Implication of AMP-Activated Protein Kinase in Transient Receptor Potential Vanilloid Type 1-Mediated Activation of Endothelial Nitric Oxide Synthase

Abstract

We investigated whether AMP-activated protein kinase (AMPK), a multifunctional regulator of energy homeostasis, is involved in transient receptor potential vanilloid type 1 (TRPV1)-mediated activation of endothelial nitric oxide synthase (eNOS) in endothelial cells (ECs) and mice. In ECs, treatment with evodiamine, the activator of TRPV1, increased the phosphorylation of AMPK, acetyl-CoA carboxylase (ACC) and eNOS, as revealed by Western blot analysis. Inhibition of AMPK activation by compound C or dominant-negative AMPK mutant abrogated the evodiamine-induced increase in phosphorylation of AMPK and eNOS and NO bioavailability, as well as tube formation in ECs. Immunoprecipitation and two-hybrid analysis demonstrated that AMPK mediated the evodiamine-induced increase in the formation of a TRPV1-eNOS complex. Additionally, TRPV1 activation by evodiamine increased the phosphorylation of AMPK and eNOS in aortas of wild-type mice but did not activate eNOS in aortas of TRPV1-deficient mice. In mice, inhibition of AMPK activation by compound C markedly decreased evodiamine-evoked angiogenesis in matrigel plugs and in a hind-limb ischemia model. Moreover, evodiamine-induced phosphorylation of AMPK and eNOS in aortas of apolipoprotein E-deficient (ApoE -/-) mice was abrogated in TRPV1-deficient ApoE -/-mice. In conclusion, TRPV1 activation may trigger AMPK-dependent signaling, which leads to enhanced activation of AMPK and eNOS and retarded development of atherosclerosis.

Evodiamine Inhibits Insulin-Stimulated mTOR-S6K Activation and IRS1 Serine Phosphorylation in Adipocytes and Improves Glucose Tolerance in Obese/Diabetic Mice

“…Therefore, AMPK is now considered to be a potential pharmacologic target for improving insulin resistance, diabetes and metabolic syndrome. Ching et al have recently reported that evodiamine increased AMPK phosphorylation in endothelial cells [34]. In the present study, we found that evodiame significantly stimulated AMPK phosphorylation in mature adipocyte culture and in WAT of KK-Ay mice.…”

Maternal exposure to di-(2-ethylhexyl) phthalate exposure deregulates blood pressure, adiposity, cholesterol metabolism and social interaction in mouse offspring

“…For example, phosphorylation of eNOS at both Ser1177 and Ser633 in human endothelial cells (Ser1179 and Ser635 in mouse ECs) by PI3K/Akt, calmodulin-dependent protein kinase and AMP-activated protein kinase increases eNOS activity. By the contrast, phosphorylation of eNOS at Thr495 in human ECs (Thr497 in mouse ECs) by protein kinase C decreases eNOS activity (Arnal et al 1999;Venema 2002;Mount et al 2007;Ching et al 2011Ching et al , 2012Ching et al , 2013Su et al 2012Su et al , 2014. Impaired eNOS activity is an important event in the development of cardiovascular diseases such as hypertension (Davignon and Ganz 2004;Vanhoutte et al 2009).…”

Activation of TRPV1 Prevents OxLDL-Induced Lipid Accumulation and TNF-α-Induced Inflammation in Macrophages: Role of Liver X Receptorα

“…For example, TRPV1 activation by capsaicin increased the activity of endothelial NO synthase (eNOS), promoted vasorelaxation, and thereby reduced blood pressure in experimental hypertensive rats [25]. Additionally, we previously reported that TRPV1 activation by evodiamine or capsaicin triggered Ca 2+ -dependent PI3 K/Akt/CaMKII/AMPK signaling, thus leading to eNOS activation in ECs [27, 56]. As well, inactivation of TRPV1 accelerates the development of metabolic disorders such as hypertension, atherosclerosis, obesity, and fatty liver, whereas TRPV1 agonist activation protects against these metabolic diseases [25, 55, 57, 58].…”