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 in vitro and in vivo. 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 2i exhibited the most potent cardioprotective effect. Compound 2i has been demonstrated to enhance Prx2, superior to HG. Taken together, our work demonstrated that, for the first time, the optimized HG derivative 2i 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.