Abstract 13696: Elevated O-Glcnacylation : An Independent Driver of Cardiomyopathy
Priya UmapathiOlurotimi MesubiP. S. BanerjeeNatasha E. ZacharaQinchuan WangJonathan GrangerElizabeth D. LuczakYuejin WuLiliana FloreaC. Conover TalbotGerald W. HartMark E. Anderson
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Heart failure is a leading cause of death and is associated with increased O-GlcNAcylation (OGN). However, it is unknown if excessive OGN is a direct contributor to cardiomyopathy. OGN modifies pro...Cite
Background: Right ventricular failure (RVF) due to abnormal hemodynamic load is a frequent complication and critical determinant of long-term outcome in many forms of congenital heart disease and p...
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Heart failure is a highly morbid and mortal clinical condition that represents the last stage of most cardiovascular disorders. Diabetes is strongly associated with an increased incidence of heart failure and directly promotes cardiac hypertrophy, fibrosis, and apoptosis. These changes, in turn, contribute to the development of ventricular dysfunction. The clinical condition associated with the spectrum of cardiac abnormalities induced by diabetes is termed diabetic cardiomyopathy. Myocardial inflammation has recently emerged as a pathophysiological process contributing to cardiac hypertrophy, fibrosis, and dysfunction in cardiac diseases. Myocardial inflammation is also implicated in the development of diabetic cardiomyopathy. Several molecular mechanisms link diabetes to myocardial inflammation. The NF-κB signalling pathway and the renin-angiotensin-aldosterone system are strongly activated in the diabetic heart, thereby promoting myocardial inflammation. Advanced glycation end-products and damage-associated molecular pattern molecules also represent strong triggers for inflammation. The mediators resulting from this inflammatory process modulate specific intracellular signalling mechanisms in cardiac cells that promote the development of diabetic cardiomyopathy. This review article will provide an overview of the signalling molecular mechanisms linking diabetic cardiomyopathy to myocardial inflammation.
Diabetic Cardiomyopathy
Myocardial fibrosis
Cardiac Fibrosis
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There is increasing evidence that diabetic cardiomyopathy increases the risk of cardiac arrhythmias and sudden cardiac death. While the detailed mechanisms remain incompletely understood, the loss of mitochondrial function, which is often observed in the heart of patients with diabetes, has emerged as a key contributor to the arrhythmogenic substrates. In this mini review, the pathophysiology of mitochondrial dysfunction in diabetes mellitus is explored in detail, followed by descriptions of several mechanisms potentially linking mitochondrial dysfunction to arrhythmogenesis in the context of diabetic cardiomyopathy.
Diabetic Cardiomyopathy
Pathophysiology
Cardiac Dysfunction
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Cardiac Dysfunction
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Increased protein O -GlcNAcylation (OGN) is a common feature of failing heart muscle. However, it is unknown if excessive OGN contributes to cardiomyopathy and heart failure. OGN levels are determined by the net activity of two enzymes: OGT ( O -GlcNAc transferase, adds OGN) and OGA ( O -GlcNAcase, removes OGN). We hypothesized that excessive myocardial OGN is a cause of cardiomyopathy. To test for a role of OGN in cardiomyopathy we developed new transgenic (TG) mouse models with myocardial overexpression of OGT or OGA. The OGT-TG hearts showed progressive decline in left ventricular (LV) systolic function, dilation, increased mass (Figure A, B) (Statistical Analysis ANOVA - *** = p<0.001) and increased OGN (Figure C) . OGT-TG mice showed premature mortality compared to WT littermates (Figure D). In contrast, OGA-TG mice exhibit normal contractility, do not have significantly different OGN and have normal lifespan compared to WT littermates. Hearts from OGT-TG and OGA-TG interbred mice have marked improvement of LV systolic function, lower OGN and normal lifespan. We next tested if attenuation of myocardial OGN was beneficial in acquired cardiomyopathy by performing transverse aortic constriction surgery (TAC) on OGA-TG and WT littermates. The OGA-TG hearts had lower OGN, improved LV systolic function, less hypertrophy, and lower expression of heart failure genes compared to WT littermates after TAC. Our data identify excessive OGN as an independent mechanism for cardiomyopathy, and suggest attenuation of OGN may be an effective therapy for heart failure.
