MuRF2 regulates PPARγ1 activity to protect against diabetic cardiomyopathy and enhance weight gain induced by a high fat diet

dc.contributor.authorHe, Junen_ZA
dc.contributor.authorQuintana, Megan T.en_ZA
dc.contributor.authorSullivan, Jenythen_ZA
dc.contributor.authorParry, Traci L .en_ZA
dc.contributor.authorGrevengoed, Trisha J.en_ZA
dc.contributor.authorSchisler, Jonathan C.en_ZA
dc.contributor.authorHill, Joseph A.en_ZA
dc.contributor.authorYates, Cecelia C.en_ZA
dc.contributor.authorMapanga, Rudo F.en_ZA
dc.contributor.authorEssop, M. Faadielen_ZA
dc.contributor.authorStansfield, William E.en_ZA
dc.contributor.authorBain, James R.en_ZA
dc.contributor.authorNewgard, Christopher B.en_ZA
dc.contributor.authorMuehlbauer, Michael J.en_ZA
dc.contributor.authorHan, Yipinen_ZA
dc.contributor.authorClarke, Brian A.en_ZA
dc.contributor.authorWillis, Monte S.en_ZA
dc.date.accessioned2017-01-19T07:12:43Z
dc.date.available2017-01-19T07:12:43Z
dc.date.issued2015
dc.date.updated2016-12-09T10:07:57Z
dc.descriptionCITATION: He, J., et al. 2015. MuRF2 regulates PPARγ1 activity to protect against diabetic cardiomyopathy and enhance weight gain induced by a high fat diet. Cardiovascular Diabetology, 14:97, doi:10.1186/s12933-015-0252-x.en_ZA
dc.descriptionThe original publication is available at http://cardiab.biomedcentral.comen_ZA
dc.description.abstractBackground: In diabetes mellitus the morbidity and mortality of cardiovascular disease is increased and represents an important independent mechanism by which heart disease is exacerbated. The pathogenesis of diabetic cardiomyopathy involves the enhanced activation of PPAR transcription factors, including PPARα, and to a lesser degree PPARβ and PPARγ1. How these transcription factors are regulated in the heart is largely unknown. Recent studies have described post-translational ubiquitination of PPARs as ways in which PPAR activity is inhibited in cancer. However, specific mechanisms in the heart have not previously been described. Recent studies have implicated the musclespecific ubiquitin ligase muscle ring finger-2 (MuRF2) in inhibiting the nuclear transcription factor SRF. Initial studies of MuRF2−/− hearts revealed enhanced PPAR activity, leading to the hypothesis that MuRF2 regulates PPAR activity by post-translational ubiquitination. Methods: MuRF2−/− mice were challenged with a 26-week 60% fat diet designed to simulate obesity-mediated insulin resistance and diabetic cardiomyopathy. Mice were followed by conscious echocardiography, blood glucose, tissue triglyceride, glycogen levels, immunoblot analysis of intracellular signaling, heart and skeletal muscle morphometrics, and PPARα, PPARβ, and PPARγ1-regulated mRNA expression. Results: MuRF2 protein levels increase ~20% during the development of diabetic cardiomyopathy induced by high fat diet. Compared to littermate wildtype hearts, MuRF2−/− hearts exhibit an exaggerated diabetic cardiomyopathy, characterized by an early onset systolic dysfunction, larger left ventricular mass, and higher heart weight. MuRF2−/− hearts had significantly increased PPARα- and PPARγ1-regulated gene expression by RT-qPCR, consistent with MuRF2’s regulation of these transcription factors in vivo. Mechanistically, MuRF2 mono-ubiquitinated PPARα and PPARγ1 in vitro, consistent with its non-degradatory role in diabetic cardiomyopathy. However, increasing MuRF2:PPARγ1 (>5:1) beyond physiological levels drove poly-ubiquitin-mediated degradation of PPARγ1 in vitro, indicating large MuRF2 increases may lead to PPAR degradation if found in other disease states. Conclusions: Mutations in MuRF2 have been described to contribute to the severity of familial hypertrophic cardiomyopathy. The present study suggests that the lack of MuRF2, as found in these patients, can result in an exaggerated diabetic cardiomyopathy. These studies also identify MuRF2 as the first ubiquitin ligase to regulate cardiac PPARα and PPARγ1 activities in vivo via post-translational modification without degradation.en_ZA
dc.description.urihttp://cardiab.biomedcentral.com/articles/10.1186/s12933-015-0252-x
dc.description.versionPublisher's versionen_ZA
dc.format.extent24 pages : illustrationsen_ZA
dc.identifier.citationHe, J., et al. 2015. MuRF2 regulates PPARγ1 activity to protect against diabetic cardiomyopathy and enhance weight gain induced by a high fat diet. Cardiovascular Diabetology, 14:97, doi:10.1186/s12933-015-0252-xen_ZA
dc.identifier.issn1475-2840 (online)
dc.identifier.issn1475-2840 (Print)
dc.identifier.otherdoi:10.1186/s12933-015-0252-x
dc.identifier.urihttp://hdl.handle.net/10019.1/100487
dc.language.isoen_ZAen_ZA
dc.publisherBioMed Centralen_ZA
dc.rights.holderAuthors retain copyrighten_ZA
dc.subjectCardiovascular diseaseen_ZA
dc.subjectDiabetes mellitusen_ZA
dc.subjectDiabetic cardiomyopathyen_ZA
dc.subjectMuscle ring finger-2 (MuRF2)en_ZA
dc.titleMuRF2 regulates PPARγ1 activity to protect against diabetic cardiomyopathy and enhance weight gain induced by a high fat dieten_ZA
dc.typeArticle
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