Evidence for Angiotensin-converting Enzyme 2 as a Therapeutic Target for the Prevention of Pulmonary Hypertension

Abstract

Rationale: It has been proposed that an activated renin angiotensin system (RAS) causes an imbalance between the vasoconstrictive and vasodilator mechanisms involving the pulmonary circulation leading to the development of pulmonary hypertension (PH). Recent studies have indicated that angiotensin-converting enzyme 2 (ACE2), a member of the vasoprotective axis of the RAS, plays a regulatory role in lung pathophysiology, including pulmonary fibrosis and acute lung disease. Based on these observations, we propose the hypothesis that activation of endogenous ACE2 can shift the balance from the vasoconstrictive, proliferative axis (ACE-Ang II-AT1R) to the vasoprotective axis [ACE2-Ang-(1-7)-Mas] of the RAS, resulting in the prevention of PH. Objectives: We have taken advantage of a recently discovered synthetic activator of ACE2, XNT (1-[(2-dimethylamino) ethylamino]-4-(hydroxymethyl)-7-[(4-methylphenyl) sulfonyl oxy]-9H-xanthene-9-one), to study its effects on monocrotaline-induced PH in rats to support this hypothesis. Methods: The cardiopulmonary effects of XNT were evaluated in monocrotaline-induced PH rat model. Measurements and Main Results: A single subcutaneous treatment of monocrotaline in rats resulted in elevated right ventricular systolic pressure, right ventricular hypertrophy, increased pulmonary vessel wall thickness, and interstitial fibrosis. These changes were associated with increases in the mRNA levels of renin, ACE, angiotensinogen, AT1 receptors, and proinflammatory cytokines. All these features of PH were prevented in these monocrotaline-treated rats by chronic treatment with XNT. In addition, XNT caused an increase in the antiinflammatory cytokine, IL-10. Conclusions: These observations provide conceptual support that activation of ACE2 by a small molecule can be a therapeutically relevant approach for treating and controlling PH.Keywords: renin angiotensin system; angiotensin-converting enzyme 2; pulmonary heart disease.Pulmonary hypertension (PH) presents a diverse etiology and is defined by a mean pulmonary arterial pressure of greater than 25 mm Hg at rest, or greater than 30 mm Hg with exercise (1). The most common causes of PH include chronic obstructive pulmonary disease (often caused by smoking), left heart failure, substance abuse, schistosomiasis, high altitude exposure, drugs, toxins (e.g., chemical warfare), and HIV infection (2, 3). It has been proposed that these risk factors, coupled with predisposing genetic factors, lead to an imbalance between vasoconstrictor and vasodilator mechanisms. This imbalance initiates a cascade of pathophysiological events in the lungs leading to PH (4). These events are suggested to be set in motion by pulmonary vascular endothelial dysfunction causing enhanced proliferation and activation of lung fibroblasts, leading to extracellular matrix formation and fibrosis, infiltration of inflammatory cells, increased production of proinflammatory cytokines, exaggerated pulmonary vascular remodeling, and smooth muscle hypertrophy (5, 6). Vasodilatory ther...

ACE2 Activation Promotes Antithrombotic Activity

“…This hypothesis is supported by recent data (18). Although neither Ang II nor Ang-(1-7) levels in the thrombi were determined in the present investigation, a large number of studies have shown that Ang II is a prothrombotic agent (19,20).…”

“…Unfortunately, no Mas antagonists were used in the present study. However, an experimental model of pulmonary hypertension demonstrated that the protective effects evoked by XNT were completely abolished by the coadministration of A-779 (18). This important finding should be taken into consideration in future experiments.…”

“…XNT is a small-molecule ACE2 activator that was recently discovered based on the crystal structure of ACE2 and a virtual screening strategy (9). This compound enhances ACE2 activity, causes a reduction in arterial blood pressure and an impressive reversal of cardiac and renal fibrosis in SHR, and also prevents pulmonary hypertension (9,18). It is important to note that the increase in thrombus weight caused by DX600 administration in SHR (46%) and in WKY (37%) was not statistically different (P > 0.05).…”

Renin-angiotensin system in the kidney: What is new?

“…Consequently, it decreases blood pressure, improves cardiac function and decreases renal fibrosis in SHR [142] . It also has antihypertensive effects in rats with pulmonary hypertension [143] . These results together suggest that, besides inhibition of renin and ACE, associated or not with the blocking of AT1 receptor, activation of the ACE2/Ang-(1-7)/Mas axis and its protective effects is emerging as an excellent alternative therapy for the treatment of hypertension and cardiovascular diseases.…”

Present and Prospective Pharmacotherapies in Pulmonary Arterial Hypertension

“…47 Other potential therapies currently being investigated include PPRgamma agonists, angiotensin converting enzyme 2, selective serotonin receptor inhibitors, vasoactive intestinal peptide, soluble glucocorticoid stimulators, tetrahydrobiopterin, aspirin, statins, and serine protease inhibitors. 20,[48][49][50][51][52][53][54] Sex hormone manipulation is another potential therapeutic target given the female predominance in PAH. 55 Finally, since right ventricular function is the primary determinant of survival in PAH, future therapies may directly target the right ventricle.…”