title: [Oxidative stress and calcium/calmodulin-dependent protein kinase II contribute to the development of sustained β adrenergic receptor-stimulated cardiac hypertrophy in rats].
abstract: Sustained activation of β adrenergic receptor (βAR) leads to pathologic cardiac hypertrophy. However, the related mechanisms still remain unclear. In this study, we observe how N-acetylcysteine (NAC) affects the oxidative stress and calcium/calmodulin-dependent protein kinase II (CaMKII) expression in heart of isoproterenol (ISO)-stimulated rats, and investigate whether oxidative stress and CaMKII contribute to the development of sustained βAR-stimulated cardiac hypertrophy. Healthy male Wistar rats were randomly separated into 4 groups: control (CTRL), ISO-treated (ISO), control with NAC supplement (CTRL+NAC) and ISO-treated with NAC supplement (ISO+NAC) groups (6 rats in each group). Systolic blood pressure (SBP) was measured in awake rats with the tail-cuff method every week for two weeks. Heart weight/body weight ratio (HW/BW) and HE staining were used for the detection of myocardial hypertrophy. Myocardial mitochondrial reactive oxygen species (ROS) levels were measured by DCF fluorometry. The expressions of activated-CaMKII (p-CaMKII/CaMKII) and NADPH oxidase 4 (NOX(4)) were determined by Western blot analysis. The results showed that ISO-treated (i.p., daily 3 mg/kg, 2 weeks) rats developed an obvious cardiac hypertrophy as expressed by increases of HW/BW and myocyte cross-section area. Cardiac mitochondrial ROS level was significantly enhanced in ISO group as compared to CTRL group (P < 0.05). The expressions of NOX(4) and p-CaMKII in ISO group were also up-regulated as compared to CTRL group (1.4 and 1.6 times of CTRL, respectively, P < 0.05). NAC supplement significantly suppressed the hypertrophic development of heart in ISO-stimulated rats. The cardiac mitochondrial ROS level showed a significant decrease in rats of ISO+NAC group (P < 0.05 vs ISO). In accordance with this, ISO+NAC group rats also showed marked reductions in the expressions of NOX(4) and p-CaMKII/CaMKII compared to ISO group rats (P < 0.05). There were no significant differences of the detected indices between the rats from CTRL+NAC and CTRL groups. SBP showed no differences among four groups. These results suggest that both oxidative stress and CaMKII play important roles in sustained βAR-stimulated cardiac hypertrophy. NAC may suppress ISO-induced cardiac hypertrophy by down-regulating the expression of activated-CaMKII, and by reducing the level of oxidative stress originated from mitochondria and NADPH oxidase pathways.
authors: Department of Physiology and Pathophysiology, Basic Medical School, Tianjin Medical University, China.
authors: Yan-Li
authors: YL
authors: Liu
authors: Ben
authors: B
authors: Liu
authors: Yang-Yang
authors: YY
authors: Qu
authors: Hui-Juan
authors: HJ
authors: Chai
authors: Rui
authors: R
authors: Li
authors: Ling
authors: L
authors: Zhang
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D006332:Cardiomegaly / Q000503:physiopathology*; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008929:Mitochondria, Heart / Q000378:metabolism; D009206:Myocardium / Q000473:pathology; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D011943:Receptors, Adrenergic, beta; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498911:Nox4 protein, rat; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D007545:Isoproterenol; D000111:Acetylcysteine