Sustained Increases in Cardiomyocyte Protein O ‐Linked β‐N‐Acetylglucosamine Levels Lead to Cardiac Hypertrophy and Reduced Mitochondrial Function Without Systolic Contractile Impairment

Abstract

Background Lifestyle and metabolic diseases influence the severity and pathogenesis of cardiovascular disease through numerous mechanisms, including regulation via posttranslational modifications. A specific posttranslational modification, the addition of O ‐linked β‐ N acetylglucosamine ( O ‐GlcNAcylation), has been implicated in molecular mechanisms of both physiological and pathologic adaptations. The current study aimed to test the hypothesis that in cardiomyocytes, sustained protein O ‐GlcNAcylation contributes to cardiac adaptations, and its progression to pathophysiology. Methods and Results Using a naturally occurring dominant‐negative O ‐GlcNAcase (dnOGA) inducible cardiomyocyte‐specific overexpression transgenic mouse model, we induced dnOGA in 8‐ to 10‐week‐old mouse hearts. We examined the effects of 2‐week and 24‐week dnOGA overexpression, which progressed to a 1.8‐fold increase in protein O‐ GlcNAcylation. Two‐week increases in protein O ‐GlcNAc levels did not alter heart weight or function; however, 24‐week increases in protein O ‐GlcNAcylation led to cardiac hypertrophy, mitochondrial dysfunction, fibrosis, and diastolic dysfunction. Interestingly, systolic function was maintained in 24‐week dnOGA overexpression, despite several changes in gene expression associated with cardiovascular disease. Specifically, mRNA‐sequencing analysis revealed several gene signatures, including reduction of mitochondrial oxidative phosphorylation, fatty acid, and glucose metabolism pathways, and antioxidant response pathways after 24‐week dnOGA overexpression. Conclusions This study indicates that moderate increases in cardiomyocyte protein O ‐GlcNAcylation leads to a differential response with an initial reduction of metabolic pathways (2‐week), which leads to cardiac remodeling (24‐week). Moreover, the mouse model showed evidence of diastolic dysfunction consistent with a heart failure with preserved ejection fraction. These findings provide insight into the adaptive versus maladaptive responses to increased O‐ GlcNAcylation in heart.

O-GlcNAcylation in ischemic diseases

“…During myocardial ischemia, OGT expression increases and OGA expression decreases ( Dassanayaka et al, 2020 ), which contributes to the elevation of O-GlcNAcylation to achieve protection. However, Ha et al (2023) employed a mouse model with cardiomyocyte-specific dnOGA overexpression, resulting in increased O-GlcNAcylation protein levels. Persistently high levels of cardiac O-GlcNAc resulted in heart enlargement, heightened heart fibrosis, and impaired diastolic function.…”

Roles of O-GlcNAcylation in Mitochondrial Homeostasis and Cardiovascular Diseases

“…An increase in O-GlcNAc levels during hypoxia or reperfusion can improve functional recovery and exert anti-ischemic myocardial protection through various mechanisms [38,54]. However, excessive increased O-GlcNAcylation leads to cardiomyocyte hypertrophy, fibrosis and diastolic dysfunction [14,55]. O-GlcNAcylation levels are increased in the cardiac tissue of patients who undergo aortic valve stenosis surgery and rat models of hypertension [56].…”

“…Mitochondrial protein O-GlcNAcylation plays an important role in regulating cellular function; the destruction of O-GlcNAcylation homeostasis is involved in the pathogenesis of chronic diseases such as diabetes [43,72,73], neurodegenerative diseases [74,75], tumors [28,76,77] and CVDs [14,26,44]. Insulin resistance and diabetic CVDs are promoted by O-GlcNAcylation through an increase in the imbalance of multiple signaling pathways at the transcriptional, translational and posttranslational levels.…”

“…O-GlcNAcylation plays a role in the high-glucose-induced myocardial hypertrophy of neonatal rat cardiomyocytes via ERK1/2 and cyclin D2 [34]. Heart failure has been associated with an increase in the O-GlcNAcylation rate, which induces cardiomyopathy, suggesting a possible role for O-GlcNAcylation in the development of chronic heart dysfunction [14,44,57,121,[137][138][139]. Heart failure (regardless of diabetes) both experimentally and clinically is accompanied by marked increases in O-GlcNAcylation.…”

“…As the main energy-demanding organ, the heart largely relies on ATP produced by mitochondrial energy metabolism to promote contractile function and myocardial cell metabolism [14,15]. Integral mitochondrial homeostasis is crucial for cardiac contractile function and myocardial cell metabolism, and the imbalance in mitochondrial homeostasis plays a crucial role in the pathogenesis of cardiovascular diseases (CVDs) [16], mainly by regulating cellular energy metabolism [17], reactive oxygen species (ROS) and autophagy [18], intracellular calcium level [19], apoptotic [20] and other cell-or tissuespecific mechanisms [21].…”