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Diabetes. 2014 Mar;63(3):1124-39. doi: 10.2337/db13-1267. Epub 2013 Nov 22.

Heat shock prevents insulin resistance-induced vascular complications by augmenting angiotensin-(1-7) signaling.

Author information

1
Laboratory of Chromatin Biology, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, SAS Nagar, Mohali, Punjab, India.

Abstract

We have investigated the role of heat shock (HS) in preventing insulin resistance-induced endothelial dysfunction. To the best of our knowledge, we report here for the first time that insulin resistance inhibits vascular HS protein (HSP) 72 expression. HS treatment (41 °C for 20 min) restored the HSP72 expression. High-fat diet (HFD)-fed, insulin-resistant rats show attenuated angiotensin (ANG)-(1-7)-induced vasodilator effect, endothelial nitric oxide synthase (eNOS) phosphorylation, AMP-activated protein kinase phosphorylation, and sirtuin 1 (SIRT1) expression. Interestingly, HS prevented this attenuation. We also provide the first evidence that HFD-fed rats show increased vascular DNA methyltransferase 1 (DNMT1) expression and that HS prevented this increase. Our data show that in HFD-fed rats HS prevented loss in the expression of ANG-(1-7) receptor Mas and ACE2, which were responsible for vascular complications. Further, the inhibition of eNOS (l-N(G)-nitro-L-arginine methyl ester), Mas (A-779), and SIRT1 (nicotinamide) prevented the favorable effects of HS. This suggests that HS augmented ANG-(1-7) signaling via the Mas/eNOS/SIRT1 pathway. Our study, for the first time, suggests that induction of intracellular HSP72 alters DNMT1 expression, and may function as an epigenetic regulator of SIRT1 and eNOS expression. We propose that induction of HSP72 is a novel approach to prevent insulin resistance-induced vascular complications.

PMID:
24270982
DOI:
10.2337/db13-1267
[Indexed for MEDLINE]
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