Abstract 19251: Glucose-6-Phosphate Dehydrogenase Regulates Myocardin and Phenotype of Arterial Smooth Muscle Cells in Metabolic Syndrome Swine and Humans
We discovered that activity of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme in the pentose phosphate pathway, is increased and expression of myocardin, the key co-transcription factor that regulates the vascular smooth muscle cell (VSMC) phenotype and plasticity, is decreased in the arteries of metabolic sydnrome (MetS) pigs and humans. Therefore, in this study, we investigated whether there is any correlation between reprograming of glucose metabolism/increase of G6PD activity and decrease of myocardin expression in arteries of MetS pigs. We measured G6PD activity and expression of myocardin and myocardin-dependent contractile protein genes in coronary and carotid arteries of lean and MetS Ossabaw miniature pigs. We found a negative correlation (R2=0.89; P<0.05; n=6) between G6PD activity and myocardin expression in coronary arteries of lean pigs. Furthermore, we found in MetS vs. Lean pigs that G6PD activity increased by 2-fold (Lean: 1.25±0.47, n=13; MetS: 3.54±0.89, n=8; P<0.05) and myocardin expression decreased by 35% (Lean: 0.17±0.01, n=5; MetS: 0.11±0.03, n=4; P<0.05) in diseased coronary, but not in non-diseased carotid, arteries. Expression of myocardin-dependent contractile gene products - smooth muscle myosin heavy chain (Lean: 0.22±0.06, n=10; MetS: 0.03±0.02, n=10; P<0.05) and SM22α (Lean: 0.21±0.02, n=6; MetS: 0.13±0.04, n=6; P<0.05) - was also decreased in coronary arteries of MetS pigs. Very interestingly, we also found that G6PD activity was increased, while expression of myocardin and myocardin-dependent genes were decreased, in the internal mammary/radial arteries from obese-diabetic as compared to non-obese-diabetic humans. Furthermore, we found that downregulation of myocardin is blocked by G6PD inhibition or knockdown. These results suggest that VSMC phenotype is controlled by glucose metabolism and increase of G6PD activity is associated in downregulating myocardin expression. In conclusion, we propose that G6PD is a metabolic switch that changes VSMC from contractile to synthetic phenotype in arteries of obese-diabetics.
Author Disclosures: V. Dhagia: None. M. Alloosh: None. M. Sturek: None. R. Gupte: None. S.A. Gupte: None.
- © 2014 by American Heart Association, Inc.