Interaction of the Renin Angiotensin System with the Fibrinolytic System and Platelets

Another important proposed mechanism of the renin-angiotensin system in acute coronary syndromes concerns the ability to modulate the plasma fibrinolytic system, which is based on the balance between plasminogen activator inhibitor-1 (PAI-1) and tissue-type plasminogen activator (tPA). tPA is released from endothelial cells and is present in small amounts in plasma where it catalyzes the conversion of plasminogen to plasmin. Plasmin proteolytically degrades fibrin, hence its antithrombotic activity. PAI-1, also secreted mainly from endothelial cells is a major inhibitor of tPA, thereby slowing degradation of the fibrin clot and promoting hemostasis. Both have short plasma half-lives, on the order of 5 min, and their relative concentrations play an integral role in modulation of both thrombosis and fibrinolysis. PAI-1 is elevated in a variety of pro-thrombotic or ischemic states, including young survivors of MI (58). Angiotensin II stimulates endothelial cells in culture to release PAI (59,60), an observation confirmed in vivo in normal volunteers (61). Furthermore, bradykinin, a vasoactive peptide that is

Angiotensin Fibrinolysis

Vascular wall

Lumen

Fig. 6. ACE plays a crucial dual role in the fibrinolytic balance between PAI-1 and tPA. Conversion of angiotensin I to angiotensin II leads to increased expression of PAI-1; degradation of bradykinin inhibits the production of tPA. Inhibition of ACE enhances bradykinin-mediated release of tPA from the endothelium while decreasing angiotensin-II-mediated release of PAI-1. The net effect is a shift in the fibrinolytic balance toward lysis, which is an advantageous condition during acute ischemic syndromes (59).

Vascular wall

Lumen

Fig. 6. ACE plays a crucial dual role in the fibrinolytic balance between PAI-1 and tPA. Conversion of angiotensin I to angiotensin II leads to increased expression of PAI-1; degradation of bradykinin inhibits the production of tPA. Inhibition of ACE enhances bradykinin-mediated release of tPA from the endothelium while decreasing angiotensin-II-mediated release of PAI-1. The net effect is a shift in the fibrinolytic balance toward lysis, which is an advantageous condition during acute ischemic syndromes (59).

degraded by ACE, induces dose-dependent increases in circulating plasminogen activator levels (62).

Vaughan et al. studied plasma fibrinolytic balance in patients following anterior MI randomized to ramipril or placebo in the Healing and Early Afterload Reducing Therapy (HEART) study. At d 14 after the infarct, PAI levels were 44% lower in the ramipril-treated group (p = 0.004) than in placebo patients. Furthermore, the ratio of circulating PAI to tPA was higher than at baseline in those patients not treated with ACE inhibition (63). Also, Miani et al. (64) demonstrated that intracoronary infusion of bradykinin stimulates tPA release without causing any change in PAI-1 levels in the human coronary circulation. An ACE inhibitor augmented this effect. Furthermore, Soejima et al. (65) demonstrated that administration of enalapril reduces the increased procoagulant activity in patients with MI associated with inhibition of the activation and accumulation of macrophages and monocytes by reduction of plasma tissue factor (TF), tissue factor pathway inhibitor (TFPI) and monocyte chemoattractant protein-1 (MCP-1) levels. These observations form the basis of a new paradigm for the treatment of acute coronary syndromes.

Protection against intravascular thrombosis depends on the balance between pro-thrombotic influences, such as PAI, and fibrinolytic influences, such as tPA (66). ACE inhibition, through nonhemodynamic humoral mechanisms, may favorably shift this balance towards fibrinolysis and prevention of thrombotic events (Fig. 6). The proposed beneficial effects of ACE inhibition on vascular reactivity and the coagulation system are supported by a recent study (67). In a prospective cohort of 301 patients with non-ST-segment elevation acute coronary syndrome, 53 patients had been pretreated with ACE inhibitors. This intervention significantly reduced the likelihood of troponin I

release and was associated with lower maximum troponin I concentrations. These findings were independent of aspirin treatment and not associated with ACE genotype.

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