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.

• Authors: Woong Bi Jang, Ji Hye Park, Seung Taek Ji, Na Kyung Lee, Da Yeon Kim, Yeon Ju Kim, Seok Yun Jung, Songhwa Kang, Shreekrishna Lamichane, Babita Dahal Lamichane, Jongseong Ha, Jisoo Yun, Hyung Ryong Moon, Sang Hong Baek, Hae Young Chung, Sang-Mo Kwon
• Journal: Oxidative medicine and cellular longevity (Oxid Med Cell Longev) Vol. 2018 Pg. 4528184 ( 2018) ISSN: 1942-0994 [Electronic] United States
• PMID: 30002788 (Publication Type: Journal Article)

Chemical References

• Antioxidants
• FIS1 protein, human
• Membrane Proteins
• Microtubule-Associated Proteins
• Mitochondrial Proteins
• Reactive Oxygen Species
• Peroxynitrous Acid
• GTP Phosphohydrolases
• DNM1L protein, human
• Dynamins

Topics

• Antioxidants (pharmacology)
• Blotting, Western
• Cell Survival (drug effects)
• Cells, Cultured
• Dynamins
• GTP Phosphohydrolases (genetics, metabolism)
• Humans
• Hyperglycemia (metabolism)
• Membrane Proteins (genetics, metabolism)
• Microtubule-Associated Proteins (genetics, metabolism)
• Mitochondria (metabolism)
• Mitochondrial Proteins (genetics, metabolism)
• Oxidative Stress (drug effects)
• Peroxynitrous Acid (metabolism)
• Reactive Oxygen Species (metabolism)
• Signal Transduction (physiology)
• Stem Cells (cytology, drug effects, metabolism)