AQP4‐knockout aggravation of isoprenaline‐induced myocardial injury is mediated by p66Shc and endoplasmic reticulum stress

Abstract

Aquaporin 4 (AQP4) is a type of water channel protein that maintains the water balance of cardiomyocytes. However, the physiological role of AQP4 in cardiovascular disease is poorly understood. We wanted to explore whether p66Shc and endoplasmic reticulum stress participates in AQP4 knockout (KO)-mediated cardiac injury. There were two types of mice: AQP4 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 AQP4. Results showed increased left ventricular weight index and more severe myocardial inflammation were induced in AQP4 knockout mice relative to wild-type mice, accompanied by significantly increased levels of the oxidative stress biomarkers MDA and NOX4. In addition, the expressions of p66Shc, ER stress markers PERK, GRP78 and CHOP and proinflammatory factors such as ET , IL6 and TNFα were upregulated in the myocardium of AQP4 knockout mice or AQP4 siRNA treated cardiomyocytes, whereas CASQ2 was downregulated. ISO stimulation aggravated these abnormalities, which were significantly attenuated by apocynin. This study showed that AQP4 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.

The PKCβ-p66shc-NADPH oxidase pathway plays a crucial role in diabetic nephropathy

“…found that p66shc gene‐deficient mice had increased resistance to environmental stressors such as hydrogen peroxide and ultraviolet rays, while their life expectancy increased by 30%. Cheng YS et al demonstrated that upregulation of p66shc increased the production of ROS, aggravated oxidative damage of cells and participated in myocardial injury, corpus cavernosum dysfunction and renal dysfunction . Diabetic nephropathy and ageing have a common mechanism, oxidative stress, and p66shc plays a key role in ageing‐related diseases.…”

“…Cheng YS et al demonstrated that upregulation of p66shc increased the production of ROS, aggravated oxidative damage of cells and participated in myocardial injury, corpus cavernosum dysfunction and renal dysfunction. [5][6][7] Diabetic nephropathy and ageing have a common mechanism, oxidative stress, and p66shc plays a key role in ageing-related diseases. Therefore, there is increasing recognition of the role of p66shc in DN.…”

Identification of biomarkers, pathways and potential therapeutic targets for heart failure using bioinformatics analysis

“…[109], FGF12 [110], AQP4 [111], LMOD2 [112], SELENBP1 [113], MB (myoglobin) [114], S100A1 [115], RYR2 [116], GPC5 [117], JARID2 [118], EGFR (epidermal growth factor receptor) [119], FUNDC1 [120], S1PR1 [121], EPAS1 [122] and OSBPL11 [123] genes are a potential biomarkers for the detection and prognosis of HF at an early age. A previous study reported that CALR (calreticulin) [124], BSCL2 [125], PKD1 [126], TMBIM1 [127], CHST15 [128], NAA10 [129], TCF3 [130], CNN1 [131], TAF1A [132], ACAD9 [133], KLHL24 [134], MYOM2 [135], TRIM63 [136] [210] are the key biomarkers in cardiac hypertrophy.…”

Aquaporin Channels in the Heart—Physiology and Pathophysiology

“…At first glance, heart morphology appeared largely normal in various AQP deficient mice [58,78,83]. However, upon more close examination, cardiac weight was increased in AQP4 KO mice [79,80], but decreased in AQP1 KO mice [32]. The latter was accompanied by decreased cardiomyocyte dimensions [125].…”