| New therapies targeting myocardial ischemia/reperfusion (I/R) injury are key to averting the adverse remodeling process and subsequent heart failure (HF) post myocardial infarction (MI). S100A6 is a member of the superfamily of EF-hand Ca2+-binding proteins that modulate many key pathways involved in myocardial I/R injury and adverse left ventricular remodeling including cardiomyocyte apoptosis and hypertrophy.;Methods and Results. S100A6 overexpression improved calcium transients and protected against apoptosis induced by hypoxia-reoxygenation via enhanced calcineurin activity, while knockdown of S100A6 had detrimental effects in rat neonatal cardiomyocytes, in vitro. Moreover, S100A6 overexpressing HUVECs show enhanced tube formation and augmented migration as markers of angiogenesis in vitro.;In a rat model of myocardial I/R, S100A6 expression is up-regulated in the infarct and peri-infarct regions of the left ventricle (LV) following myocardial I/R injury but occurs simultaneous or just after the peak of apoptosis and LV functional deterioration.;Ultrasound-targeted microbubble destruction (UTMD) delivery of hS100A6-plasmid prior to I/R yields a survival advantage, improves LV systolic function and myocardial perfusion, attenuates cardiac hypertrophy and reduces infarct size through prevention of apoptosis and necrosis and enhancement of calcium handing post myocardial I/R injury, in vivo.;Finally, UTMD delivery of hS100A6-minicircle (MC) immediately after I/R injury yields similar therapeutic benefits on reduction of infarct size, improved LV systolic function and myocardial perfusion, as compared to control and empty minicircle UTMD.;Conclusion. The present study is the first to demonstrate the therapeutic benefits of targeted hS100A6 gene delivery in the setting of cardiac I/R injury, resulting in a significant improvement in LV function, a reduction in infarct size and prevention of adverse LV remodeling. Gene therapy by UTMD of S100A6 holds promise as adjunctive therapy to primary percutaneous coronary intervention to help ameliorate ischemia/reperfusion injury. |
