Cytoprotective Roles of a Novel Compound, MHY‐1684, against Hyperglycemia‐Induced Oxidative Stress and Mitochondrial Dysfunction in Human Cardiac Progenitor Cells

Abstract

Diabetic cardiomyopathy (DCM) is tightly linked to heart disorders and dysfunction or death of the cardiomyocytes including resident cardiac progenitor cells (CPCs) in diabetic patients. In order to restore loss of function of resident or transplanted CPCs, much research has focused on novel therapeutic strategies including the discovery of novel function-modulating factors such as reactive oxygen species (ROS) scavengers. Here, we developed and defined a novel antioxidant, MHY-1684, for enhancing the angiogenic potential of CPCs against ROS-related DCM. Short-term treatment with MHY-1684 restored ROS-induced CPC cell death. Importantly, MHY-1684 decreased hyperglycemia-induced mitochondrial ROS generation and attenuated hyperglycemia-induced mitochondrial fragmentation. We observed that the activation process of both Drp1 (phosphorylation at the site of Ser616) and Fis-1 is drastically attenuated when exposed to high concentrations of D-glucose with MHY-1684. Interestingly, phosphorylation of Drp1 at the site of Ser637, which is an inhibitory signal for mitochondrial fusion, is restored by MHY-1684 treatment, suggesting that this antioxidant may affect the activation and inhibition of mitochondrial dynamics-related signaling and mitochondrial function in response to ROS stress. In conclusion, our finding of the novel compound, MHY-1684, as an ROS scavenger, might provide an effective therapeutic strategy for CPC-based therapy against diabetic cardiomyopathy.

Antioxidant and Anti-Inflammatory Properties of Anthocyanins Extracted from Oryza sativa L. in Primary Dermal Fibroblasts

“…ERK1/2 activation is associated with cell death induced by ROS [36]. However, signaling through ERK1/2 also has a prosurvival effect [55]. We demonstrated that H 2 O 2 stimulated strong phosphorylation of Akt; however, ANT pretreatment suppressed this Akt signaling in a dose-dependent manner in RDFs.…”

Acetaldehyde induces phosphorylation of dynamin-related protein 1 and mitochondrial dysfunction via elevating intracellular ROS and Ca2+ levels

“…However, the phosphorylation of Drp1 at Ser616 was significantly increased in acetaldehyde-treated cells. Drp1 is regulated by various posttranslational modifications, among which phosphorylation has been extensively studied [67,68]. Phosphorylation of Drp1 at Ser616 promotes both the localization of Drp1 to mitochondria and its assembly into large oligomeric structures at mitochondrial fission sites, which are important for initiating the fission event [[17], [18], [19]].…”

DRP1 deficiency induces mitochondrial dysfunction and oxidative stress-mediated apoptosis during porcine oocyte maturation

“…The roles of DRP1 on the induction of oxidative stress have been reported in many models: T-2 toxin treatment of human liver cells causes an increase in DRP1 expression which causes overproduction of ROS [28]. MHY-1684 activates DRP1 and inhibits mitochondrial fusion in cardiac progenitor cells, which further induces oxidative stress [29]. Prx5 inhibits ERK-Drp1-induced mitochondrial fragmentation by regulating oxidative stress [30].…”