Cardiomyocyte Ogt limits ventricular dysfunction in mice following pressure overload without affecting hypertrophy

Abstract

The myocardial response to pressure overload involves coordination of multiple transcriptional, post-transcriptional, and metabolic cues. The previous studies show that one such metabolic cue, O-GlcNAc, is elevated in the pressure-overloaded heart, and the increase in O-GlcNAcylation is required for cardiomyocyte hypertrophy in vitro. Yet, it is not clear whether and how O-GlcNAcylation participates in the hypertrophic response in vivo. Here, we addressed this question using patient samples and a preclinical model of heart failure. Protein O-GlcNAcylation levels were increased in myocardial tissue from heart failure patients compared with normal patients. To test the role of OGT in the heart, we subjected cardiomyocyte-specific, inducibly deficient Ogt (i-cmOgt−/−) mice and Ogt competent littermate wild-type (WT) mice to transverse aortic constriction. Deletion of cardiomyocyte Ogt significantly decreased O-GlcNAcylation and exacerbated ventricular dysfunction, without producing widespread changes in metabolic transcripts. Although some changes in hypertrophic and fibrotic signaling were noted, there were no histological differences in hypertrophy or fibrosis. We next determined whether significant differences were present in i-cmOgt−/− cardiomyocytes from surgically naïve mice. Interestingly, markers of cardiomyocyte dedifferentiation were elevated in Ogt-deficient cardiomyocytes. Although no significant differences in cardiac dysfunction were apparent after recombination, it is possible that such changes in dedifferentiation markers could reflect a larger phenotypic shift within the Ogt-deficient cardiomyocytes. We conclude that cardiomyocyte Ogt is not required for cardiomyocyte hypertrophy in vivo; however, loss of Ogt may exert subtle phenotypic differences in cardiomyocytes that sensitize the heart to pressure overload-induced ventricular dysfunction.

Integration of flux measurements to resolve changes in anabolic and catabolic metabolism in cardiac myocytes

“…In the heart, the PPP is activated during hypertrophy [ 2 – 4 ] and heart failure [ 5 ], and modulating the activity of this pathway regulates the severity of cardiac pathology [ 6 – 11 ]. Similarly, O-linked β- N -acetylglucosamine ( O -GlcNAc)-modified proteins, which require synthesis of the sugar donor UDP-GlcNAc via the HBP [ 12 , 13 ], are elevated in hypertrophied and failing hearts [ 14 – 17 ]. Although less is known about the glycerolipid synthesis pathway (GLP), increased activity of this pathway may underlie pathologic cardiac hypertrophy [ 18 ].…”

AMPK activation counteracts cardiac hypertrophy by reducing O-GlcNAcylation

“…In agreement, it has been shown that GFAT inhibition by DON prevents PE-induced hypertrophic markers to progress in NRVMs 23 . In contrast to these in vitro data, it has to be mentioned that a very recent study performed by the same research group and using inducible/cardio-specific OGT-deficient mice submitted to TAC surgery revealed that OGT does not appear to be essential for cardiac hypertrophy development 20 . However, the inducible animal model used in this study, the classical α-MHC-driven mutated estrogen receptor-flanked Cre recombinase, allowed only partial OGT deletion 20 .…”

“…In contrast to these in vitro data, it has to be mentioned that a very recent study performed by the same research group and using inducible/cardio-specific OGT-deficient mice submitted to TAC surgery revealed that OGT does not appear to be essential for cardiac hypertrophy development 20 . However, the inducible animal model used in this study, the classical α-MHC-driven mutated estrogen receptor-flanked Cre recombinase, allowed only partial OGT deletion 20 . It is tempting to hypothesize that such partial deletion is not sufficient to have a significant impact on hypertrophy development.…”

“…HBP is involved in multiple physiological processes but is also associated with undesirable cellular events in chronic diseases, such as diabetes inducing adverse effects in the heart 18 , 19 . In relation to cardiac pathologies, O-GlcNAcylation levels are increased during acute myocardial ischemia and chronic heart failure, but in these cases, with a cardioprotective effect 18 , 20 , 21 . The role of O-GlcNAc during cardiac hypertrophy development is complex and still remains partly unclear 18 , 21 .…”

Cardiac-specific overexpression of aldehyde dehydrogenase 2 exacerbates cardiac remodeling in response to pressure overload

“…All surgical animal procedures were performed in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and were approved by the University of Louisville Institutional Animal Care and Use Committee. Adult,12–20-week-old, male wild-type (WT) mice on the C57BL/6J background were subjected to transverse aortic constriction (TAC) as previously described [22] , [23] , [24] . To examine the influence of ALDH2 expression, we used ALDH2 Tg mice and their nontransgenic (NTg) littermates.…”