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In Person Special Seminar: Cardiac Protein O-GlcNAcylation Induces Cardiac Hypertrophy and Increases Risk of Heart Failure

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Adam Wende, Ph.D., FAHA

Associate Professor
Division of Molecular and Cellular Pathology
Department of Pathology
Heersink School of Medicine
University of Alabama at Birmingham 

In Person Seminar: Cardiac Protein O-GlcNAcylation Induces Cardiac Hypertrophy and Increases Risk of Heart Failure

Date: May 15, 2023

Time:  11 a.m.

About this Seminar

The severity and development of cardiovascular disease can be affected by lifestyle and metabolic diseases, which can impact various mechanisms, including post-translational modifications (PTM). A specific PTM, known as protein O-linked β-N acetylglucosamine modification (O-GlcNAc), has been linked to both physiological responses and pathological progression of heart failure. Dr. Wende’s lab’s work aims to test whether sustained O-GlcNAc of proteins in cardiomyocytes contributes to cardiac adaptations or is sufficient to progress toward pathophysiology. Using a novel transgenic mouse model to overexpress a naturally occurring dominant-negative O-GlcNAcase (dnOGA) in an inducible and cardiomyocyte-specific manner (dnOGAh), the lab induced dnOGA in male and female 8-10-weeks-old mice, and examined the effects of 2-weeks (2wk) and 24-weeks (24wk) dnOGA overexpression (which leads to a 1.8-fold increase in O-GlcNAc levels). A 2wk increase in protein O-GlcNAc levels did not impact heart weight or function; however, 24wk of elevated protein O-GlcNAc led to cardiac hypertrophy, mitochondrial dysfunction, fibrosis, and diastolic dysfunction compared to Control (Con; single transgenic mice). Others have shown in clinical studies that diabetes increases cardiac disease risk, even after patients return to tight glycemic control. Dr. Wende hypothesizes that an increase in O-GlcNAc (known to occur in diabetes) is sufficient to exacerbate adverse cardiac remodeling under subsequent pressure-overload. He proposes that this is due to epigenetic modifications causing persistent changes in gene expression. Using the model described above the lab subjected Con and dnOGAh mice to 2-wk induction and subsequent 2-wk washout, followed by transverse-aortic constriction (TAC) or Sham surgery. In both Con+TAC and dnOGA+TAC vs. Sham groups, systolic function decreased, and ventricular weight is increased. Interestingly, the lab sees further exacerbation of cardiac hypertrophy and pulmonary edema between dnOGA+TAC vs. Con+TAC groups. These results support the hypothesis that a transient increase in cardiac O-GlcNAc levels is sufficient to increase susceptibility to subsequent cardiac pathology.

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