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
0
Citation
0
Reference
20
Related Paper
Abstract:
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
Pressure overload
Volume overload
Cite
Citations (11)
Background: Heart failure is a leading cause of death worldwide and is associated with the rising prevalence of obesity, hypertension, and diabetes. O -GlcNAcylation (the attachment of O -linked β-N-acetylglucosamine [ O -GlcNAc] moieties to cytoplasmic, nuclear, and mitochondrial proteins) is a posttranslational modification of intracellular proteins and serves as a metabolic rheostat for cellular stress. Total levels of O -GlcNAcylation are determined by nutrient and metabolic flux, in addition to the net activity of 2 enzymes: O -GlcNAc transferase (OGT) and O -GlcNAcase (OGA). Failing myocardium is marked by increased O -GlcNAcylation, but whether excessive O -GlcNAcylation contributes to cardiomyopathy and heart failure is unknown. Methods: We developed 2 new transgenic mouse models with myocardial overexpression of OGT and OGA to control O -GlcNAcylation independent of pathologic stress. Results: We found that OGT transgenic hearts showed increased O -GlcNAcylation and developed severe dilated cardiomyopathy, ventricular arrhythmias, and premature death. In contrast, OGA transgenic hearts had lower O -GlcNAcylation but identical cardiac function to wild-type littermate controls. OGA transgenic hearts were resistant to pathologic stress induced by pressure overload with attenuated myocardial O -GlcNAcylation levels after stress and decreased pathologic hypertrophy compared with wild-type controls. Interbreeding OGT with OGA transgenic mice rescued cardiomyopathy and premature death, despite persistent elevation of myocardial OGT. Transcriptomic and functional studies revealed disrupted mitochondrial energetics with impairment of complex I activity in hearts from OGT transgenic mice. Complex I activity was rescued by OGA transgenic interbreeding, suggesting an important role for mitochondrial complex I in O -GlcNAc–mediated cardiac pathology. Conclusions: Our data provide evidence that excessive O -GlcNAcylation causes cardiomyopathy, at least in part, attributable to defective energetics. Enhanced OGA activity is well tolerated and attenuation of O -GlcNAcylation is beneficial against pressure overload–induced pathologic remodeling and heart failure. These findings suggest that attenuation of excessive O -GlcNAcylation may represent a novel therapeutic approach for cardiomyopathy.
Dilated Cardiomyopathy
Sudden Death
Cite
Citations (90)
Introduction: The failing heart is characterized by high rates of glycolysis and low rates of fatty acid oxidation, whereas the diabetic heart shows an opposite cardiac metabotype; however, the rol...
Cite
Citations (1)
Cite
Citations (0)
Hypertension increases the risk of heart disease, and key hallmark features of hypertensive heart disease is sympatho-excitation and mitochondrial injury. However, the molecular intermediary link between enhanced sympatho-excitation and cardiac mitochondrial injury remains unclear. Sprague-Dawley rats (250-300g) were subjected to a central infusion of Ang II (20ng/min for 14days, 0.5μl/h, i.c.v.; neurogenic hypertension (NG-HTN)) or isotonic saline (0.9% saline, i.c.v; Control (Con)) through osmotic mini-pumps. Mitochondrial injury and cardiac remodeling were assessed using Western blot, histology, immunocytochemistry and electron microscopy. Sympatho-excitatory effect on mitochondrial injury was examined in in vitro by administration of norepinephrine (NE) on H9c2 rat cardiomyocytes. Our NG-HTN rat model exhibited increased sympatho-excitaton and hypertension. Concomitantly, there was reduced miRNA-18a-5p (NG-HTN: 0.65±0.05 vs. Con: 1.06±0.04 vs.), but increased HIF-1α levels in the heart (NG-HTN: 1.82±0.4 vs. Con: 0.88±0.13). Increased mitochondrial untranslated protein response (UPR mt ) marker HSP60 (NG-HTN: 1.22±0.08 vs. Con: 0.81±0.07) indicated mitochondrial proteinopathy and proteotoxic stress associated with increased mito-ROS and altered mitochondrial oxidative phosphorylation. Further, there was reduced mitochondrial biogenesis and fusion, but increased mitochondrial fission, coupled with impaired mitochondrial TIM-TOM translocase performance in NG-HTN hearts. Electron microscopy revealed mitochondrial injury in NG-HTN hearts, linked with hypertrophic cardiomyopathy and fibrosis remodeling. Our In-silico data showed increased NE decreased miR-18a-5p to target HIF-1α, and corroborated mitochondrial injury and cardiomyocyte hypertrophy in, in vitro studies. In conclusion, these results demonstrate that enhanced sympatho-excitation contributes to reduced miR-18a-5p causing increased HIF-1α in the heart leading to mitochondrial proteotoxic stress and metabolic shift, which underlies mitochondrial injury. This study identifies the key molecular intermediary links that can potentially be manipulated for therapeutic benefits for pathological cardiac remodeling in clinical HTN.
