Increased expression of vascular endothelin type B and angiotensin type 1 receptors in patients with ischemic heart disease

Abstract

BackgroundEndothelin-1 and angiotensin II are strong vasoconstrictors. Patients with ischemic heart disease have elevated plasma levels of endothelin-1 and angiotensin II and show increased vascular tone. The aim of the present study was to examine the endothelin and angiotensin II receptor expression in subcutaneous arteries from patients with different degrees of ischemic heart disease.MethodsSubcutaneous arteries were obtained, by biopsy from the abdomen, from patients undergoing coronary artery bypass graft (CABG) surgery because of ischemic heart disease (n = 15), patients with angina pectoris without established myocardial infarction (n = 15) and matched cardiovascular healthy controls (n = 15). Endothelin type A (ETA) and type B (ETB), and angiotensin type 1 (AT1) and type 2 (AT2) receptors expression and function were examined using immunohistochemistry, Western blot and in vitro pharmacology.ResultsETA and, to a lesser extent, ETB receptor staining was observed in the healthy vascular smooth muscle cells. The level of ETB receptor expression was higher in patients undergoing CABG surgery (250% ± 23%; P < 0.05) and in the patients with angina pectoris (199% ± 6%; P < 0.05), than in the healthy controls (100% ± 28%). The data was confirmed by Western blotting. Arteries from CABG patients showed increased vasoconstriction upon administration of the selective ETB receptor agonist sarafotoxin S6c, compared to healthy controls (P < 0.05). No such difference was found for the ETA receptors. AT1 and, to a lesser extent, AT2 receptor immunostaining was seen in the vascular smooth muscle cells. The level of AT1 receptor expression was higher in both the angina pectoris (128% ± 25%; P < 0.05) and in the CABG patients (203% ± 41%; P < 0.05), as compared to the healthy controls (100% ± 25%). The increased AT1 receptor expression was confirmed by Western blotting. Myograph experiment did however not show any change in vasoconstriction to angiotensin II in CABG patients compared to healthy controls (P = n.s).ConclusionThe results demonstrate, for the first time, upregulation of ETB and AT1 receptors in vascular smooth muscle cells in ischemic heart disease. These receptors may play a role in the pathophysiology of ischemic heart disease and could provide important targets for pharmaceutical interventions.

Activation of nuclear factor-κB pathway is responsible for tumor necrosis factor-α-induced up-regulation of endothelin B2 receptor expression in vascular smooth muscle cells in vitro

“…The up-regulation of ETB2 receptors has been observed in VSMC of patients with various atherosclerotic CVDs, for example, peripheral artery disease (Lind et al, 1999), severe pulmonary hypertension (Bauer et al, 2002), subarachnoidal hemorrhage (Hansen-Schwartz et al, 2003), ischemic heart disease (Dimitrijevic et al, 2009) and after cerebral ischemic stroke (Stenman et al, 2002), as well as in animal models with subarachnoid hemorrhage (Hansen-Schwartz et al, 2003), cerebral ischemia (Stenman et al, 2002), hypertension (Fink et al, 2007) and diabetes (Kelly-Cobbs et al, 2011). The increased expression of ETB2 receptors in VSMC has also been found in atherosclerotic plaques and neointimas (Iwasa et al, 1999).…”

“…The ETB2 receptors are not expressed in VSMC under physiological conditions, but under pathophysiological conditions, they could be induced and mediate vasoconstriction and proliferation, which is closely associated with atherosclerotic CVDs (Janakidevi et al, 1992). The up-regulation of ETB2 receptors in VSMC was observed in animal models with subarachnoid hemorrhage (Hansen-Schwartz et al, 2003), cerebral ischemia (Stenman et al, 2002), hypertension (Fink et al, 2007) and diabetes (Kelly-Cobbs et al, 2011), as well as in patients with peripheral artery disease (Lind et al, 1999), severe pulmonary hypertension (Bauer et al, 2002), subarachnoidal hemorrhage (Hansen-Schwartz et al, 2003), ischemic heart disease (Dimitrijevic et al, 2009) and after cerebral ischemic stroke (Stenman et al, 2002). Interestingly, up-regulation of ETB2 receptors was also found in in vitro organ culture model of rat mesenteric arteries after long-term exposure (1-5 days) to serum-free medium (Adner et al, 1998).…”

Cardiovascular risk factors regulate the expression of vascular endothelin receptors

“…ET B2 receptor expression is increased in the VSMC of resistance arteries from patients with ischemic heart disease, while no alteration is seen in the expression of ET A receptors. The level of upregulation of ET B2 receptors is associated with the degree of ischemic heart disease (Dimitrijevic et al, 2009). These data suggest that vascular hypoxia due to reduced blood flow by vascular spasm and/or obstruction in ischemic CVD may contribute to an alteration of endothelin receptors.…”

Endothelin Receptor Antagonists

“…In rats with systemic hypertension, diabetes mellitus, or hypercholesterolemia, ET B receptor immunostaining is reduced in endothelial cells and increased in vascular smooth muscle (Kakoki et al 1999). Upregulation of smooth muscle ET B receptors has been observed in animal models of heart failure (Gray et al 2000) and subarachnoid hemorrhage (Roux et al 1995) and in human diseases including chronic thromboembolic pulmonary hypertension (PH) (Bauer et al 2002), atherosclerosis (Dagassan et al 1996), ischemic heart disease (Dimitrijevic et al 2009), and scleroderma (Shi-Wen et al 2001. In such pathological situations, both ET A and ET B receptors mediate the detrimental actions of ET-1.…”