Cationic microbubble loading hSIRT3 and hTIMP3 optimize cardiac-targeted delivery and myocardial protection in the porcine MI/R model

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.