Cardiomyocyte Oga haploinsufficiency increases O-GlcNAcylation but hastens ventricular dysfunction following myocardial infarction
| Autor: | John A. Hanover, Linda T. Harrison, Timothy N. Audam, James Bradley, Sujith Dassanayaka, Anna M. Gumpert, Bethany W. Long, Béla Merkely, Steven P. Jones, Andrea Jurkovic, István Hartyánszky, Lauren A. Higgins, Péter Perge, Kenneth R. Brittian, Tamás Radovits |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Glycosylation Exacerbation Physiology Myocardial Infarction Infarction Apoptosis Haploinsufficiency Cardiovascular Physiology Diagnostic Radiology Mice Animal Cells Ultrasound Imaging Ventricular Dysfunction Medicine and Health Sciences Ventricular Function Myocardial infarction Mice Knockout Cardiomyocytes Multidisciplinary Ejection fraction Cell Death Radiology and Imaging Heart Animal Models Middle Aged Cardiovascular physiology Up-Regulation Experimental Organism Systems Echocardiography Cell Processes Cardiology Medicine Female Anatomy Cellular Types Research Article Cardiac function curve medicine.medical_specialty Imaging Techniques Science Muscle Tissue Mouse Models N-Acetylglucosaminyltransferases Research and Analysis Methods 03 medical and health sciences Model Organisms Diagnostic Medicine Internal medicine medicine Animals Humans Heart Failure Muscle Cells 030102 biochemistry & molecular biology business.industry Myocardium Biology and Life Sciences Cell Biology medicine.disease Tamoxifen 030104 developmental biology Biological Tissue Heart failure Cardiovascular Anatomy Animal Studies business |
| Zdroj: | PLoS ONE PLoS ONE, Vol 15, Iss 11, p e0242250 (2020) |
| ISSN: | 1932-6203 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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