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ACE2 Activation Confers Endothelial Protection and Attenuates Neointimal Lesions in Prevention of Severe Pulmonary Arterial Hypertension in Rats

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Abstract

Background

Angiotensin-converting enzyme 2 (ACE2), an ACE homolog, hydrolyzes angiotensin II and opposes its actions, and plays a protective role in the pathogenesis of pulmonary arterial hypertension (PAH). However, the underlying mechanisms involved in the effect of ACE2 on PAH are still uncertain. In this study, we observed the effects of ACE2 activation on endothelial dysfunction and vascular remodeling in the development of severe PAH in rats.

Methods

Severe PAH was induced by monocrotaline injection 1 week following left pneumonectomy, and ACE2 was activated by continuous injection of resorcinolnaphthalein. The PAH-related hemodynamics, pathological changes, and endothelium-dependent vasorelaxation were examined to assess the effects of ACE2 activation. In addition, the changes of the main components of the renin-angiotensin system were identified by ELISA or Western blotting.

Results

Severe PAH was established at 3 weeks and was characterized by high pulmonary arterial pressure (45 mmHg), significant right ventricular hypertrophy, neointimal occlusive lesions, and impaired endothelium-dependent relaxation in pulmonary arteries. Coadministration of resorcinolnaphthalein reduced pulmonary arterial pressure, right ventricular hypertrophy, and neointimal formation and shifted the endothelial-dependent responses toward values measured in normal rats. Theses changes were associated with an increase in ACE2 and angiotensin-(1–7) levels and a decrease in ACE and angiotensin II levels, in addition to a decrease in the ACE/ACE2 ratio and the angiotensin II/angiotensin-(1–7) ratio. The beneficial effects of resorcinolnaphthalein were abolished by A-779.

Conclusions

These findings suggested that ACE2 activation by resorcinolnaphthalein improved endothelial function and suppressed neointimal formation in the prevention of severe PAH by the mechanism of mediating the levels of the components of the renin-angiotensin system.

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Acknowledgments

This study was supported by Grants from the Specialized Research Fund for the Doctoral Program of Higher Education (20111107110006).

Conflict of interest

The authors have no conflicts of interest to disclose.

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Authors and Affiliations

  1. Pediatric Cardiac Center, Beijing Anzhen Hospital, Capital Medical University, Beijing, China

    Gang Li, Yinglong Liu, Yaobin Zhu, Aijun Liu, Yulin Xu, Xiaofeng Li, Zhiqiang Li & Junwu Su

  2. Cardiovascular Center, Beijing Anzhen Hospital, Capital Medical University, Beijing, China

    Lizhong Sun

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  1. Gang Li
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  2. Yinglong Liu
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  3. Yaobin Zhu
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  4. Aijun Liu
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  7. Zhiqiang Li
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  8. Junwu Su
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  9. Lizhong Sun
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Correspondence to Lizhong Sun.

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Li, G., Liu, Y., Zhu, Y. et al. ACE2 Activation Confers Endothelial Protection and Attenuates Neointimal Lesions in Prevention of Severe Pulmonary Arterial Hypertension in Rats. Lung 191, 327–336 (2013). https://doi.org/10.1007/s00408-013-9470-8

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  • DOI: https://doi.org/10.1007/s00408-013-9470-8

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