Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Cardiac & Cardiovascular Systems, Peripheral Vascular Disease, Cardiovascular System & Cardiology, cardiac dysfunction, heart failure, metabolic remodeling, microRNA, KETOGLUTARATE DEHYDROGENASE COMPLEX, HEART-FAILURE, ENDOTHELIAL DYSFUNCTION, METABOLISM, DICHLOROACETATE, GLYCOLYSIS, OXIDATION, STRESS, Acyltransferases, Animals, Animals, Newborn, Cardiomegaly, Cells, Cultured, Gene Expression Regulation, Enzymologic, Humans, Mice, Mice, Inbred C57BL, Mice, Knockout, MicroRNAs, Myocytes, Cardiac, Rats, Rats, Inbred Lew, Ventricular Dysfunction, Left, 1102 Cardiorespiratory Medicine and Haematology, 1103 Clinical Sciences, 1117 Public Health and Health Services, Cardiovascular System & Hematology, 3201 Cardiovascular medicine and haematology, 3202 Clinical sciences, 4207 Sports science and exercise

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 (TAC). 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 (AAV9). Results -MicroRNA-146a was up-regulated in whole heart tissue in multiple murine pressure overload models. Also, microRNA-146a levels were moderately increased in left ventricular biopsies of aortic stenosis patients. While overexpression of microRNA-146a in cardiomyocytes provoked cardiac hypertrophy and LV dysfunction in vivo, genetic knockdown or pharmacological blockade of microRNA-146a blunted the hypertrophic response and attenuated cardiac dysfunction in vivo. Mechanistically, microRNA-146a reduced its target dihydrolipoyl succinyltransferase (DLST) - the E2 subcomponent of the α-ketoglutarate dehydrogenase complex (KGDHC), a rate-controlling tricarboxylic acid (TCA) cycle enzyme. While DLST protein levels significantly decreased upon pressure overload in wild type mice - paralleling a decreased oxidative metabolism, 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 LV dysfunction.