High Glucose Upregulated Vascular Smooth Muscle Endothelin Subtype B Receptors via Inhibition of Autophagy in Rat Superior Mesenteric Arteries

Abstract

Autophagy plays an important role in cardiovascular diseases. High glucose (HG) upregulates endothelin subtype B (ET_B) receptors in vascular smooth muscle cells (VSMCs). However, it is unclear as to whether autophagy is involved in HG-induced upregulation of ET_B receptors in VSMCs. The present study was designed to examine the hypothesis that HG upregulates ET_B receptors by inhibiting autophagy in VSMCs. We studied HG-treated rat superior mesenteric artery (SMA) without endothelium in the presence and absence of 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR), rapamycin, or MHY1485 for 24 hr. We measured contractile responses to sarafotoxin 6c (S6c) (an ET_B receptor agonist) using a sensitive myograph. Levels of protein expression were determined using Western blotting. HG impaired autophagy and increased the levels of ET_B receptor protein expression and ET_B receptor-mediated contractile responses to S6c in SMA. However, these effects were reversed by AICAR (an agonist of adenosine monophosphate [AMP]-activated protein kinase [AMPK]) and rapamycin (an inhibitor of mammalian target of rapamycin [mTOR]). However, MHY1485 (an agonist of mTOR) did not upregulate the AICAR-inhibited ET_B receptor-mediated contractile responses or ET_B receptor protein expression in the presence of HG. These data suggest that HG upregulated ET_B receptors by inhibiting autophagy in VSMCs via AMPK and mTOR signaling pathways.