Discovery of potent and selective peroxiredoxin 2 agonist natural products and derivatives against myocardial ischemia-reperfusion injury

Oxidative stress and apoptosis of cardiomyocytes are critical factors in the pathophysiology of myocardial ischemia-reperfusion (MI/R) injury. In this investigation, we explored the cardioprotective effects of higenamine (HG) and discovered its optimized derivatives. The influence of HG on MI/R injury in MI/R rats and H9c2 cells subjected to H₂O₂ injury was evaluated. Alterations in peroxidase and other antioxidant enzymes were evaluated both <em>in vitro </em>and<em> in vivo</em>. Furthermore, oxidative stress, cardiac function, LDH release, ROS levels, and infarct size were quantified. Importantly and finally, HG exhibited a significant reduction in oxidative damage induced by MI/R injury and improvements in cardiomyocyte apoptosis. Moreover, HG markedly blocked apoptosis by upregulating the level of peroxiredoxin 2 (Prx2). The protective effects of HG against hydrogen peroxide induced injury were markedly attenuated by siRNA-Prx2, and the cardioprotective effects of HG were significantly inhibited by Conoidin A-mediated inhibition of Prx2. Furthermore, we conducted cell viability assays on the structure-derived compounds of HG and discovered that compound <strong>2i</strong> exhibited the most potent cardioprotective effect. Compound <strong>2i</strong> has been demonstrated to enhance Prx2, superior to HG. Taken together, our work demonstrated that, for the first time, the optimized HG derivative <strong>2i</strong> dramatically improved cardiac function post MI/R injury by mitigating oxidative stress and cardiomyocyte apoptosis via Prx2 activation, which is stronger than that of HG. Therefore, compound 2i holds promise as a novel drug candidate for alleviating MI/R injury. Moreover, the aftermentioned findings suggested that the tetrahydroisoquinoline scaffold may hold potential as a pharmacodynamic privileged structure for interventions in ischemic heart disease.