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

Autor: V.J. Kosgei, C. Arnold, F. Elkhafifi, P. Lacolley, S. Hergalant, L. Monassier, M. Fatiha, J.L. Guéant, R.M. Guéant-Rodriguez
Přispěvatelé: Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), ICS, Mouse Clinical Institute, Illkirch-Graffenstaden, France, Nancyclotep- Experimental Imaging Platform = Plate-forme d'imagerie moléculaire, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Lorraine (UL)
Rok vydání: 2019
Předmět:
medicine.medical_specialty
Cardiac fibrosis
[SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC]
Cobalamin
chemistry.chemical_compound
[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry
Molecular Biology/Genomics [q-bio.GN]
Internal medicine
[SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB]
[SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO]
[SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO]
Medicine
Vitamin B12
Methionine synthase
[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry
Molecular Biology/Biochemistry [q-bio.BM]
ComputingMilieux_MISCELLANEOUS
2. Zero hunger
[INFO.INFO-DB]Computer Science [cs]/Databases [cs.DB]
Ejection fraction
Methionine
biology
business.industry
Hypertrophic cardiomyopathy
[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry
Molecular Biology/Molecular biology
[SDV.BBM.MN]Life Sciences [q-bio]/Biochemistry
Molecular Biology/Molecular Networks [q-bio.MN]
[SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism
medicine.disease
[SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM]
3. Good health
[MATH.MATH-PR]Mathematics [math]/Probability [math.PR]
[SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics
Endocrinology
chemistry
Heart failure
biology.protein
[INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM]
Cardiology and Cardiovascular Medicine
business
[SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Zdroj: Archives of Cardiovascular Diseases Supplements
Archives of Cardiovascular Diseases Supplements, Elsevier/French Society of Cardiology, 2019, 11 (2), pp.242. ⟨10.1016/j.acvdsp.2019.02.131⟩
ISSN: 1878-6480
DOI: 10.1016/j.acvdsp.2019.02.131
Popis: Introduction 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. Purpose 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. Methods 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. Results 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. Conclusion 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.
Databáze: OpenAIRE
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