MFN2
PINK1
FIS1
Hypertensive heart disease
Cite
Citations (3)
Heart requires high energy metabolism to maintain contractile activity and pump sufficient blood flow to body. The optimal supply of energy from the mitochondria is very important for maintaining normal cardiac function. Crif1 is a critical protein for the synthesis and insertion of the OxPhos complex in mitochondria. Recent studies reported that conditional knockout of Crif1 in specific tissues is associated with mitochondrial dysfunction. To investigate the role of Crif1 and mitochondrial dysfunction in heart, we generated cardiac-specific, Crif1 haploinsufficient mice. Haploinsufficient Crif1 in heart resulted in abnormal structure of mitochondria and decreased maximal values of oxygen consumption rates in cardiomyocytes. Although cardiac specific, haploinsufficient Crif1 results in mitochondrial dysfunction, cardiac phenotype was still normal. However, their cardiac function was aggravated by stress condition, showing more decreased EF and FS after 4 weeks isoproterenol infusion. Cardiac hypertrophy, which is considered as normal compensatory mechanism, was not occurred during isoproterenol infusion. These indicate that Crif1 plays a critical role in the maintenance of mitochondrial structure and function of cardiomyocyte. Also, mitochondrial abnormalities in heart inhibit the compensatory mechanisms for stress and aggravate cardiac function.
Haploinsufficiency
Cite
Citations (0)
Cite
Citations (37)
Introduction: Diabetic cardiomyopathy is typified by alterations in cardiac metabolism, morphology, and function independent of hypertension and coronary artery disease. We have shown previously th...
Ventricular remodeling
FOXO1
Cite
Citations (0)
Chronic pressure-overload (PO) induced-dilated cardiomyopathy (DCM) is one of the leading causes of left ventricular (LV) remodeling and heart failure. The role of glycogen synthase kinase-3α (GSK-3α) in PO-induced remodeling is not clear and existing dataset with global transgenic and knockout (KO) models show opposing roles. We sought to identify the specific role of GSK-3α in PO-induced dilatative cardiac remodeling. To better understand the role of GSK-3α, we employed cardiomyocyte-specific GSK3A ( GSK3A fl/fl MerCreMer ) KO mice. Post-tamoxifen treatment, the GSK-3α KO and littermate control mice underwent sham or trans-aortic constriction (TAC) surgery. Heart function was assessed at 0, 2, 4 and 6 week post-TAC using serial M-mode echocardiography. Cardiac function in the KOs and littermate controls declines equally up to 2 weeks of TAC. At 4 week, KO hearts underwent further hypertrophy, retaining concentric LV remodeling and preserved contractile function both at systole and diastole. In contrast, wild-type LV showed significant chamber dilatation with an impaired contractility. Significantly reduced LV chamber dilatation [LVIDd(mm); 5.4±0.4 vs. 4.9±0.4, P =0.01] and preserved contractile function [LVEF(%); 22.2±12.6 vs. 40.0±18.7, P =0.02] remains same in the KO mice until the end of the study (6 wk). Furthermore, LV posterior wall thickness in the KO hearts, both at systole and diastole, were significantly greater in comparison to the controls. Consistent with preserved LV dimension, significantly less mortality was observed in the KO vs. control group during the remodeling phase. Histological analysis of heart sections further revealed better preserved LV chamber and protection against TAC-induced cellular hypertrophy in the GSK-3α KOs. Moreover, KO hearts showed significantly less fibrosis accompanied with low level of cardiomyocyte apoptosis post-6 wk of TAC. Taken together, these observations show that cardiomyocyte-specific deletion of GSK-3α protects against chronic PO-induced adverse LV remodeling and preserves contractile function. Inhibiting specifically GSK-3α using isoform-specific inhibitor could be a viable therapeutic strategy to limit the PO-induced DCM, adverse remodeling and heart failure.
Pressure overload
Contractility
Systole
Concentric hypertrophy
Dilated Cardiomyopathy
Preload
Ventricular remodeling
Cite
Citations (0)
Diabetic cardiomyopathy is an independent, specific cardiomyopathy, closely related with heart failure and high mortality. Cardiovascular complications related to hyperglycemia induced cardiomyopathy and pathophysiology of vascular disease, changes of myocardial structure, the signaling pathways, and alteration in inflammatory cytokines, leading to myocardial fibrosis, myocardial hypertrophy, cardiac hypertrophy, heart failure and arrhythmias. The paper mainly reviewed several signaling pathways which studied more on the pathogenesis of diabetic cardiomyopathy, to explore the various signaling pathways in the development of diabetic cardiomyopathy.
Diabetic Cardiomyopathy
Pathogenesis
Myocardial fibrosis
Pathophysiology
Cite
Citations (0)