Mitochondria-targeting EGCG derivatives protect H9c2 cardiomyocytes from H(2)O(2)-induced apoptosis: design, synthesis and biological evaluation

Pathologies related to cardiovascular diseases mostly emerge as a result of oxidative stress buildup in cardiomyocytes. The heavy load of mitochondrial oxidative phosphorylation in cardiac tissues corresponds to a surge in oxidative stress leading to mitochondrial dysfunction and cellular apoptosis. Thus, scavenging the reactive oxygen species (ROS) linked to mitochondria can significantly improve cardio-protection. Epigallocatechin-3-gallate (EGCG), the major polyphenol found in green tea has been extensively studied for its profound health-beneficial activities. Herein, we designed and synthesized a series of mitochondrial-targeting EGCG derivatives, namely MitoEGCG(n) (n = 4, 6, 8) by incorporating triphenylphosphonium ion onto it using different linkers. MitoEGCG(n) were found to be non-toxic to H9c2 rat cardiomyocyte cells even at higher doses in comparison to its parent molecule EGCG. Interestingly, MitoEGCG(4) and MitoEGCG(6) protected the H9c2 cardiomyocyte cells from the oxidative damage induced by H(2)O(2) whereas EGCG was found to be toxic and ineffective in protecting the cells from H(2)O(2) damage. MitoEGCG(4) and MitoEGCG(6) also protected the cells from the H(2)O(2)-induced disruption of mitochondrial membrane potential as well as activation of apoptosis as revealed by pro-caspase 3 expression profile, DNA fragmentation assay, and AO/EtBr staining. Taken together, our study shows that the mitochondria targeting EGCG derivatives were able to effectively combat the H(2)O(2)-induced oxidative stress in H9c2 cardiomyocytes. They eventually augmented the mitochondrial health of cardiomyocytes by maintaining the mitochondrial function and attenuating apoptosis. Overall, MitoEGCG(4) and MitoEGCG(6) could provision a cardioprotective role to H9c2 cardiomyocytes at the time of oxidative insults related to mitochondrial dysfunction-associated injuries.