Contractility
Dilated Cardiomyopathy
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Section I. Basic Concepts Of Myocardial Architecture And Physiology. Cellular And Molecular Basis Of Myocardial Contraction The Mechanics, Determinants And Regulation Of Cardiac Contraction. Myocardial Energetics And Cardiac Contractility. Transcriptional Circuits Mediating Cardiac Hypertrophy And Heart Failure. Histopathologic Basis Of Cardiomyopathic Disorders. Classification And Nomenclature Of Cardiomyopathic Disorders. Section II. Pathogenetic Mechanisms On Evolution Of Cardiomyopathic Disorders. Gene Mutations That Cause Hypertrophic Cardiomyopathy. Abnormalities Of Calcium Homeostasis And Defective Excitation-Contraction Coupling In Cardiomyopathy. Local Hormonal Adaptations Of The Myopathic Hearts. Molecular Basis Of Cardiac Hypertrophy. Endothelial In Myocardial Remodeling And Failure. Mitochondrial Abnormalities In Cardiomyopathy. Altered Receptor-Mediated Signaling In Cardiomyopathy. Role Of Altered Ion-Channel Expression In Sudden Death In Heart Failure. Viral Myocardial Disease. Auto-Immune Basis of Myocardial Disease. Myocardial Inflammation and Myocellular Damage. Apoptosis in Congestive Heart Failure. Myocellular And Myocardial Extracellular Matrix Remodeling. Section III. Pathogenetic Basis of Secondary Cardiomyopathic Disorders. Myocardial Involvement in Ischemic Heart Disease: Role of Hibernating Myocardium. Hypertensive Heart Disease and Progressive Myocellular Loss. The Myocardium in Diabetes Mellitus. Infective Disease Of The Myocardium. Molecular Basis Of Post-Infective Auto-Immune Myocardial Disorders. Alcohol-Induced Myocardial Damage: Reversibility and Clinical Implications. HIV-Related Cardiomyopathic Disease. Cardiac Involvement in Systemic Disorders. Iatrogenic Myocardial Dysfunction. Section IV. Pathogenetic Basis Of Management of Cardiomyopathies. Newer Pharmacologic Options in Myocardial Diseases. Targeting Genes and Modulating Signal Transduction in Cardiomyopathies. Congestive Heart Failure: Contemporary Medical Therapy. Relentlessly Progressive Congestive Heart Failure: Can it be Prevented? Spatial Orientation of the Ventricular Muscle Band and Approach to Partial Ventriculotomy in Heart Failure. Section V. Non-Transplant Surgery for End-Stage Cardiomyopathy. Exploiting our Understanding of Pathogenetic Mechanisms in Developing Surgical Interventions. Coronary Revascularization as an Alternative to Transplantation. Left Ventricular Remodeling and Mitral Valve Repair. Mechanical Circulatory Support and Myocyte Recovery.
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Mitochondrial dysfunction and increased oxidative stress are hallmarks of diabetic cardiomyopathy, a condition characterized by increased risk of heart failure, independent of coronary atherosclerosis. Mitochondria not only are the major site of energy production, but also generate reactive oxygen species (ROS), and metabolic signals that produce coronary metabolic vasodilation (coupling of flow to metabolism). Accordingly, we hypothesized that elevations in mitochondrial ROS in obesity and diabetes produce oxidative mitochondrial DNA (mtDNA) injury (fragmentation); thus by repairing mtDNA fragmentation, we would restore coronary metabolic dilation. To test this hypothesis, we studied Zucker fatty obese rats (ZOF), lean littermates (ZL), and ZOF in which mtDNA fragmentation was repaired by administration of a cell permeable recombinant protein containing endonucleaseIII and a mitochondrial localization sequence (mt-tat-ENDOIII), which repairs fragmented mtDNA and restores mitochondrial functions. ZOF were treated daily for 3 days (1 µg/g body weight of mt-tat-ENDOIII). ZOF and ZL rats treated with vehicle were positive and negative controls, respectively. The product of mean arterial pressure and heart rate was used as a surrogate of cardiac work (CW). Myocardial blood flow (MBF) was measured by contrast echocardiography under baseline conditions (hexamethonium) and during NE infusion (i.v. norepinephrine, NE) to increase CW. During metabolic stress, ZOF showed coronary insufficiency compared to ZL (P<0.05). Importantly, coronary metabolic dilation in ZOF was restored by the administration of mt-tat-ENDOIII versus ZL (P=NS). We conclude that mitochondrial dysfunction participates to decrease the efficiency of the coronary metabolic regulation in diabetes. By preventing mt-DNA damage, adequate coronary metabolic dilatation can be restored; this could be a therapeutic approach for the prevention of diabetic cardiomyopathy.
Diabetic Cardiomyopathy
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Metabolic pathway
Anaerobic glycolysis
Carbohydrate Metabolism
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Background: Hypertension is a leading risk factor for heart disease. Because the beta-O-linkage of N-acetylglucosamine (O-GlcNAc) post-translational modification plays a significant, pro-adaptive role in the cardiovascular system's response to various stressors, we hypothesized that this stress response (protein O-GlcNAcylation) was important in mitigating pressure overload-induced cardiac dysfunction. Methods and Results: Wild-type mice were randomly assigned to drug or vehicle groups and followed for seven days after transverse aortic constriction (TAC, i.e., pressure overload). The drug group was given TT04 (10mg/kg, bid), a specific inhibitor of O-GlcNAc transferase (the enzyme that adds O-GlcNAc to proteins). TT04 treatment significantly exacerbated systolic dysfunction (Fig 1B) despite no change in diastolic diameter (Fig 1A). TT04 treatment also diminished ejection fraction (Fig 1C) and reduced levels of protein O-GlcNAcylation (Fig 1D) compared to vehicle (p<0.05). Conclusions: O-GlcNAc signaling plays an important, seemingly pro-adaptive role in the heart during pressure overload-induced cardiac dysfunction.
Pressure overload
Ventricular pressure
Ventricular Function
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The myocardium is among the most energy-consuming tissues in the body, burning from 6 to 30 kg of ATP per day within the mitochondria, the so-called powerhouse of the cardiomyocyte. Although mitochondrial genetic disorders account for a small portion of cardiomyopathies, mitochondrial dysfunction is commonly involved in a broad spectrum of heart diseases, and it has been implicated in the development of heart failure via maladaptive circuits producing and perpetuating mitochondrial stress and energy starvation. In this bench-to-bedside review, we aimed to (i) describe the key functions of the mitochondria within the myocardium, including their role in ischemia/reperfusion injury and intracellular calcium homeostasis; (ii) examine the contribution of mitochondrial dysfunction to multiple cardiac disease phenotypes and their transition to heart failure; and (iii) discuss the rationale and current evidence for targeting mitochondrial function for the treatment of heart failure, including via sodium-glucose cotransporter 2 inhibitors.
Mitochondrial disease
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