Fumarate hydratase ameliorates pressure overload induced cardiac remodeling by controlling Elovl7-mediated biosynthesis of unsaturated fatty acids.

Pathological cardiac hypertrophy as a major contributor to heart failure is characterized by complicated mechanisms. Fumarate hydratase (FH) is a crucial enzyme in the tricarboxylic acid cycle. FH mutations and dysfunction have been implicated in various pathological processes including hereditary leiomyomatosis and renal cell cancer, neurodegenerative diseases, metabolic syndrome and cardiovascular diseases. In this study we investigated the role of FH in cardiac hypertrophy. Cardiac hypertrophy was induced in mice by transverse aortic constriction (TAC) surgery as well as in neonatal rat cardiomyocytes (NRCMs) by phenylephrine (PE) stimulation. We showed that the expression levels of FH were gradually increased with development of cardiac hypertrophy in TAC mice. Cardiomyocyte-specific overexpression of FH by intravenous injection of recombinant adeno-associated virus serotype 9 (AAV9) carrying FH two weeks before TAC surgery prevented the morphological changes, cardiac dysfunction and remodeling in TAC mice; FH overexpression also significantly attenuated PE-induced hypertrophy in NRCMs along with suppressed expression of hypertrophic markers ANP, BNP and β-MHC. We demonstrated that FH overexpression alleviated TAC-induced mitochondrial structural damage in cardiomyocytes and facilitated metabolic remodeling. RNA sequencing and untargeted metabolomics revealed that FH overexpression mitigated myocardial remodeling and mitochondrial metabolism dysfunction in TAC mice mainly by suppressing the transcription factor SREBP and reducing the gene expression of elongation of very long chain fatty acids protein 7 (Elovl7). Overexpression of Elovl7 reversed the protective effects of FH in both TAC mice and PE-stimulated NRCMs. Knockdown of the transcription factor SREBP reduced Elovl7 expression, thereby exerting cardioprotective effects. In conclusion, we demonstrate that FH overexpression prevents cardiac hypertrophy in mice by regulating glucose and lipid metabolism through the malate-SREBP-Elovl7 pathway.