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

Autophagy plays an important role in cardiovascular diseases. High glucose (HG) upregulates endothelin subtype B (ET) receptors in vascular smooth muscle cells (VSMCs). However, it is unclear as to whether autophagy is involved in HG-induced upregulation of ET receptors in VSMCs. The present study was designed to examine the hypothesis that HG upregulates ET 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 receptor agonist) using a sensitive myograph. Levels of protein expression were determined using Western blotting. HG impaired autophagy and increased the levels of ET receptor protein expression and ET 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 receptor-mediated contractile responses or ET receptor protein expression in the presence of HG. These data suggest that HG upregulated ET receptors by inhibiting autophagy in VSMCs via AMPK and mTOR signaling pathways.