Du Jianfeng, Zhang Ling, Wang Zhengke, Yano Naohiro, Zhao Yu Tina, Wei Lei, Dubielecka-Szczerba Patrycja, Liu Paul Y, Zhuang Shougang, Qin Gangjian, Zhao Ting C
Department of Surgery, Roger Williams Medical Center, Boston University Medical School, Boston University, Providence, Rhode Island;
Department of Emergency Medicine, Alpert Medical School, Brown University, Providence, Rhode Island;
Am J Physiol Cell Physiol. 2016 Feb 15;310(4):C270-83. doi: 10.1152/ajpcell.00194.2015. Epub 2016 Jan 6.
We have demonstrated that glucagon like peptide-1 (GLP-1) protects the heart against ischemic injury. However, the physiological mechanism by which GLP-1 receptor (GLP-1R) initiates cardioprotection remains to be determined. The objective of this study is to elucidate the functional roles of MAPK kinase 3 (MKK3) and Akt-1 in mediating exendin-4-elicited protection in the infarcted hearts. Adult mouse myocardial infarction (MI) was created by ligation of the left descending artery. Wild-type, MKK3(-/-), Akt-1(-/-), and Akt-1(-/-);MKK3(-/-) mice were divided into one of several groups: 1) sham: animals underwent thoracotomy without ligation; 2) MI: animals underwent MI and received a daily dose of intraperitoneal injection of vehicle (saline); 3) MI + exendin-4: infarcted mice received daily injections of exendin-4, a GLP-1R agonist (0.1 mg/kg, ip). Echocardiographic measurements indicate that exendin-4 treatment resulted in the preservation of ventricular function and increases in the survival rate, but these effects were diminished in MKK3(-/-), Akt-1(-/-), and Akt-1(-/-);MKK3(-/-) mice. Exendin-4 treatments suppressed cardiac hypotrophy and reduced scar size and cardiac interstitial fibrosis, respectively, but these beneficial effects were lost in genetic elimination of MKK3, Akt-1, or Akt-1(-/-);MKK3(-/-) mice. GLP-1R stimulation stimulated angiogenic responses, which were also mitigated by deletion of MKK3 and Akt-1. Exendin-4 treatment increased phosphorylation of MKK3, p38, and Akt-1 at Ser129 but decreased levels of active caspase-3 and cleaved poly (ADP-ribose) polymerase; these proteins were diminished in MKK3(-/-), Akt-1(-/-), and Akt-1(-/-);MKK3(-/-) mice. These results reveal that exendin-4 treatment improves cardiac function, attenuates cardiac remodeling, and promotes angiogenesis in the infarcted myocardium through MKK3 and Akt-1 pathway.
我们已经证明，胰高血糖素样肽-1（GLP-1）可保护心脏免受缺血性损伤。然而，GLP-1受体（GLP-1R）启动心脏保护作用的生理机制仍有待确定。本研究的目的是阐明丝裂原活化蛋白激酶激酶3（MKK3）和Akt-1在介导艾塞那肽-4对梗死心脏的保护作用中的功能作用。通过结扎左冠状动脉前降支建立成年小鼠心肌梗死（MI）模型。将野生型、MKK3基因敲除（-/-）、Akt-1基因敲除（-/-）以及Akt-1基因敲除（-/-）；MKK3基因敲除（-/-）小鼠分为以下几组：1）假手术组：动物接受开胸手术但不结扎；2）MI组：动物接受MI手术并每日腹腔注射溶媒（生理盐水）；3）MI + 艾塞那肽-4组：梗死小鼠每日注射艾塞那肽-4，一种GLP-1R激动剂（0.1 mg/kg，腹腔注射）。超声心动图测量结果表明，艾塞那肽-4治疗可保留心室功能并提高生存率，但在MKK3基因敲除（-/-）、Akt-1基因敲除（-/-）以及Akt-1基因敲除（-/-）；MKK3基因敲除（-/-）小鼠中这些作用减弱。艾塞那肽-4治疗分别抑制了心脏肥大并减小了瘢痕大小和心脏间质纤维化，但在MKK3、Akt-1基因敲除或Akt-1基因敲除（-/-）；MKK3基因敲除（-/-）小鼠中这些有益作用消失。GLP-1R刺激可激发血管生成反应，而MKK3和Akt-1基因缺失也减弱了这种反应。艾塞那肽-4治疗增加了MKK3、p38和Akt-1在Ser129位点的磷酸化，但降低了活性半胱天冬酶-3和裂解的聚（ADP-核糖）聚合酶的水平；这些蛋白在MKK3基因敲除（-/-）、Akt-1基因敲除（-/-）以及Akt-1基因敲除（-/-）；MKK3基因敲除（-/-）小鼠中减少。这些结果表明，艾塞那肽-4治疗可通过MKK3和Akt-1途径改善梗死心肌的心脏功能、减轻心脏重塑并促进血管生成。
