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THU0056 A Small Chemical Compound Identified as an ACE2 Activator Prevented Pulmonary Arterial Hypertension Induced by Monocrotaline
  1. S. Haga1,
  2. H. Tsuchiya2,
  3. K. Hara3,
  4. A. Doi1,
  5. A. Mimori2,
  6. Y. Ishizaka1
  1. 1Department of Intractable Diseases
  2. 2Division of Rheumatic Diseases, National Center For Global Health And Medicine, Tokyo
  3. 3Discovery Research Laboratories, Nippon Chemiphar Co., Ltd., Saitama, Japan

Abstract

Background 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 disease1, 2. 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 PAH3. 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.

Objectives We identify novel ACE2 activator and evaluate its effect against pathological condition on PAH.

Methods 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 (BNP) and transforming growth factor-β (TGF-β), 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.

Results 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 (P < 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, P < 0.05, n=5 and 3, respectively). Consistent with these clinical signs, compound-A suppressed expression of BNP and TGF-β mRNA that was up-regulated by MCT (P < 0.05).

Conclusions 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.

References

  1. Galiè N et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2009; 30: 2493-2537.

  2. Yoshida S. Pulmonary arterial hypertension in connective tissue diseases. Allergol Int. 2011; 60: 405-409.

  3. Takahashi Y et al. Autoantibodies to angiotensin-converting enzyme 2 in patients with connective tissue diseases. Arthritis Res Ther. 2010; 12:R85-R92.

Acknowledgements This work was supported by Adaptable and Seamless Technology Transfer Program through target-driven R&D, Japan Science and Technology Agency.

Disclosure of Interest 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

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