Abstract 11691: Atorvastatin Reverses Impaired Voltage-gated K+ Channels-mediated Coronary Vasodilation By Upregulating PPARγ In Diabetes (Best of Basic Science Abstract)
Aims: Voltage-gated K+ (Kv) channels in vascular smooth muscle cells (VSMCs) play an important role in the regulation of coronary microcirculation. Atorvastatin (ATV) has shown some beneficial effects on vascular function, but the effect of ATV on Kv channels-mediated coronary vasodilation remains unknown. The present study was designed to investigate the role of ATV in improving Kv channels-mediated coronary dilator function in diabetes and the underlying mechanisms.
Methods: Isolated VSMCs were incubated in normal or high glucose medium plus a different dose of ATV for 24 h at 37oC. Patch-clamp recording and molecular biological techniques were used to assess the function and expression of Kv channels. Control or type 2 diabetic rats were treated with ATV (50 mg/kg daily) by oral gavage for 10 weeks. Vasodilation of isolated rat coronary arteries was measured using a pressurized myograph. GW9662, the peroxisome proliferator-activated receptor gamma (PPARγ) antagonist, was used to determine whether the mechanism of ATV-improved Kv channel function can be explained by upregulation of PPARγ pathway.
Results: Patch-clamp analysis revealed that high glucose reduced Kv current density by 58.7 ± 4.6%, which was accompanied by a downregulation of Kv1.2 and Kv1.5 expression. Treatment with ATV reversed the inhibitory effect of high glucose on Kv current density in a dose-dependent manner (1 μmol/L, 15.0 ± 2.6%; 10 μmol/L, 49.1 ± 3.8%; 100 μmol/L, 69.9 ± 4.8%; P < 0.05). In addition, ATV restored high glucose-induced downregulation of Kv channel protein expression, and the difference was significant in both 10 μmol/L and 100 μmol/L groups. For in vivo study, Kv channels-mediated coronary vasodilation was decreased in diabetic rats, compared with controls (9.1 ± 1.3 vs. 36.7 ± 1.4%, P < 0.05), whereas this decrease was partly corrected by ATV (25.0 ± 2.8 vs. 9.1 ± 1.3%, P < 0.05). Treatment with ATV prominently increased protein expression of PPARγ both in vitro and in vivo. The effect of ATV in regulating Kv channels and Kv channels-mediated vasodilation was markedly blunted by GW9662.
Conclusions: In conclusion, treatment with ATV activates PPARγ pathway and preserves Kv channel activity in VSMCs, thus providing improvement of coronary dilator function in diabetic rats.
Author Disclosures: W. Su: None. W. Li: None. M. Chen: None. H. Chen: None. H. Li: None.
- © 2015 by American Heart Association, Inc.