Cai Peian, Chen Kegong, Qin Xionghai, Jiang Xingpei, Jiao Xuan, Liu Kexun, Guo Erliang, Li Zipeng, Qiu Xianxin, Liu Chang, Sun Lu, Chuai Junbo, Wu Jie, Chen Wei, Tian Hai
Department of Cardiovascular Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang province, China.
Future Medical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang province, China.
Mater Today Bio. 2025 Aug 22;34:102234. doi: 10.1016/j.mtbio.2025.102234. eCollection 2025 Oct.
Myocardial ischemia-reperfusion (MI/R) injury limits the therapeutic effects of revascularization in acute myocardial infarction. In this study, we investigated whether human SIRT3 (hSIRT3) and TIMP3 (hTIMP3) could achieve targeted delivery with the assist of cationic microbubbles (CMBs) and a synergistic protection effect on porcine MI/R myocardium. Firstly, CMBs carrying the hSIRT3 or hTIMP3 plasmids were used individually or synergistically for cardiac-targeted delivery in MI/R pigs. After 7 days of observation, hSIRT3 and hTIMP3 were mainly enriched in myocardium, especially in the infarction center, without additional increase in cTNI and pathological damage to non-cardiac organs. At the same time, hSIRT3 and hTIMP3 exerted a protective role against myocardial injury, as gene therapy significantly inhibited myocardial apoptosis, inflammation and oxidative damage. After 90 days of observation, hSIRT3 and hTIMP3 application exerted an inhibiting effect on development of heart failure, as the strategy significantly increased the density of vascular, and limited the myocardial fibrosis, area scar size, the decline of cardiac function. As expected, collaborative applications of hSIRT3 and hTIMP3 showed a better protective effect than hSIRT3 or hTIMP3 application alone. Collectively, hSIRT3 and hTIMP3 delivered with CMBs in heart could exert positive effect on myocardial protection after MI/R in pigs.
心肌缺血再灌注（MI/R）损伤限制了急性心肌梗死血管重建术的治疗效果。在本研究中，我们探究了人SIRT3（hSIRT3）和金属蛋白酶组织抑制因子3（hTIMP3）能否在阳离子微泡（CMB）的辅助下实现靶向递送，并对猪MI/R心肌产生协同保护作用。首先，携带hSIRT3或hTIMP3质粒的CMB单独或协同用于MI/R猪的心脏靶向递送。观察7天后，hSIRT3和hTIMP3主要富集于心肌，尤其是梗死中心，而肌钙蛋白I（cTNI）无额外增加，非心脏器官也无病理损伤。同时，hSIRT3和hTIMP3对心肌损伤发挥了保护作用，因为基因治疗显著抑制了心肌细胞凋亡、炎症和氧化损伤。观察90天后，应用hSIRT3和hTIMP3对心力衰竭的发展产生了抑制作用，因为该策略显著增加了血管密度，限制了心肌纤维化、梗死面积和心脏功能下降。正如预期的那样，hSIRT3和hTIMP3联合应用比单独应用hSIRT3或hTIMP3显示出更好的保护作用。总的来说，CMB携带的hSIRT3和hTIMP3在心脏中递送可对猪MI/R后的心肌保护产生积极作用。
