Cardiac-specific overexpression of metallothionein attenuates L-NAME-induced myocardial contractile anomalies and apoptosis.

Hypertension contributes to the high cardiac morbidity and mortality. Although oxidative stress plays an essential role in hypertensive heart diseases, the mechanism remains elusive. Transgenic mice with cardiac overexpression of metallothionein, a heavy metal-binding scavenger, were challenged with N^G -nitro-L-arginine methyl ester (L-NAME) for 14 days prior to measurement of myocardial contractile and intracellular Ca²⁺ anomalies as well as cell signalling mechanisms using Western blot and immunofluorescence analysis. L-NAME challenge elicited hypertension, macrophage infiltration, oxidative stress, inflammation and cardiac dysfunction manifested as increased proinflammatory macrophage marker F4/80, interleukin-1β (IL-1β), intracellular $$ production, LV end systolic and diastolic diameters as well as depressed fractional shortening. L-NAME treatment reduced mitochondrial membrane potential (MMP), impaired cardiomyocyte contractile and intracellular Ca²⁺ properties as evidenced by suppressed peak shortening, maximal velocity of shortening/relengthening, rise in intracellular Ca²⁺ , along with elevated baseline and peak intracellular Ca²⁺ . These unfavourable mechanical changes and decreased MMP (except blood pressure and macrophage infiltration) were alleviated by overexpression of metallothionein. Furthermore, the apoptosis markers including BAD, Bax, Caspase 9, Caspase 12 and cleaved Caspase 3 were up-regulated while the anti-apoptotic marker Bcl-2 was decreased by L-NAME treatment. Metallothionein transgene reversed L-NAME-induced changes in Bax, Bcl-2, BAD phosphorylation, Caspase 9, Caspase 12 and cleaved Caspase 3. Our results suggest that metallothionein protects against L-NAME-induced myocardial contractile anomalies in part through inhibition of apoptosis. © 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

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