Cardiomyocyte Oga haploinsufficiency increases O-GlcNAcylation but hastens ventricular dysfunction following myocardial infarction

Abstract

Rationale The beta-O-linkage of N-acetylglucosamine (i.e., O-GlcNAc) to proteins is a pro-adaptive response to cellular insults. To this end, increased protein O-GlcNAcylation improves short-term survival of cardiomyocytes subjected to acute injury. This observation has been repeated by multiple groups and in multiple models; however, whether increased protein O-GlcNAcylation plays a beneficial role in more chronic settings remains an open question. Objective Here, we queried whether increasing levels of cardiac protein O-GlcNAcylation would be beneficial during infarct-induced heart failure. Methods and results To achieve increased protein O-GlcNAcylation, we targeted Oga, the gene responsible for removing O-GlcNAc from proteins. Here, we generated mice with cardiomyocyte-restricted, tamoxifen-inducible haploinsufficient Oga gene. In the absence of infarction, we observed a slight reduction in ejection fraction in Oga deficient mice. Overall, Oga reduction had no major impact on ventricular function. In additional cohorts, mice of both sexes and both genotypes were subjected to infarct-induced heart failure and followed for up to four weeks, during which time cardiac function was assessed via echocardiography. Contrary to our prediction, the Oga deficient mice exhibited exacerbated—not improved—cardiac function at one week following infarction. When the observation was extended to 4 wk post-MI, this acute exacerbation was lost. Conclusions The present findings, coupled with our previous work, suggest that altering the ability of cardiomyocytes to either add or remove O-GlcNAc modifications to proteins exacerbates early infarct-induced heart failure. We speculate that more nuanced approaches to regulating O-GlcNAcylation are needed to understand its role—and, in particular, the possibility of cycling, in the pathophysiology of the failing heart.

An Overview of Glycosylation and its Impact on Cardiovascular Health and Disease

“…OGA transgenic hearts were resistant to pathological stress due to pressure overload, with a decrease in O -GlcNAcylation levels and a decrease in hypertrophy compared to wild-type controls ( Umapathi et al, 2021 ). These results agree with those of Sujith Dassanayaka et al, who found that the OGA-deficient mice exhibited exacerbated cardiac function at 1 week following infarction ( Dassanayaka et al, 2020 ). These findings suggest that O -GlcNAcylation represents a novel therapeutic approach for cardiomyopathy ( Umapathi et al, 2021 ).…”

O-GlcNAcylation in Renal (Patho)Physiology

“…Cortical segments, including proximal tubules and distal tubules, have lower but significant expression levels. Advances in tissue-specific gene editing tools have been used to study the importance of O-GlcNAcylation in specific extrarenal cells [ 85 , 86 , 87 , 88 , 89 , 90 ]. Ono et al (2017) [ 91 ] accessed the importance of O-GlcNAcylation for podocytes, differentiated epithelial cells involved in selective permeability through the glomerular filtration barrier [ 92 ].…”

Integration of O-GlcNAc into Stress Response Pathways

“…Similarly, mice with catalytically inactive OGA (D285A) show small embryo size and perinatal lethality accompanied by structural defects in embryonic kidney, liver, and brain [ 103 ]. While no major defects in the cardiovascular system were detected in OGA D285A mice, depleting OGA by 50% in adult cardiomyocytes (OGA +/− -icko) elevates cardiac O-GlcNAcylation and modestly reduces ejection fraction at baseline [ 104 ]. These data suggest that OGA has important maintenance roles in the heart and cardiomyocytes.…”

“…In addition to PO hypertrophy cardiac stress, O-GlcNAcylation has also been investigated in cardiac remodeling following myocardial infarction (MI). Failing human hearts biopsied at the time of transplantation exhibit increased O-GlcNAcylation [ 104 ]. Similarly, investigations in animal models with acute MI and heart failure found increased cardiac O-GlcNAcylation, accompanied by increased OGT and decreased OGA abundance or activities [ 46 , 121 ].…”

“…These findings indicate that boosting O-GlcNAcylation exerts a protective role in the context of MI and heart failure. Nevertheless, mice with partial deletion of OGA in cardiomyocytes, while exhibiting increased myocardial O-GlcNAcylation, unexpectedly undergo exacerbated myocardial remodeling and dysfunction after MI [ 104 ]. These apparently conflicting outcomes are reminiscent of the findings with pressure overload hypertrophy described above.…”