Impaired capsaicin-induced relaxation of coronary arteries in a porcine model of the metabolic syndrome

Abstract

Recent studies implicate channels of the transient receptor potential vanilloid family (e.g., TRPV1) in regulating vascular tone; however, little is known about these channels in the coronary circulation. Furthermore, it is unclear whether metabolic syndrome alters the function and/or expression of TRPV1. We tested the hypothesis that TRPV1 mediates coronary vasodilation through endothelium-dependent mechanisms that are impaired by the metabolic syndrome. Studies were conducted on coronary arteries from lean and obese male Ossabaw miniature swine. In lean pigs, capsaicin, a TRPV1 agonist, relaxed arteries in a dose-dependent manner (EC50 = 116 +/- 41 nM). Capsaicin-induced relaxation was blocked by the TRPV1 antagonist capsazepine, endothelial denudation, inhibition of nitric oxide synthase, and K+ channel antagonists. Capsaicin-induced relaxation was impaired in rings from pigs with metabolic syndrome (91 +/- 4% vs. 51 +/- 10% relaxation at 100 microM). TRPV1 immunoreactivity was prominent in coronary endothelial cells. TRPV1 protein expression was decreased 40 +/- 11% in obese pigs. Capsaicin (100 microM) elicited divalent cation influx that was abolished in endothelial cells from obese pigs. These data indicate that TRPV1 channels are functionally expressed in the coronary circulation and mediate endothelium-dependent vasodilation through a mechanism involving nitric oxide and K+ channels. Impaired capsaicin-induced vasodilation in the metabolic syndrome is associated with decreased expression of TRPV1 and cation influx.

Vascular transcriptional alterations produced by juvenile obesity in Ossabaw swine

“…Notably, we identified a number of genes in the LAD (e.g., ACP5, LYZ, CXCL14, APOE, PLA2G7, LGALS3, SPP1, ITGB2, CYBB, P2RY12) that are implicated in atherosclerosis based on published literature (1, 10, 22-24, 27, 32, 33, 45, 48, 51, 56, 64, 74, 77, 84) and whose expression was markedly upregulated with juvenile obesity. Because the alterations in expression of these genes occurred in the absence of coronary artery vascular dysfunction, this study provides information regarding the initial molecular events potentially involved in creating a permissive state for the development of vascular dysfunction and disease, which is indeed manifested when obesity in the Ossabaw pig model persists into adulthood (9,25,57,65,80).…”

“…The molecular changes reported herein may be considered as very early steps that set the stage for the instigation of the disease processes. Indeed, there is compelling evidence that when the Ossabaw pig remains obese during adulthood, the coronary arteries exhibit severe vascular dysfunction and complex atherosclerotic disease (9,25,57,65,80).…”

“…These animals have a "thrifty genotype" that enabled them to survive seasonal food shortages in their native environment (75). Similar to humans in an environment of nutritional excess and physical inactivity, when mature Ossabaw pigs are fed a high-fat diet and remain inactive, they develop classic features of the metabolic syndrome, including obesity, insulin resistance, glucose intolerance, dyslipidemia, and hypertension, and exhibit complex atherosclerotic lesions (9,25,57,65).…”

Update on vascular endothelial Ca2+signalling: A tale of ion channels, pumps and transporters

“…TRPV1 may, therefore, serve as an SMOC, although the physiological ligands that are capable of recruiting this channel in ECs are yet to be elucidated. Pharmacological stimulation of TRPV1, either by capsaicin or anandamide, causes vascular relaxation upon release of several vasodilators, including NO [273][274][275] , calcitonin gene-related peptide (CGRP) [276,277] , and EDHF [273] . CGRP may also afford a protective effect against LPC-and lipopolysaccharide (LPS)-dependent injury [276,277] .…”

“…This signaling pathway might involve the AMP-activated protein kinase (AMPK), a multifunctional regulator of energy homeostasis that is phosphorylated upon TRPV1-mediated Ca 2+ influx [279] . TRPV1-induced vasodilation is impaired in obese Ossabaw swine with the metabolic syndrome and thus could be a mechanism involved in endothelial dysfunction and development of coronary disease [273] . Chronic stimulation of TRPV1 by capsaicin enhances PKA and eNOS phosphorylation, which, in turn, results in vasorelaxation, reduces blood pressure and delays the onset of brain stroke in spontaneously hypertensive rats [280] .…”