Caleb Hemphill

Background: Pulmonary arterial hypertension (PAH) is a progressive and life-threatening condition marked by elevated pulmonary artery pressure and increased vascular resistance, which may lead to right ventricular hypertrophy and heart failure.¹ Vascular remodeling is a key pathological feature of PAH, driven by proliferation and resistance to apoptosis in pulmonary artery smooth muscle cells (PASMCs), inflammation, and oxidative stress.^1,2 Current therapies primarily aim to balance vasodilation and vasoconstriction or reduce smooth muscle hypertrophy, but do not cure the disease.^2,3 Recent research suggests that dysfunction in the renin-angiotensin-aldosterone system (RAAS), particularly reduced angiotensin-converting enzyme 2 (ACE2) activity plays a major role in the pathogenesis of PAH.^3,4 ACE2 counteracts the ACE/Angiotensin II/AT1R pathway by degrading Angiotensin II and increasing Ang-(1–7), a vasodilator that also inhibits vascular remodeling.⁴

Objective: This review explores the therapeutic potential of restoring ACE2 function in PAH by summarizing current evidence on its molecular role in limiting vascular remodeling and promoting apoptosis in PASMCs.

Search Methods: A literature review was conducted using PubMed from 2017 to 2023. Keywords included “pulmonary arterial hypertension,” “ACE2,” “vascular remodeling,” and “Renin-angiotensin-aldosterone system.”

Results: Laboratory studies provide evidence for ACE2 as a promising therapeutic target in PAH. One study demonstrated that ACE2 activation promotes apoptosis through the Hippo/LATS1/YAP signaling pathway in rat models of PAH, reducing pulmonary artery pressure and right ventricular hypertrophy.⁵ Researchers also identified MDM2 as an E3 ligase that ubiquitinates ACE2, promoting its degradation.⁶ Inhibiting MDM2 or enhancing phosphorylation of ACE2 by AMP-activated protein kinase (AMPK) stabilized ACE2 and improved endothelial function both in vitro and in animal models.⁶ Another study showed that ACE2 suppresses focal adhesion kinase (FAK), an important regulator of cell proliferation and survival.⁷ ACE2 activation led to decreased FAK and survivin levels, increased caspase-3, and reduced PASMC proliferation.⁷ Additionally, researchers confirmed that overexpression of ACE2 in hypoxia-induced pulmonary hypertension models restored ACE/ACE2 balance and inhibited PASMC migration and proliferation.⁸ Finally, a clinical phase IIa trial demonstrated that recombinant human ACE2 (rhACE2) infusion improved cardiac output and reduced inflammatory and oxidative stress markers in PAH patients. However, mean pulmonary artery pressure did not significantly change.⁹

Conclusion: ACE2 is emerging as a key modulator in the pathogenesis of PAH, with the ACE2/Ang-(1–7)/Mas1 axis offering multiple mechanisms to counteract vascular remodeling.^4-9 Therapeutic strategies that aimed at enhancing ACE2 expression or its stability through gene therapy, protein infusion, or inhibition of its degradation could potentially be used in reducing the progression of PAH.^5-9 These findings highlight the need for larger, controlled clinical trials and more mechanistic studies to further confirm ACE2 as a therapeutic target and investigate its integration with existing treatment regimens.⁹

Works Cited:

1. Ruopp NF, Cockrill BA. Diagnosis and treatment of pulmonary arterial hypertension. JAMA. 2022;327(14):1379–1392. doi:10.1001/jama.2022.4402
2. Humbert M, Sitbon O, Guignabert C, et al. Treatment of pulmonary arterial hypertension: recent progress and a look to the future. Lancet Respir Med. 2023;11(9):804–819. doi:10.1016/S2213-2600(23)00264-3
3. Levine D, Gale S, Burgoyne D, et al. Pulmonary arterial hypertension: updates in epidemiology and evaluation of patients. Am J Manag Care. 2021;27(Suppl 3):S35–S41. doi:10.37765/ajmc.2021.88609
4. Papavassiliou KA, Gogou VA, Papavassiliou AG. Angiotensin-converting enzyme 2 (ACE2) signaling in pulmonary arterial hypertension: underpinning mechanisms and potential targeting strategies. Int J Mol Sci. 2023;24(24):17441. doi:10.3390/ijms242417441
5. Yan D, Li G, Zhang Y, Liu Y. ACE2 activation suppresses pulmonary vascular remodeling by inducing apoptosis via the Hippo pathway in rats with PAH. Clin Exp Hypertens. 2019;41(6):589–598. doi:10.1080/10641963.2019.1583247
6. Shen H, Zhang J, Wang C, et al. MDM2-mediated ubiquitination of ACE2 contributes to PAH development. Circulation. 2020;142(12):1190–1204. doi:10.1161/CIRCULATIONAHA.120.048191
7. Wang R, Xu J, Wu J, Gao S, Wang Z. ACE2 alleviates PAH through inhibition of focal adhesion kinase expression. Exp Ther Med. 2021;22(4):10599. doi:10.3892/etm.2021.10599
8. Hu H, Zhang R, Dong L, Chen E, Ying K. Overexpression of ACE2 prevents hypoxia-induced pulmonary hypertension in rats by inhibiting proliferation and immigration of PASMCs. Eur Rev Med Pharmacol Sci. 2020;24(7):3968–3980. doi:10.26355/eurrev_202004_20867
9. Hemnes AR, Rathinasabapathy A, Austin EA, et al. A potential therapeutic role for ACE2 in human PAH. Eur Respir J. 2018;51(6):1702638. doi:10.1183/13993003.02638-2017