ACE2 Activation Promotes Antithrombotic Activity

Rodrigo A Fraga-Silva,Michael J Katovich,Brian S Sorg,Ronald K Castellano,Matthew B Baker,Joo Y Jun,Casey Dedeugd,Yan Li,Mohan K Raizada,Anderson J Ferreira,Mamta Wankhede

doi:10.2119/molmed.2009.00160

Rodrigo A Fraga-Silva, Michael J Katovich + Show 9 more

Open Access

https://doi.org/10.2119/molmed.2009.00160

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Abstract

The aim of the present study was to test the hypothesis that the activation of the angiotensin-converting enzyme (ACE)2/angiotensin-(1-7)/Mas receptor axis by use of a novel ACE2 activator (XNT) would protect against thrombosis. Thrombi were induced in the vena cava of spontaneously hypertensive rats (SHR) and Wistar Kyoto (WKY) rats, and ACE2 and ACE activity in the thrombus was determined. Real-time thrombus formation was viewed through intravital microscopy of vessels in nude mice. Thrombus weight was 40% greater in the SHR (4.99 +/- 0.39 versus 7.04 +/- 0.66 mg). This weight increase was associated with a 20% decrease in ACE2 activity in the thrombus. In contrast, there were no differences between the WKY and SHR in ACE2 protein and ACE activity in the thrombi. ACE2 inhibition (DX600; 0.1 micromol/L/kg) increased thrombus weight by 30% and XNT treatment (10 mg/kg) resulted in a 30% attenuation of thrombus formation in the SHR. Moreover, XNT reduced platelet attachment to injured vessels, reduced thrombus size, and prolonged the time for complete vessel occlusion in mice. Thus, a decrease in thrombus ACE2 activity is associated with increased thrombus formation in SHR. Furthermore, ACE2 activation attenuates thrombus formation and reduces platelet attachment to vessels. These results suggest that ACE2 could be a novel target for the treatment of thrombogenic diseases.

Highlights

Thrombogenic events, such as ischemic stroke, pulmonary embolism, deep venous thrombosis, mesenteric ischemia and acute coronary syndrome, are major complications of certain pathological conditions, such as hypertension, atherosclerosis and diabetes mellitus [1]
ACE2 activity in thrombi from the spontaneously hypertensive rats (SHR) treated with DX600 decreased, the difference did not achieve statistical significance (Figure 3C)
The present study offers evidence that ACE2 is involved in the hemostatic process and exhibits a protective action against thrombosis

Summary

Introduction

Thrombogenic events, such as ischemic stroke, pulmonary embolism, deep venous thrombosis, mesenteric ischemia and acute coronary syndrome, are major complications of certain pathological conditions, such as hypertension, atherosclerosis and diabetes mellitus [1]. Despite the many therapeutic advances and increasingly effective drug treatments, thrombogenic events remain the major cause of morbidity and mortality worldwide [2]. Increased activity of the vasoconstrictive and proliferative axis (angiotensin [Ang] II/angiotensinconverting enzyme [ACE]/AT1 receptor) has been reported to be associated with a higher risk of acute thrombosis through the destabilizing of atherosclerotic plaque and enhancing of platelet activity and coagulation [3]. Ang II has many adverse cardiovascular effects when acting through the AT1 receptor. This simplistic concept of a linear RAS cascade has given way to a more complex concept since the discovery of ACE2, which is an ACE homologue [4,5]

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