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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. Insulin resistance is a prominent component of metabolic syndrome, which is characterized by obesity, hypertension, and atherosclerosis. A reciprocal relationship has been established between insulin resistance and endothelial dysfunction, which may lead to cardiovascular disorders (1). Apart from the metabolic actions, insulin performs various important hemodynamic functions such as peripheral vasodilation and increased regional blood flow via stimulation of nitric oxide (NO). Therefore, anything that impairs insulin action is expected to result in endothelial dysfunction and vice versa (2). Insulin has been shown to induce endothelial-dependent vasodilation without affecting endothelium-independent vasodilation. We and others (3,4) have reported that insulin resistance impairs endothelium-dependent vasodilation.Several studies have pointed out active involvement of renin-angiotensin system (RAS) in cardiovascular disorders and insulin resistance (5,6). RAS further splits in two, as follows: angiotensin (ANG) II/ACE1 and ANG-(1-7)/ACE2 axis. ANG-(1-7), acting through receptor Mas (G-protein-coupled), counter-regulates the actions of ANG II. Mas receptor dimerizes with AT 1 receptor and COMPLICATIONS inhibits ANG II signaling, suggesting direct interaction of ANG II and the ANG-(1-7) axis (7). ANG-(1-7) promotes vasodilation and inhibits cell proliferation thrombosis, hence opposing the effects of ANG II (8,9). In endothelial cells, ANG-(1-7) inhibited ANG II-induced c-Src, extracellular signal-related kinase 1/2, and NADPH oxidase by activating SHP-2 phosphatase (10). ANG-(1-7) als...

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BACKGROUND AND PURPOSEOestrogen therapy is known to induce cardioprotection in post-menopausal metabolic syndrome (PMS). Hence, we investigated the effect of 17-β oestradiol (E2) on functional responses to angiotensin II and cardiovascular dysfunction in a rat model of PMS. EXPERIMENTAL APPROACHPMS was induced in ovariectomized rats by feeding a high-fat diet for 10 weeks. Isometric tension responses of aortic rings to angiotensin II were recorded using an isometric force transducer. TUNEL assay and immunoblotting was performed to assess apoptosis and protein expression respectively in PMS. KEY RESULTSEndothelial dysfunction in PMS was characterized by enhanced angiotensin II-induced contractile responses and impaired endothelial dependent vasodilatation. This was associated with an increased protein expression of AT1 receptors in the aorta and heart in PMS. PMS induced cardiac apoptosis by activating Bax and PARP protein expression. These changes were associated with a down-regulation in the expression of silent information regulation 2 homologue (SIRT1)/P-AMP-activated PK (AMPK) and increased H3 acetylation in aorta and heart. E2 partially suppressed angiotensin II-induced contractions, restored the protein expression of SIRT1/P-AMPK and suppressed H3 acetylation. The role of SIRT1/AMPK was further highlighted by administration of sirtinol and compound C (ex vivo), which enhanced angiotensin II contractile responses and ablated the protective effect of E2 on PMS. CONCLUSION AND IMPLICATIONSOur results provide novel mechanisms for PMS-induced cardiovascular dysfunction involving SIRT1/AMPK/ histone H3 acetylation, which was prevented by E2. The study suggests that therapies targeting SIRT1/AMPK/epigenetic modifications may be beneficial in reducing the risk of cardiovascular disorders. AbbreviationsAMPK, AMP-activated PK; Ang II, angiotensin II; E2, 17-β oestradiol; PMS, post-menopausal metabolic syndrome; SIRT1, silent information regulation 2 homologue BJP British Journal of Pharmacology

We provide first evidence that insulin resistance induces segmental difference in thoracic and abdominal aorta and this may provide reason of heterogeneity for incidence of aneurysms.