Role of the Angiotensin AT ₁ Receptor in Rat Aortic and Cardiac PAI-1 Gene Expression

Abstract

Abstract-Although the renin-angiotensin system has been implicated in increasing plasminogen activator inhibitor-1 (PAI-1) expression, the role of the angiotensin type 1 (AT 1 ) receptor is controversial. This report examines the effects of angiotensin peptides, angiotensin-converting enzyme inhibition, and AT 1 antagonism on rat aortic and cardiac PAI-1 gene expression. In vitro, angiotensin (Ang) I, Ang II, and angiotensin Arg 2 -Phe 8 (Ang III) were potent agonists of PAI-1 mRNA expression in rat aortic smooth muscle cells (RASMCs), and stimulation of PAI-1 by these peptides was blocked by the AT 1 antagonist candesartan. Angiotensin Val 3 -Phe 8 (Ang IV) and angiotensin Asp 1 -Pro 7 (Ang [1-7]) did not affect PAI-1 expression in RASMCs. In neonatal rat cardiomyocytes, Ang II increased PAI-1 mRNA expression by 4-fold (PϽ0.01), and this response was completely blocked by AT 1 receptor antagonism. Continuous intrajugular infusion of Ang II into Sprague-Dawley rats for 3 hours increased aortic and cardiac PAI-1 mRNA expression by 17-and 9 fold, respectively, and these Ang II responses were completely blocked by coinfusion with candesartan. Aortic and cardiac PAI-1 expressions were compared in spontaneously hypertensive rats and Wistar-Kyoto rats. PAI-1 expression in the aorta and heart from spontaneously hypertensive rats was 5.8-fold and 2-fold higher, respectively, than in control Wistar-Kyoto rats (PϽ0.05). Candesartan treatment for 1 week reduced aortic and cardiac PAI-1 expression in spontaneously hypertensive rats by 94% and 72%, respectively (PϽ0.05), but did not affect vascular PAI-1 levels in Wistar-Kyoto rats. These results demonstrate a role for the AT 1 receptor in mediating the effects of Ang II on aortic and cardiac PAI-1 gene expression. Key Words: angiotensin II Ⅲ plasminogen activator inhibitor Ⅲ hypertension Ⅲ aorta Ⅲ vascular smooth muscle cells P lasminogen activator inhibitor-1 (PAI-1) is the major inhibitor of tissue and urokinase plasminogen activators and thereby reduces the conversion of plasminogen to plasmin, an extracellular protease that mediates fibrinolysis and activates matrix metalloproteinases. 1-3 An elevated level of PAI-1, which occurs in diabetes, insulin resistance, obesity, and hypertension, has been implicated as a contributing risk factor for cardiovascular disease. 4 -7 Recent studies suggest that the renin-angiotensin system (RAS) may exert an important role in the regulation of circulating and vascular PAI-1 expression and may thereby affect the fibrinolytic balance. Reports from our laboratory and others have demonstrated that angiotensin II (Ang II) is a potent stimulator of PAI-1 mRNA and protein expression in both cultured endothelial and vascular smooth muscle cells. 8 -11 The physiological importance of the RAS in modulating PAI-1 levels is supported by in vivo studies, which have demonstrated that treatment of rats with the angiotensin-converting enzyme (ACE) inhibitor captopril suppresses the induction of PAI-1 expression in the aortic neointima induced by b...

International Union of Basic and Clinical Pharmacology. XCIX. Angiotensin Receptors: Interpreters of Pathophysiological Angiotensinergic Stimuli

“…Abnormal accumulation of proteoglycans is known in atherosclerotic lesions (Evanko et al, 1998;Iozzo, 1998), and treatment with ARBs induces proteoglycan changes that favor healthier cell adhesion, migration, and differentiation (Iozzo, 1998;Moriguchi et al, 1999;Sasamura et al, 2001). In aortic VSMCs and ECs as well as in cardiac cells, the AT 1 receptor-EGFR transactivation pathway also regulates fibronectin synthesis, production of matrix metalloproteinases and breakdown of collagen IV, expression of plasminogen activator inhibitor-1 (Feener et al, 1995;Chen et al, 2000b;Kawano et al, 2000;Nakamura et al, 2000). Regulation of PAI-1 by the AT 1 receptor seems to be important in many contexts; for instance, in human adipocytes, impairment of the fibrinolysis has been implicated in obesity (Skurk et al, 2001) and in reduced trophoblast invasion (Xia et al, 2002;Abbasi et al, 2005).…”

Angiotensin AT 1 receptor antagonism normalizes retinal blood flow and acetylcholine-induced vasodiliation in normotensive diabetic rats

“…Rats were treated with captopril (100 mg/kg/day, Sigma), candesartan cilexetil (TCV-116, 2 mg/kg/day, provided by Dr. Peter Morsing, Astra Hassle AB, Mölndal, Sweden), or vehicle in drinking water for 2 weeks [26]. The treatment was started immediately after diabetes was diagnosed.…”

Review of the molecular pharmacology of Losartan and its possible relevance to stroke prevention in patients with hypertension

“…118,119 The different observations about PAI-1 activity and expression may reflect the manner in which the analyses were conducted, such as timing of sample collection and duration of treatment, u3 Reduction of PAI-1 levels by candesartan, valsartan, and irbesartan would, however, suggest that All-mediated inhibition of fibrinolysis may be affected by the AT 1 receptor. 17, 109,120,121 It is widely acknowledged that transformation of arachidonic acid into prostaglandins such as prostaglandin F2c ~ (PGF2~) and thromboxane a 2 (TXA2) is associated with increased platelet aggregation. J. Dfez platelet function plays a critical role in the development of thrombi.…”