St Louis, Mo; Institut National de la Santé et de la Recherche Médicale, U-637 (O.C.), Université Montpellier 1, Unité de Formation et de Recherche de Médecine, Montpellier, France; and Pfizer Global Research & Development (T.E.H., M.A.T., A.B., R.E.N.), Chesterfield, Mo
| | - Todd E. Haim
- From the Departments of Cell Biology and Physiology (T.P.F., M.S.R., C.G.N.), Molecular Biology and Pharmacology (J.M.N.), and Internal Medicine (A.K., J.E.S.), Washington University School of Medicine, St Louis, Mo; Institut National de la Santé et de la Recherche Médicale, U-637 (O.C.), Université Montpellier 1, Unité de Formation et de Recherche de Médecine, Montpellier, France; and Pfizer Global Research & Development (T.E.H., M.A.T., A.B., R.E.N.), Chesterfield, Mo
| | - Michael A. Tones
- From the Departments of Cell Biology and Physiology (T.P.F., M.S.R., C.G.N.), Molecular Biology and Pharmacology (J.M.N.), and Internal Medicine (A.K., J.E.S.), Washington University School of Medicine, St Louis, Mo; Institut National de la Santé et de la Recherche Médicale, U-637 (O.C.), Université Montpellier 1, Unité de Formation et de Recherche de Médecine, Montpellier, France; and Pfizer Global Research & Development (T.E.H., M.A.T., A.B., R.E.N.), Chesterfield, Mo
| | - Anthony Bahinski
- From the Departments of Cell Biology and Physiology (T.P.F., M.S.R., C.G.N.), Molecular Biology and Pharmacology (J.M.N.), and Internal Medicine (A.K., J.E.S.), Washington University School of Medicine, St Louis, Mo; Institut National de la Santé et de la Recherche Médicale, U-637 (O.C.), Université Montpellier 1, Unité de Formation et de Recherche de Médecine, Montpellier, France; and Pfizer Global Research & Development (T.E.H., M.A.T., A.B., R.E.N.), Chesterfield, Mo
| | - Randal E. Numann
- From the Departments of Cell Biology and Physiology (T.P.F., M.S.R., C.G.N.), Molecular Biology and Pharmacology (J.M.N.), and Internal Medicine (A.K., J.E.S.), Washington University School of Medicine, St Louis, Mo; Institut National de la Santé et de la Recherche Médicale, U-637 (O.C.), Université Montpellier 1, Unité de Formation et de Recherche de Médecine, Montpellier, France; and Pfizer Global Research & Development (T.E.H., M.A.T., A.B., R.E.N.), Chesterfield, Mo
| | - Attila Kovacs
- From the Departments of Cell Biology and Physiology (T.P.F., M.S.R., C.G.N.), Molecular Biology and Pharmacology (J.M.N.), and Internal Medicine (A.K., J.E.S.), Washington University School of Medicine, St Louis, Mo; Institut National de la Santé et de la Recherche Médicale, U-637 (O.C.), Université Montpellier 1, Unité de Formation et de Recherche de Médecine, Montpellier, France; and Pfizer Global Research & Development (T.E.H., M.A.T., A.B., R.E.N.), Chesterfield, Mo
| | - Jean E. Schaffer
- From the Departments of Cell Biology and Physiology (T.P.F., M.S.R., C.G.N.), Molecular Biology and Pharmacology (J.M.N.), and Internal Medicine (A.K., J.E.S.), Washington University School of Medicine, St Louis, Mo; Institut National de la Santé et de la Recherche Médicale, U-637 (O.C.), Université Montpellier 1, Unité de Formation et de Recherche de Médecine, Montpellier, France; and Pfizer Global Research & Development (T.E.H., M.A.T., A.B., R.E.N.), Chesterfield, Mo
| | - Colin G. Nichols
- From the Departments of Cell Biology and Physiology (T.P.F., M.S.R., C.G.N.), Molecular Biology and Pharmacology (J.M.N.), and Internal Medicine (A.K., J.E.S.), Washington University School of Medicine, St Louis, Mo; Institut National de la Santé et de la Recherche Médicale, U-637 (O.C.), Université Montpellier 1, Unité de Formation et de Recherche de Médecine, Montpellier, France; and Pfizer Global Research & Development (T.E.H., M.A.T., A.B., R.E.N.), Chesterfield, Mo
| | - Jeanne M. Nerbonne
- From the Departments of Cell Biology and Physiology (T.P.F., M.S.R., C.G.N.), Molecular Biology and Pharmacology (J.M.N.), and Internal Medicine (A.K., J.E.S.), Washington University School of Medicine, St Louis, Mo; Institut National de la Santé et de la Recherche Médicale, U-637 (O.C.), Université Montpellier 1, Unité de Formation et de Recherche de Médecine, Montpellier, France; and Pfizer Global Research & Development (T.E.H., M.A.T., A.B., R.E.N.), Chesterfield, Mo
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22
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Abstract
Diabetes mellitus increases the risk of heart failure independently of underlying coronary artery disease, and many believe that diabetes leads to cardiomyopathy. The underlying pathogenesis is partially understood. Several factors may contribute to the development of cardiac dysfunction in the absence of coronary artery disease in diabetes mellitus. This review discusses the latest findings in diabetic humans and in animal models and reviews emerging new mechanisms that may be involved in the development and progression of cardiac dysfunction in diabetes.
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Affiliation(s)
- Sihem Boudina
- Division of Endocrinology, Metabolism and Diabetes and Program in Human Molecular Biology and Genetics, University of Utah School of Medicine, Salt Lake City 84112, USA
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