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J Cell Mol Med. 2019 Jul;23(7):4640-4652. doi: 10.1111/jcmm.14375. Epub 2019 May 18.

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

Yang L1,2, Ma J2,3, Tan Y2,4, Zheng Q3, Dong M2,4,5, Guo W6, Xiong L7, Yang J3, Ren J2.

Author information

1
Department of Anesthesiology, Xi'an Children Hospital, Xi'an, China.
2
Center for Cardiovascular Research and Alternative Medicine, University of Wyoming, Laramie, Wyoming.
3
Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
4
Department of Emergency Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China.
5
Department of Burns, Nanfang Hospital, Southern Medical University, Guangzhou, China.
6
Department of Animal Sciences, University of Wyoming, Laramie, Wyoming.
7
Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.

Abstract

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 NG -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 O 2 - 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.

KEYWORDS:

L-NAME; apoptosis; heart; hypertension; metallothionein

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