Department of Experimental Medicine and Oncology, University of Turin, Corso Raffaello 30, Turin, 10125, Italy.
Cardiovasc Diabetol. 2012 Oct 15;11:129. doi: 10.1186/1475-2840-11-129.
The aim of this study was to investigate whether obestatin (OB), a peptide mediator encoded by the ghrelin gene exerting a protective effect in ischemic reperfused heart, is able to reduce cardiac dysfunctions in adult diabetic rats.
Diabetes was induced by STZ injection (50 mg/kg) in Wistar rats (DM). OB was administered (25 μg/kg) twice a day for 6 weeks. Non-diabetic (ND) rats and DM rats were distributed into four groups: untreated ND, OB-treated ND, untreated DM, OB-treated DM. Cardiac contractility and ß-adrenergic response were studied on isolated papillary muscles. Phosphorylation of AMPK, Akt, ERK1/2 and GSK3ß as well ß-1 adrenoreceptors levels were detected by western blot, while α-MHC was measured by RT-PCR.
OB preserved papillary muscle contractility (85 vs 27% of ND), ß-adrenergic response (103 vs 65% of ND), as well ß1-adrenoreceptors and α-MHC levels in diabetic myocardial tissue. Moreover, OB up-regulated the survival kinases Akt and ERK1/2, and enhanced AMPK and GSK3ß phosphorylation. OB corrected oxidative unbalance, reduced pro-inflammatory cytokine TNF-α plasma levels, NFkB translocation and pro-fibrogenic factors expression in diabetic myocardium.
OB displays a significant beneficial effect against the alterations of contractility and ß-adrenergic response in the heart of STZ-treated diabetic rats, which was mainly associated with the ability of OB to up-regulate the transcription of ß1-adrenergic receptors and α-MHC; this protective effect was accompanied by the ability to restore oxidative balance and to promote phosphorylation/modulation of AMPK and pro-survival kinases such as Akt, ERK1/2 and GSK3ß.
本研究旨在探讨由 ghrelin 基因编码的肽介体 obestatin (OB) 是否具有保护缺血再灌注心脏的作用，是否能减轻成年糖尿病大鼠的心脏功能障碍。
STZ 注射（50mg/kg）诱导 Wistar 大鼠（DM）糖尿病。OB 每天两次（25μg/kg）给药 6 周。非糖尿病（ND）大鼠和 DM 大鼠分为四组：未治疗 ND、OB 治疗 ND、未治疗 DM、OB 治疗 DM。用离体乳头肌研究心脏收缩性和 β-肾上腺素能反应。通过 Western blot 检测 AMPK、Akt、ERK1/2 和 GSK3ß 的磷酸化以及 β1-肾上腺素能受体水平，同时通过 RT-PCR 测量 α-MHC。
OB 保留了乳头肌的收缩力（85% vs ND 的 27%），β-肾上腺素能反应（103% vs ND 的 65%），以及糖尿病心肌组织中的 β1-肾上腺素能受体和 α-MHC 水平。此外，OB 上调了存活激酶 Akt 和 ERK1/2，并增强了 AMPK 和 GSK3ß 的磷酸化。OB 纠正了氧化失衡，降低了糖尿病心肌中促炎细胞因子 TNF-α 的血浆水平、NFkB 易位和促纤维化因子的表达。
OB 对 STZ 处理的糖尿病大鼠心脏收缩力和 β-肾上腺素能反应的改变具有显著的有益作用，这主要与 OB 上调 β1-肾上腺素能受体和 α-MHC 转录的能力有关；这种保护作用伴随着恢复氧化平衡和促进磷酸化/调节 AMPK 和 Akt、ERK1/2 和 GSK3ß 等存活激酶的能力。
