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Inhibition of MicroRNA-146a and Overexpression of Its Target Dihydrolipoyl Succinyltransferase Protect Against
Ward A Heggermont1, Anna-Pia Papageorgiou1, Annelies Quaegebeur1
1From 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.).
Insights
MicroRNA-146a and its target DLST are key metabolic factors in heart failure. Inhibiting microRNA-146a or increasing DLST protects against cardiac dysfunction and hypertrophy.
Area of Science:
- Cardiovascular Research
- Molecular Biology
- Metabolic Regulation
Background:
- Cardiovascular diseases, particularly heart failure, are a leading global cause of death.
- Despite understanding metabolic changes in heart failure, effective therapies remain limited.
Purpose of the Study:
- To investigate the role of microRNA-146a in pressure overload-induced cardiac dysfunction.
- To explore the therapeutic potential of targeting microRNA-146a and its downstream effectors.
Main Methods:
- Utilized murine models of pressure overload (angiotensin-II infusion, aortic constriction).
- Manipulated microRNA-146a levels (knockout, overexpression) and dihydrolipoyl succinyltransferase (DLST) expression in cardiomyocytes.
- Employed adeno-associated virus for DLST overexpression in murine hearts.
Main Results:
- MicroRNA-146a was upregulated in pressure-overloaded murine hearts and human aortic stenosis biopsies.
- MicroRNA-146a overexpression induced cardiac hypertrophy and dysfunction; its inhibition attenuated these effects.
- MicroRNA-146a targets DLST, a key enzyme in the tricarboxylic acid cycle, impacting oxidative metabolism.
- DLST levels decreased with pressure overload, correlating with reduced oxidative metabolism; this was preserved in microRNA-146a knockout models.
- DLST overexpression protected against cardiac hypertrophy and dysfunction.
Conclusions:
- MicroRNA-146a and its target DLST are critical metabolic regulators in left ventricular dysfunction.
- Targeting the microRNA-146a/DLST axis presents a potential therapeutic strategy for heart failure.
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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