Ward A Heggermont1, Anna-Pia Papageorgiou1, Annelies Quaegebeur1, Sophie Deckx1, Paolo Carai1, Wouter Verhesen1, Guy Eelen1, Sandra Schoors1, Rick van Leeuwen1, Sergey Alekseev1, Ies Elzenaar1, Stefan Vinckier1, Peter Pokreisz1, Ann-Sophie Walravens1, Rik Gijsbers1, Chris Van Den Haute1, Alexander Nickel1, Blanche Schroen1, Marc van Bilsen1, Stefan Janssens1, Christoph Maack1, Yigal Pinto1, Peter Carmeliet1, Stephane Heymans2. 1. From Center for Molecular and Vascular Research, Leuven, Belgium (W.H., A.P., S.D., Pa.C., P.P., A.S.W., S.J., S.H.); Center for Heart Failure Research, Department of Cardiology, CARIM School for Cardiovascular Diseases, Maastricht University, The Netherlands (W.H., A.P., S.D., Pa.C., W.V., R.v.L., B.S., M.v.B., S.H.); Cardiovascular Research Center, OLV Hospital, Aalst, Belgium (W.H.); Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, Department of Oncology, Leuven, Belgium (A.Q., G.E., S.S., S.V., Pe.C.); Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, Leuven, Belgium (A.Q., G.E., S.S., S.V., Pe.C.); Amsterdam Medical Center, Amsterdam University, The Netherlands (S.A., I.E., Y.P.); Laboratory for Viral Vector Technology and Gene Therapy, Department of Pharmaceutical and Pharmacological Sciences (R.G., C.V.D.H.), Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences (R.G., C.V.D.H.), Leuven Viral Vector Core, Belgium (R.G., C.V.D.H.); and Klinik für Innere Medezin III, Universitätsklinikum des Saarlandes, Homburg, Germany (A.N., C.M.). 2. From Center for Molecular and Vascular Research, Leuven, Belgium (W.H., A.P., S.D., Pa.C., P.P., A.S.W., S.J., S.H.); Center for Heart Failure Research, Department of Cardiology, CARIM School for Cardiovascular Diseases, Maastricht University, The Netherlands (W.H., A.P., S.D., Pa.C., W.V., R.v.L., B.S., M.v.B., S.H.); Cardiovascular Research Center, OLV Hospital, Aalst, Belgium (W.H.); Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, Department of Oncology, Leuven, Belgium (A.Q., G.E., S.S., S.V., Pe.C.); Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, Leuven, Belgium (A.Q., G.E., S.S., S.V., Pe.C.); Amsterdam Medical Center, Amsterdam University, The Netherlands (S.A., I.E., Y.P.); Laboratory for Viral Vector Technology and Gene Therapy, Department of Pharmaceutical and Pharmacological Sciences (R.G., C.V.D.H.), Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences (R.G., C.V.D.H.), Leuven Viral Vector Core, Belgium (R.G., C.V.D.H.); and Klinik für Innere Medezin III, Universitätsklinikum des Saarlandes, Homburg, Germany (A.N., C.M.). s.heymans@maastrichtuniversity.nl.
Abstract
BACKGROUND: Cardiovascular diseases remain the predominant cause of death worldwide, with the prevalence of heart failure continuing to increase. Despite increased knowledge of the metabolic alterations that occur in heart failure, novel therapies to treat the observed metabolic disturbances are still lacking. METHODS: Mice were subjected to pressure overload by means of angiotensin-II infusion or transversal aortic constriction. MicroRNA-146a was either genetically or pharmacologically knocked out or genetically overexpressed in cardiomyocytes. Furthermore, overexpression of dihydrolipoyl succinyltransferase (DLST) in the murine heart was performed by means of an adeno-associated virus. RESULTS: MicroRNA-146a was upregulated in whole heart tissue in multiple murine pressure overload models. Also, microRNA-146a levels were moderately increased in left ventricular biopsies of patients with aortic stenosis. Overexpression of microRNA-146a in cardiomyocytes provoked cardiac hypertrophy and left ventricular dysfunction in vivo, whereas genetic knockdown or pharmacological blockade of microRNA-146a blunted the hypertrophic response and attenuated cardiac dysfunction in vivo. Mechanistically, microRNA-146a reduced its target DLST-the E2 subcomponent of the α-ketoglutarate dehydrogenase complex, a rate-controlling tricarboxylic acid cycle enzyme. DLST protein levels significantly decreased on pressure overload in wild-type mice, paralleling a decreased oxidative metabolism, whereas DLST protein levels and hence oxidative metabolism were partially maintained in microRNA-146a knockout mice. Moreover, overexpression of DLST in wild-type mice protected against cardiac hypertrophy and dysfunction in vivo. CONCLUSIONS: Altogether we show that the microRNA-146a and its target DLST are important metabolic players in left ventricular dysfunction.
BACKGROUND:Cardiovascular diseases remain the predominant cause of death worldwide, with the prevalence of heart failure continuing to increase. Despite increased knowledge of the metabolic alterations that occur in heart failure, novel therapies to treat the observed metabolic disturbances are still lacking. METHODS:Mice were subjected to pressure overload by means of angiotensin-II infusion or transversal aortic constriction. MicroRNA-146a was either genetically or pharmacologically knocked out or genetically overexpressed in cardiomyocytes. Furthermore, overexpression of dihydrolipoyl succinyltransferase (DLST) in the murine heart was performed by means of an adeno-associated virus. RESULTS: MicroRNA-146a was upregulated in whole heart tissue in multiple murine pressure overload models. Also, microRNA-146a levels were moderately increased in left ventricular biopsies of patients with aortic stenosis. Overexpression of microRNA-146a in cardiomyocytes provoked cardiac hypertrophy and left ventricular dysfunction in vivo, whereas genetic knockdown or pharmacological blockade of microRNA-146a blunted the hypertrophic response and attenuated cardiac dysfunction in vivo. Mechanistically, microRNA-146a reduced its target DLST-the E2 subcomponent of the α-ketoglutarate dehydrogenase complex, a rate-controlling tricarboxylic acid cycle enzyme. DLST protein levels significantly decreased on pressure overload in wild-type mice, paralleling a decreased oxidative metabolism, whereas DLST protein levels and hence oxidative metabolism were partially maintained in microRNA-146a knockout mice. Moreover, overexpression of DLST in wild-type mice protected against cardiac hypertrophy and dysfunction in vivo. CONCLUSIONS: Altogether we show that the microRNA-146a and its target DLST are important metabolic players in left ventricular dysfunction.
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