Cardiac manifestations of inherited metabolic disease linked to cellular vitamin B12 uptake: Study in murine model of invalidation of Mtr gene in the heart

Abstract

Heart failure is one of the most common causes of death in the Western societies and its incidence is increasing in the non developing countries. Deficiency in methyl donors (folates and vitamin B12) during gestation and lactation causes a foetal programming effect with cardiomyopathy related to decreased synthesis of methionine by methionine synthase (MTR). Methionine is the precursor for S-adenosyl methionine (SAM) the universal methyl donor for epigenomic regulations. Mutation in MTR gene causes cardiac decompensation in the new-borns by unknown mechanisms. The objective of our study is to investigate the metabolic and functional consequences of long-term inhibition of synthesis of methionine and SAM in mice model of conditional knock out of Mtr gene in the heart (MTR KO). Deletion of the Mtr gene in C57BL/6 mice was achieved by Cre/Lox system. Systolic Blood Pressure (SBP) in conscious mice was measured by tail-cuff system. left-ventricular (LV) function, cardiac morphology and tissue perfusion were assessed by MiniPET and Echocardiography. RT-qPCR was used for gene expression analysis while proteomic study on total heart proteins was achieved by LC-MS/MS. Systolic hypertension, a significant decrease in LV ejection fraction percentage and increase in LV mass was observed in MTR KO mice as compared to the control. Moreover, RT-qPCR confirmed an upregulated expression of the hallmarks of heart failure: natriuretic peptides (ANP and BNP) in MTR KO mice. Metabolic and biochemical studies in heart tissue showed significant decrease in SAM/SAH, cardiac fibrosis, elevated plasma acyl carnitine levels and different mitochondrial protein expression in MTR KO mice. Our results suggest that methionine synthase dysfunction induces hypertension, cardiac hypertrophy, fibrosis, ventricular dysfunction and dysregulated energy metabolism in the heart.