Abstract 209: Resistin Regulates Dynamin-Related Protein 1, a Mitochondrial Fission Protein in Vascular Smooth Muscle Cells
Recent studies indicate increased mitochondrial fission and organ dysfunction in models of obesity. While the mechanisms for this morphological alteration are not completely understood it is likely that the altered adipokine profile that occurs during obesity may play a permissive role in enhanced mitochondrial fragmentation. In this study, we investigated the role of resistin, a pro-inflammatory adipokine that is elevated in the plasma of obese individuals, on regulation of the mitochondrial fission protein, dynamin-related protein 1(DNM1L) in vascular smooth muscle cells (VSMCs). We hypothesized that serum and glucocorticoid inducible kinase 1 (SGK1) plays a role in resistin-induced mitochondrial fission expression in VSMCs. In dose and time response studies, we found that resistin stimulated DNM1L protein levels in both rat and human aortic smooth muscle cells suggesting a role for resistin in regulation of mitochondrial fission. In addition, we observed that resistin enhances expression and activity of SGK1. To determine whether SGK1 regulates resistin-mediated expression of DNM1L, we examined the effect of SGK1 over-expression, or inhibition on resistin-induced expression of DNM1L. Over-expression of wildtype SGK1 potentiated resistin-mediated DNM1L expression, while dominant-negative SGK1 inhibited resistin-mediated expression of DNM1L in human VSMC. In conclusion, we have demonstrated for the first time that SGK1 is a potential downstream mediator of resistin. Interestingly, SGK1 activity has been linked to pathological vascular remodeling in various cardiovascular disease settings. Our data suggests that the elevated plasma levels of resistin that occur in obese individuals may lead to activation of SGK1. This in turn, could exacerbate mitochondrial fragmentation in VSMC and predispose to the development of vascular dysfunction that is evident during obesity. Together with further mitochondrial fission studies, additional elucidation of how resistin also alters components of mitochondrial fusion machinery may uncover novel mechanisms of potential theraputic targets for obesity-mediated vascular dysfunction.
- © 2013 by American Heart Association, Inc.