Hypertension is an independent risk factor for
heart disease and is responsible for the increased cardiac morbidity and mortality. Oxidative stress plays a key role in hypertensive
heart diseases although the precise mechanism remains unclear. This study was designed to examine the effect of cardiac-specific overexpression of
metallothionein, a cysteine-rich
antioxidant, on myocardial contractile and intracellular Ca(2+) anomalies in
N(G)-nitro-l-arginine methyl ester (
l-NAME)-induced experimental
hypertension and the mechanism involved with a focus on autophagy. Our results revealed that
l-NAME treatment (14 days) led to
hypertension and myocardial anomalies evidenced by interstitial
fibrosis, cardiomyocyte
hypertrophy, increased LV end systolic and diastolic diameters (LVESD and LVEDD) along with suppressed fractional shortening.
l-NAME compromised cardiomyocyte contractile and intracellular Ca(2+) properties manifested as depressed peak shortening, maximal velocity of shortening/relengthening, electrically-stimulated rise in intracellular Ca(2+), elevated baseline and peak intracellular Ca(2+). These
l-NAME-induced histological and mechanical changes were attenuated or reconciled by
metallothionein.
Protein levels of autophagy markers LC3B and p62 were decreased and increased, respectively. Autophagy signaling molecules AMPK, TSC2 and ULK1 were inactivated while those of mTOR and
p70s6K were activated by
l-NAME, the effects of which were ablated by
metallothionein. Autophagy induction mimicked whereas autophagy inhibition nullified the beneficial effect of
metallothionein against
l-NAME. These findings suggested that
metallothionein protects against
l-NAME-induced myocardial anomalies possibly through restoration of autophagy.