THU0056 A Small Chemical Compound Identified as an ACE2 Activator Prevented Pulmonary Arterial Hypertension Induced by Monocrotaline
Authors: S. Haga, H. Tsuchiya, K. Hara, A. Doi, A. Mimori, Y. Ishizaka
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Pulmonary arterial hypertension (PAH) is a lethal clinical symptom characterized by progressive increase in pulmonary arterial pressure and causes right ventricular hypertrophy (RVH) with RV failure. Complications of PAH are observed in 10-15% of patients of connective tissue diseases (CTD) that include systemic sclerosis (SSc), systemic lupus erythematosus and mixed connective tissue disease<sup>1, 2</sup>. Recently, we reported that autoantibodies to angiotensin-converting enzyme 2 (ACE2), a homologue of ACE that functions as negative regulator of renin-angiotensin system by converting angiotensin (Ang) II to Ang-(1-7), were detected in a SSc patient who died due to PAH<sup>3</sup>. Moreover, we further detected that CTD-patients were frequently positive for ACE2-autoantibodies that neutralized ACE2 activity. Because recent lines of evidence revealed that deregulation of ACE2 has a positive link with the development of PAH, we here identified a small chemical compound (compound-A) that activates ACE2 activity. <h3>Objectives</h3> We identify novel ACE2 activator and evaluate its effect against pathological condition on PAH. <h3>Methods</h3> To prepare animal models of PAH, Sprague-Dawley rats were subcutaneously injected with monocrotaline (MCT). Immediately after single injection of MCT, compound-A was continuously administered for 4 weeks by osmotic pumps. Pulmonary compliance was evaluated by echocardiography, and we monitored the ratio of the acceleration time to ejection time (AcT/ET) of pulmonary artery flow for 4 weeks post-infusion (4 wpi). The right ventricular systolic pressure (RVSP) was measured by catheterization at 4 wpi. Expression of brain natriuretic peptide (<i>BNP</i>) and transforming growth factor-β (<i>TGF-β</i>), which are markers of cardiac failure and lung remodeling, respectively, were also examined at 4 wpi by real-time RT-PCR using RV and lung, respectively. <h3>Results</h3> AcT/ET values were significantly reduced in the MCT+vehicle group (n=13). In contrast, co-administration of compound-A significantly improved the AcT/ET value (<i>P</i> &lt; 0.05, n=9). Co-injection of compound-A also ameliorated the increase of RVSP that was induced by MCT (37.18 ± 4.76 mmHg, vs. 49.76 ± 6.04 mmHg, <i>P</i> &lt; 0.05, n=5 and 3, respectively). Consistent with these clinical signs, compound-A suppressed expression of <i>BNP</i> and <i>TGF-β</i> mRNA that was up-regulated by MCT (<i>P</i> &lt; 0.05). <h3>Conclusions</h3> Compound-A, a novel ACE2 activator, prevented MCT-induced PAH and vascular remodeling. Along together with data that compound-A inhibited the activity of autoantibodies to ACE2 in CTD-patients, we propose that compound-A is a candidate compound that can be useful to PAH in CTD-patients. We also discuss modes of PAH in CTD-patients, and possible application of ACE2 activators as therapeutics for CTD-patients with vasculopathy. <h3>References</h3> Galiè N <i>et al</i>. Guidelines for the diagnosis and treatment of pulmonary hypertension. <i>Eur Heart J</i>. 2009; 30: 2493-2537. Yoshida S. Pulmonary arterial hypertension in connective tissue diseases. <i>Allergol Int</i>. 2011; 60: 405-409. Takahashi Y <i>et al</i>. Autoantibodies to angiotensin-converting enzyme 2 in patients with connective tissue diseases. <i>Arthritis Res Ther</i>. 2010; 12:R85-R92. <h3>Acknowledgements</h3> This work was supported by Adaptable and Seamless Technology Transfer Program through target-driven R&amp;D, Japan Science and Technology Agency. <h3>Disclosure of Interest</h3> S. Haga: None Declared, H. Tsuchiya: None Declared, K. Hara Grant/research support from: Matching research funds of Nippon chemiphar Co. Ltd. and Japan Science and Technology Agency (JST), A. Doi: None Declared, A. Mimori: None Declared, Y. Ishizaka: None Declared