林西替尼(OSI-906)通过AMPK/SIRT3信号通路 抑制血管紧张素n诱导的小鼠心肌肥大袞.

AIM: To explore the beneficial effects and underlying mechanisms of linsitinib (OSI-906) on angiotensin II (Ang II) -induced cardiac hypertrophy in mice. METHODS: Thirty C57BL/6J mice were randomly divided into 3 groups (10 mice each group): control group, model (Ang II)group, and Ang II+OSI-906 group. Myocardial hypertrophy mouse model was constructed by treating with Ang II(2 mg* *kg_1 *d_1) with the subcutaneous injection for 2 weeks, and the Ang II+OSI-906 group was given OSI-906(50 mg/kg) by gastric irrigation on this basis. Using hematoxylin-eosin (HE)staining, the pathological changes of heart tissue of mice were evaluated. Using RT-qPCR, the related mRNA levels of heart tissues of mice were detected. The protein expressions of the AMPK/SIRT3 signaling pathway were detected using Western blot assay. The indicators of oxidative stress, including malondialdehyde(MDA), catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were detected by ELISA kits. RESULTS: Compared with model group, the cardiac mass indexes(HW/BW and HW/TL) were significantly decreased in Ang Il-treated mice with OSI-906-treatment (PVO. 05). Moreover, OSI-906-treatment showed the similar alterations on the pathological changes of heart tissues. The mRNA levels of atrial natriuretic peptide(ANP), brain natriuretic peptide(BNP), and the inflammatory cytokines of tumor necrosis factor-a(TNF-ot), interleukin lp(IL-Ip) and interleukin 6(IL-6) were all significantly down-regulated in the heart tissues of mice in Ang II+OSI-906 group (PV0. 05). Furthermore, the level of MDA was significantly decreased(PVO.01), but the levels of SOD, CAT and GSH-Px were increased (P<0. 05). The phosphorylation of AMP-activated protein kinase (p-AMPK)and silent information regulator 3 (SIRT3) were up-regulated (P<0. 05). Consistently, the mRNA expressions of ANP, BNP and myosin heavy chain (p-MHC) were significantly increased in primary neonatal mice cardiomyocytes treated with Compound C, a blocker of AMPK signaling. CONCLUSION: OSI-906 significantly inhibited Ang Il-induced myocardial inflammation and oxidative stress in mice, and may play a cardioprotective role through the AMPK/SIRT3 signaling pathway. [ABSTRACT FROM AUTHOR]