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

Autor: Dassanayaka S; Department of Medicine, University of Louisville, Louisville, KY, United states of America., Brittian KR; Department of Medicine, University of Louisville, Louisville, KY, United states of America., Long BW; Department of Medicine, University of Louisville, Louisville, KY, United states of America., Higgins LA; Department of Medicine, University of Louisville, Louisville, KY, United states of America., Bradley JA; Department of Medicine, University of Louisville, Louisville, KY, United states of America., Audam TN; Department of Medicine, University of Louisville, Louisville, KY, United states of America., Jurkovic A; Department of Medicine, University of Louisville, Louisville, KY, United states of America., Gumpert AM; Department of Medicine, University of Louisville, Louisville, KY, United states of America., Harrison LT; Department of Medicine, University of Louisville, Louisville, KY, United states of America., Hartyánszky I; Heart and Vascular Center, Semmelweis University, Budapest, Hungary, United states of America., Perge P; Heart and Vascular Center, Semmelweis University, Budapest, Hungary, United states of America., Merkely B; Heart and Vascular Center, Semmelweis University, Budapest, Hungary, United states of America., Radovits T; Heart and Vascular Center, Semmelweis University, Budapest, Hungary, United states of America., Hanover JA; Laboratory of Cell and Molecular Biology, NIH-NIDDK, Bethesda, MD, United states of America., Jones SP; Department of Medicine, University of Louisville, Louisville, KY, United states of America.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2020 Nov 30; Vol. 15 (11), pp. e0242250. Date of Electronic Publication: 2020 Nov 30 (Print Publication: 2020).
DOI: 10.1371/journal.pone.0242250
Abstrakt: 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.
Competing Interests: The authors have declared that no competing interests exist.
Databáze: MEDLINE
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