Abstract 360: Role Of Mitochondrial Dynamics In Vascular Smooth Muscle Cell Death

Background: Vascular smooth muscle cell (VSMC) death has been linked to the pathogenesis of various vascular diseases. Excessive mitochondrial fission in response to pathological stimuli contributes to cell death, thus, inhibition of mitochondrial fission can be a promising therapeutic target in vascular diseases. Mitochondrial division inhibitor 1 (mdivi-1) inhibits Drp1-dependent mitochondrial fission by attenuation of its GTPase activity. As association between fission inhibition & VSMCs cell death has been implicated in vascular diseases, the underlying mechanism warrants further investigation. We assessed the effects of mdivi-1 (an inhibitor of Drp1-mediated mitochondrial fission) on staurosporine (STS)-induced mitochondrial dysfunction, impaired autophagy, & cell death in aortic VSMC. Methods & Results: The flow cytometry analysis demonstrated reduced cell death in VSMCs-treated with mdivi-1. The mitochondrial fission was evaluated using Mitotracker Red staining. mdivi-1-treated VSMCs showed significantly higher mitochondrial networks, mean branch length, & mitochondrial footprint compared to STS-treated cells indicating reduced mitochondrial fragmentation. Inhibitory effects of mdivi-1 on fission were exerted by reduced Drp1 phosphorylation at 616. Mitochondrial function via evaluation of mitochondrial permeability transition pore opening, mitochondrial membrane potential & bioenergetic profile showed restored mitochondrial function & metabolic potential in the mdivi-1-treated cells compared to the STS group. The mdivi-1-treated VSMCs showed significantly reduced ROS generation indicating suppressed oxidative stress. The improved mitochondrial structural integrity due to inhibition of fission was associated with reduced mitophagy & cell death-related proteins. Conclusion: In response to apoptotic stimuli, excessive Drp1-dependent mitochondrial fission leads to mitochondrial damage, playing a key role in VSMC death. Inhibition of Drp1-dependent mitochondrial fission by mdivi-1 attenuated mitochondrial fission & prevented cell death in VSMCs. Pharmacological inhibition of mitochondrial fission provides a potential therapeutic target in vascular diseases associated with loss of VSMC.