Background: Angiotensin-converting enzyme 2 (ACE2), a primary component of the vasoprotective axis in the renin-angiotensin system (RAS), has recently been found to have regulatory actions in hypoxic pulmonary hypertension and monocrotaline-induced pulmonary hypertension. We explored the hypothesis that the level of ACE2 protein contents may be decreased in patients with pulmonary arterial hypertension (PAH) due to congenital heart disease (CHD). Objective: We observed the serum ACE2 protein contents in patients with PAH due to CHD (CHD-PAH), and investigated their correlation with mean pulmonary arterial pressure (mPAP). Methods: One hundred and four patients with CHD and 33 normal control patients (group A) were involved in the research. The patients with CHD were divided into 55 cases of nonpulmonary hypertension (group B), 25 cases of mild to moderate pulmonary hypertension (group C) and 24 cases of severe pulmonary hypertension (group D). The serum level of ACE2 protein contents were detected by enzyme-linked immunosorbent assay (ELISA), and the relationship between these contents and mPAP were analyzed. Results: ACE2 protein contents significantly declined as mPAP increased. The mPAP was negatively correlated with the level of ACE2 protein contents. Conclusions: These results demonstrated that ACE2 may play an important regulatory role in CHD-PAH.

We read with great interest the Review by Latus et al. (Treatment of pulmonary arterial hypertension in children. Nat. Rev. Cardiol. 12, 244-254; 2015), 1 in which the authors thoroughly summarize the latest developments in drug therapy for patients with pulmonary arterial hypertension (PAH). They mention some novel therapeutic targets in PAH; however, they do not discuss the angiotensin-converting enzyme (ACE) 2-angiotensin-(1-7)-Mas axis in their article. The ACE2-angiotensin-(1-7)-Mas receptor axis is an important component of the renin-angiotensin system. ACE2 is highly expressed in the lungs, and converts angiotensin II into angiotensin-(1-7). Angiotensin-(1-7) mediates vasodilatation, antiproliferation, antiapoptosis, and antifibrosis by stimulating the receptor Mas, which counterbalances the vasoconstrictive, proliferative, and fibrotic pathways (ACE-angiotensin II-type 1 angiotensin II receptor [AT 1 R] axis). Studies have indicated that an imbalance between the mechanisms of the ACE-angiotensin II-AT 1 R and the ACE2-angiotensin-(1-7)-Mas pathways involved in the pulmonary circulation might lead to the development of PAH. 2-5 ACE inhibitors and AT 1 R blockers inhibit the ACE-angiotensin II-AT 1 R axis, but their primary effects are to reduce systemic blood pressure. Consequently, these drugs are unsuccessful in treating patients with PAH, who are already at high risk of developing hypotension owing to right ventricular overload. Some studies have shown that ACE2 or angiotensin-(1-7), in the form of a synthetic molecule, continuous injection of resorcinolnaphthalein, or gene transfer, can induce beneficial pulmonary outcomes in a monocrotaline-induced model of PAH, with no adverse effects on systemic blood pressure. 6-9 Our studies have shown that serum ACE2 and angiotensin-(1-7) levels were decreased in patients with PAH due

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