Endogenous NO Regulates Plasminogen Activator Inhibitor-1 During Angiotensin-Converting Enzyme Inhibition

Abstract

Abstract-To test the hypothesis that NO contributes to effects of angiotensin-converting enzyme inhibitors on fibrinolysis, fibrinolytic balance was assessed in 17 normal subjects during placebo and after randomized, double-blind 4-week treatment with the NO precursor L-arginine (3 g TID), ramipril (10 mg QD), or L-arginineϩramipril. Neither L-arginine nor ramipril alone affected basal plasminogen activator inhibitor-1 or tissue-type plasminogen activator (t-PA) antigen in these salt-replete subjects in whom plasma renin activity was suppressed (meanϮSD 0.7Ϯ0.5 ng angiotensin I/mL per hour). In contrast, L-arginineϩramipril reduced morning plasminogen activator inhibitor-1 antigen (10.8Ϯ9.5 ng/mL) and the molar ratio of plasminogen activator inhibitor-1: During ramipril, the NO synthase inhibitor L-N G -nitro-arginine-methyl-ester (2 mg/kg) significantly increased plasminogen activator inhibitor-antigen after 2 hours (from 9.4Ϯ8.6 ng/mL during vehicle to 13.5Ϯ11.0 ng/mL during L-N G -nitro-arginine-methyl-ester; Pϭ0.020), consistent with an effect on expression but rapidly increased t-PA activity (from 0. Key Words: nitric oxide Ⅲ nitric oxide synthase Ⅲ angiotensin Ⅲ renin Ⅲ plasminogen P lasminogen activators play a critical role in the regulation of vascular fibrinolysis and the degradation of extracellular matrix. Plasminogen activator inhibitor-1 (PAI-1), a principal inhibitor of plasminogen activators, promotes thrombosis and fibrosis. 1 PAI-1 expression is increased in atherosclerotic lesions and at sites of vascular injury. 2,3 Circulating PAI-1 concentrations are increased in patients with risk factors for atherosclerosis, particularly in those with insulin resistance. 4 Furthermore, increased PAI-1 concentrations are associated with increased risk of myocardial infarction. 5 In addition to glucose and insulin, other growth factors, cytokines, and hormones regulate PAI-1 expression, including transforming growth factor-␤, tumor necrosis factor-␣, and angiotensin II (Ang II). 1 Increasing evidence suggests that the deleterious vascular effects of activation of the renin-angiotensin-aldosterone system (RAAS) derive in part from Ang II and aldosterone-induced PAI-1 expression. 6 On the other hand, studies in vitro and in animal models suggest that NO inhibits PAI-1 release and expression. For example, NO donors reduce PAI-1 release from platelets. 7,8 Feener et al reported that NO diminishes Ang II or plateletderived growth factor-stimulated PAI-1 expression in vascular smooth muscle cells via a cGMP-dependent pathway. 9 In rodents, NO synthase (NOS) inhibition using L-N G -nitroarginine-methyl-ester (L-NAME) induces vascular PAI-1 expression. 10,11 Coadministration of an angiotensin-converting enzyme (ACE) inhibitor abolishes L-NAME-induced PAI-1 expression and vascular injury, further suggesting that NO modulates Ang II-stimulated PAI-1 expression in vivo. 10 The role of NO in the regulation of PAI-1 expression in humans has not been established. Korbut et al reported that intravenous infusion of the NO ...

Apelin protects against angiotensin II-induced cardiovascular fibrosis and decreases plasminogen activator inhibitor type-1 production

“…In contrast, the effects of apelin on PAI-1 expression were abolished by pre-treatment of cells with L-NAME (Figure 3B–D). Because PAI-1 is regulated by NO [30, 31] and apelin appears to regulate PAI-1 in part by its effects on NO production, we confirmed the presence of nitric oxide synthase (NOS) in the HASM and CHO cells used in this study (Supplemental Digital Content Figure 4). …”

“…As in the present study, reduction or inhibition of PAI-1 by genetic or pharmacological manipulation protects against fibrosis in a variety of models, including chronic infusion of Ang II [30, 34]. The role of PAI-1 and the fibrinolytic system in vascular biology extends beyond thrombosis and into vascular tissue housekeeping.…”

Interaction of Endothelial Nitric Oxide and Angiotensin in the Circulation

“…Brown et al (2006) provided evidence from studies on normotensive salt-replete subjects treated for 4 weeks with L-arginine, ramipril, or L-arginine plus ramipril that during ACE inhibition, endogenous NO decreases plasminogen activator inhibitor-1 antigen and improves fibrinolytic balance.…”

Soy protein hydrolysate ameliorates cardiovascular remodeling in rats with l-NAME-induced hypertension

“…However, we found no differences among groups in terms of the level of the PAI-1 antigen or its activity in the plasma, aorta and heart. Although some studies have reported that ACE inhibitors might abolish the effects of L-NAME on PAI-1 expression, another study showed that long-term administration of the ACE inhibitor, ramipril, or L-arginine alone had no effect on the fibrinolytic balance in vivo; the PAI-1 antigen level and activity decreased only when treated with a combination of ramipril and DNP [31]. Another reason might be that ACE inhibitors with different lipophilic properties and tissue affinities have dissimilar physiological influences in vivo [33].…”

“…Therefore, we suggest that SPH inhibits ACE activity in cardiovascular tissues by decreasing the effects of angiotensin II, which may lead to a reduction in both oxidative damage and further inflammatory reactions. Studies have also shown that the expression of PAI-1 increased in vascular lesions and cardiac injuries [29,30], and endogenous NO and ACE activity is important in regulating PAI-1 levels [31]. An animal study has shown that NO inhibits the release of PAI-I, and L-NAME may induce vascular PAI-I expression [32].…”