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AQP4‐knockout aggravation of isoprenaline‐induced myocardial injury is mediated by p66Shc and endoplasmic reticulum stress
Author(s) -
Cheng Yusi,
Chao Jie,
Dai Dezai,
Dai Yin,
Zhu Dongdong,
Liu Bicheng
Publication year - 2017
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/1440-1681.12812
Subject(s) - endoplasmic reticulum , proinflammatory cytokine , apocynin , unfolded protein response , knockout mouse , endocrinology , oxidative stress , medicine , isoprenaline , nox4 , chemistry , nadph oxidase , wild type , inflammation , stimulation , mutant , biochemistry , receptor , gene
Summary Aquaporin 4 ( AQP 4) is a type of water channel protein that maintains the water balance of cardiomyocytes. However, the physiological role of AQP 4 in cardiovascular disease is poorly understood. We wanted to explore whether p66Shc and endoplasmic reticulum stress participates in AQP 4 knockout ( KO )‐mediated cardiac injury. There were two types of mice: AQP 4 knockout and wild‐type mice. Each type was randomly divided into three groups: Control group, isoprenaline stimulation group ( ISO , 1 mg/kg, s.c., 5 days), and apocynin treatment group ( APO , 100 mg/kg, p.o., 3 days). H9c2 rat cardiomyocytes were cultured for RNA interference of AQP 4. Results showed increased left ventricular weight index and more severe myocardial inflammation were induced in AQP 4 knockout mice relative to wild‐type mice, accompanied by significantly increased levels of the oxidative stress biomarkers MDA and NOX 4. In addition, the expressions of p66Shc, ER stress markers PERK , GRP 78 and CHOP and proinflammatory factors such as ET A , IL 6 and TNF α were upregulated in the myocardium of AQP 4 knockout mice or AQP 4 si RNA treated cardiomyocytes, whereas CASQ 2 was downregulated. ISO stimulation aggravated these abnormalities, which were significantly attenuated by apocynin. This study showed that AQP 4 knockout mice were susceptible to cardiac injury induced by ISO . The mechanism was closely connected with p66Shc and proinflammatory factors. Endoplasmic reticulum stress was also involved in the pathological process.