Abstract
Heart failure is one of the most common cause of death in Western societies. Deficiency in folates and vitamin B12 during gestation and lactation causes foetal programming effect with metabolic cardiomyopathy related to decreased synthesis of methionine by methionine synthase encoded by MTR Gene. Methionine is the precursor for S-adenosyl methionine (SAM) the universal methyl donor. Mutations in MTR gene causes cardiac decompensation in new-borns by unknown mechanisms. To investigate cardiac metabolic and functional consequences of inhibition of methionine synthesis in conditional knock out of Mtr gene in the heart of C57BL/6 mice. Systolic Blood Pressure in conscious mice was measured using tail-cuff plethysmography. Left ventricular (LV) functions were assessed by Mini-PET and Echocardiography. Transcriptomics analysis was achieved by RNA deep sequencing and proteomic study by LC-MS/MS. Systolic hypertension, decreased LV ejection fraction, increased LV mass and heart/body weight ratio were observed in Mtr KO compared to control. RT-qPCR confirmed upregulated expression of natriuretic peptides (ANP and BNP) and decreased alpha MHC/beta MHC ratio in Mtr KO. Biochemical studies revealed decreased SAM/SAH ratio, elevated plasma acylcarnitine and cardiac fibrosis in Mtr KO. The whole heart transcriptome consisted of 16540 expressed genes which were clustered by K-means into three signatures, these signatures were correlated to proteomic results. Dysregulated genes and proteins in Mtr KO were implicated in cardiac contraction, cell growth and energy metabolism. Our results suggest that silencing of Methionine synthase in the heart induces hypertension, hypertrophic cardiomyopathy with LV systolic dysfunction. The related mechanisms were dysregulation of energy metabolism and fibrosis. This data provides a novel insight on physiopathological mechanisms of cardiomyopathies of inherited disorders of cobalamin metabolism.
Published Version
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