Drp1 inhibitor mdivi‐1 attenuates disturbed flow‐induced metabolic shift and prevents cell activation in endothelial cells
The FASEB Journal(2019)
Abstract
PURPOSE The purpose of this study was to investigate the effect of mitochondrial fission inhibitor, mdivi‐1, on disturbed flow (DF)‐mediated mitochondrial remodeling, metabolic shift, and cell activation in endothelial cells (EC). METHODS & RESULTS We generated EC‐specific photoactivatable mitochondria mice (EC‐PhAM) to analyze mitochondrial morphology specifically within the endothelium. Increased mitochondrial fission was observed at atheroprone regions (DF‐encountered, i.e. lesser curvature (LC) and carotid artery bifurcation (BC)) when compared with atheroprotective region (unidirectional flow (UF)‐encountered, i.e. thoracic aorta (TA)) (49% and 48% increase, respectively). The atheroprone regions showed elevated phosphorylation of p‐Drp1 Ser616 (activation site) along with decreased phosphorylation of p‐Drp1 Ser637 (inhibition site). The atheroprone region also showed increased VCAM‐1 and mtROS. Partially ligated carotid artery (LCA), a surgical model of DF, showed significant induction of mitochondrial fragmentation (up to 55%) compared to the intact carotid artery confirming mitochondrial fragmentation is occurred in DF region in vivo . A 7‐week voluntary wheel‐running exercise training (as a UF enhancing intervention model) significantly decreased mitochondrial fragmentation in the atheroprone regions compared to sedentary animals (~41.5 %). Similarly, in both HAEC and primary‐cultured MAEC, DF ( ± 5 dyne/cm 2 , 1 Hz, 48 h) induced mitochondrial fragmentation (~57.6%) along with increased phosphorylation of p‐Drp1 Ser616 (~184%), decreased phosphorylation of p‐Drp1 Ser637 (~48.5%), higher mtROS production (58.3%) and greater VCAM‐1 expression (~283%) compared to EC applied to UF (20 dyne/cm 2 , 48h). In addition, DF enhanced glucose uptake (2‐NBDG) by ~50% and decreased fatty acid uptake (BODIPY) by ~20% compared to UF. Inhibition of Drp1 by mdivi‐1 (25 uM) abrogated DF‐induced phosphorylation of Drp1 ser616 (~48.5 %), glucose uptake (~20.9%), VCAM‐1 expression (~73.4 %), and mtROS generation (~21.1%) and increased fatty acid uptake (~63 %). Regarding molecular mechanisms, nuclear translocation of hypoxia‐inducible factor 1 α (HIF‐1α), an inducer of glycolysis, was significantly increased at atheroprone region (i.e. LC) compared to atheroprotective region (i.e. TA) in vivo . In vitro studies also showed that DF increased HIF‐1α expression and its nuclear translocation, which were attenuated by mdivi‐1 treatment. CONCLUSION Data suggest that DF induces mitochondrial fragmentation in a Drp‐1‐dependent mechanism, which is associated with metabolic shift toward glycolysis and endothelial activation. Our data propose a novel molecular mechanism by which exercise‐induced laminar flow improves endothelial function and prevents endothelial activation associated with atherogenesis. Support or Funding Information Supported by NIH Grant R01 HL126952 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
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Key words
Mitochondrial Fission
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