ACE Inhibitor and AT ₁ Antagonist Blockade of Deformation-Induced Gene Expression in the Rabbit Jugular Vein Through B ₂ Receptor Activation

Abstract

Abstract-Deformation-induced endothelin-1 synthesis in endothelial cells may contribute to the intimal hyperplasia of venous bypass grafts. ACE inhibitors and angiotensin II type 1 (AT 1 ) receptor antagonists are capable of reducing vein graft disease. Therefore, the effects of these drugs on endothelial preproendothelin-1 (ppET-1) and smooth muscle endothelin B receptor (ET B -R) expression were investigated in isolated perfused segments of the rabbit jugular vein. Pretreatment with ramiprilat (0.3 mol/L) or irbesartan (0.01 to 1 mol/L) had no effect on basal ppET-1 or ET B -R expression but markedly attenuated the deformation-induced expression of these gene products, and these effects were reversed by the B 2 receptor antagonist icatibant (Hoe 140) and by the NO synthase inhibitor N G -nitro-L-arginine. Candesartan (1 mol/L) mimicked the inhibitory effect of irbesartan. Moreover, reporter gene analysis with a rat ppET-1 promoter-luciferase construct transiently transfected into porcine aortic cultured endothelial cells revealed that the inhibitory effect of both ramiprilat and irbesartan on deformation-induced ppET-1 expression is species independent and mediated at the level of transcription. In addition, RT-PCR analysis detected only AT 1 receptor expression in the endothelium-intact rabbit jugular vein, and neither irbesartan nor ramiprilat affected endothelial NO synthase expression. Thus, ACE inhibitors and AT 1 receptor antagonists are capable of suppressing deformation-induced gene expression in the vessel wall in both an autocrine (ppET-1) and a paracrine (ET B -R) manner via a common mechanism of action that constitutes a B 2 receptor-mediated increase in endothelial NO release. Key Words: blood pressure Ⅲ endothelin-1 Ⅲ gene expression Ⅲ graft failure Ⅲ nitric oxide E xcessive mechanical strain after exposure to arterial levels of blood pressure could trigger the vasculopathy of venous bypass grafts and lead to graft failure. 1 Moreover, pressure overload of the vessel wall seems to be involved in both hypertension-induced arterial remodeling 2 and restenosis after PTCA. 3 Among the various mediators implicated in these putatively deformation-induced changes in smooth muscle cell (SMC) phenotype, endothelin-1 (ET-1), a potent comitogen for vascular SMCs, may play a pivotal role. [3][4][5] Thus, rhythmic deformation has been shown to enhance the synthesis of ET-1 in cultured endothelial cells (ECs), and this effect is presumed to occur at the level of transcription of the preproendothelin-1 (ppET-1) gene. 6,7 To investigate whether a pressure-induced deformation of ECs also affects ppET-1 gene expression in the vessel wall in situ, we developed an experimental model in which isolated rabbit blood vessel segments are perfused at different levels of intraluminal pressure. With the aid of this model, we were recently able to demonstrate that ET-1 synthesis in the endothelium of both the carotid artery and the jugular vein of the rabbit is markedly upregulated on exposure to a supraphysiological increas...

Prevention of pulmonary vascular remodeling and of decreased BMPR-2 expression by losartan therapy in shunt-induced pulmonary hypertension

“…These latter effects could be related to decreased pulmonary artery pressures, resulting in decreased shear stress-induced overexpression of ET-1. Losartan could also have inhibited an ANG II-induced inflammatory reaction, part of it being an overexpression of ET-1 (30), or could have prevented ANG II-induced ET-1 gene expression (9,12). It is of interest that losartan therapy reverted BMPR-2 expression to normal, which could also be related to decreased pulmonary artery pressures or to yet unknown interactions between BMPR-2 expression and ET-1 or ANG II signaling pathways.…”

RNA-stabilizing proteins as molecular targets in cardiovascular pathologies

“…Angiotensin II (Ang II) receptors have a pathophysiological role in hypertension, cardiac hypertrophy and heart failure [49]. Ang II type 1 receptor (AT1R) is responsible for the majority of the effects of Ang II on the heart, including stimulated increases in heart rate, contractility, and cardiomyocyte growth [50].…”

Mineralocorticoid receptor expression in human venous smooth muscle cells: a potential role for aldosterone signaling in vein graft arterialization

“…Several studies have suggested that the RAAS is locally active in the healing vein graft wall and has an important role in vein graft remodeling (4,19,24,35). In addition, the inhibition of components of the RAAS has been shown to limit the progression of vein graft disease in experimental animal models (10,14,36).…”