ACE2 Activation Promotes Antithrombotic Activity

Abstract

Hyperactivity of the axis ACE/AngII/AT1R of the renin‐angiotensin system is associated with occurrence of acute thrombotic event. Recently a novel concept of a counterrugulatory axis, ACE2/Ang‐(1‐7)/Mas, has emerged. We hypothesized that ACE2 would be protective against thrombosis. Thrombus was induced in the vena cava of SHR and WKY rats by FeCl3 solution. ACE2 and ACE protein expression and activities in the thrombus were determined by Western blot and fluorogenic kinetic assays, respectively. Real time thrombus formation was visualized by intravital microscopy of the vessels of nude mice. Ferric chloride‐induced thrombus weight was 40% higher in the SHR compared to WKY rats. This was associated with a 20% decreased in ACE2 activity in the thrombus of the SHR. In contrast, ACE2 protein expression and ACE activity did not differ between the thrombus of WKY rats and SHR. Inhibition of ACE2 by DX600 increased the thrombus weight by 30%, preferentially in the SHR. Furthermore, treatment with XNT resulted in a 30% attenuation of thrombus formation in both the SHR and WKY. In addition, XNT treatment prolonged the time for complete vessel occlusion and reduced thrombus size when observed under real‐time intravital microscopy. Our data demonstrated that a decrease in ACE2 activity is associated with increased thrombus formation in the SHR. Furthermore, activation of ACE2 attenuates thrombus formation.

Circulating ACE2 activity is increased in patients with type 1 diabetes and vascular complications

“…Experimental data support the concept that intrarenal expression of ACE2 is altered in diabetes [12,27,28]. Furthermore, ACE2 may provide vascular and renal protection since a genetic deficiency or pharmacological inhibition of ACE2 causes increased prothrombotic, atherogenic and inflammatory activity as well as worsening of albuminuria [9,12,[29][30][31].…”

“…Our results partly confirm the observations made in experimental diabetes, but also raise the question of whether data from rodents with experimental diabetes can be readily translated into human disease. Recent experimental data prove that overexpression of ACE2 counterbalances the harmful effects of Ang II in the vasculature [44,45], and that genetic deficiency or pharmacological inhibition of ACE2 causes increased prothrombotic, atherogenic and inflammatory activity [29,30]. Whether an alteration in ACE2 gene and/or protein expression contributes to the progression of diabetic nephropathy or vascular injury remains still an open question.…”

Angiotensin-converting enzyme 2 is subject to post-transcriptional regulation by miR-421

“…Nevertheless, these findings open the door to the possibility that miR-421 may be useful as a diagnostic or prognostic indicator in cardiovascular disease. To date, understanding the biological roles of miR-421 is limited, but a recent study identified a possible role for miR-421 in thrombosis [20], a pathology also linked to ACE2 dysregulation [33]. Furthermore, Marchand et al [20] identified SERPINE-1 as a direct target of miR-421.…”

Angiotensin converting enzyme 2 and atherosclerosis

“…T-lymphocytes [52] and platelets [53] are implicated in contributing to atherosclerosis formation. Intraperitoneal administration of human recombinant ACE2 inhibits T-cell infiltration into the kidney [54] and pharmacological activation of ACE2 by XNT, a small-molecular ACE2 activator [33], inhibits platelets from attaching to ECs [55]. It is therefore possible that these two cell types might be important in the anti-atherosclerotic effects of ACE2 and future work is needed to clarify this.…”