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

The pathogenesis of hypertension-related cognitive impairment has not been sufficiently clarified, new molecular targets are needed. p38 MAPK pathway plays an important role in hypertensive target organ damage. Activated p38 MAPK was seen in AD brain tissue. In this study, we found that long-term potentiation (LTP) of hippocampal CA1 was decreased, the density of the dendritic spines on the CA1 pyramidal cells was reduced, the p-p38 protein expression in hippocampus was elevated, and cognitive function was impaired in angiotensin II-dependent hypertensive C57BL/6 mice. In vivo, using a p38 heterozygous knockdown mice (p38KI/+) model, we showed that knockdown of p38 MAPK in hippocampus leads to the improvement of cognitive function and hippocampal synaptic plasticity in angiotensin II-dependent p38KI/+ hypertensive mice. In vitro, LTP was improved in hippocampal slices from C57BL/6 hypertensive mice by treatment with p38MAPK inhibitor SKF86002. Our data demonstrated that p38 MAPK may be a potential therapeutic target for hypertension-related cognitive dysfunction.

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Cerebral ischemia/reperfusion (I/R) injury is a complex pathophysiological process that can lead to neurological function damage and the formation of cerebral infarction. The p38 MAPK pathway has attracted considerable attention in cerebral I/R injury (IRI), but little research has been carried out on its direct role in vivo. In this study, to observe the effects of p38 MAPK endogenous inhibition on cerebral IRI, p38 heterozygous knockdown (p38KI/+) mice were used. We hypothesized that p38 signaling might be involved in I/R injury and neurological damage reduction and that neurological behavioral deficits improve when p38 MAPK is inhibited. First, we examined the neurological damage and neurological behavioral deficit effects of I/R injury in WT mice. Cerebral I/R injury was induced by the bilateral common carotid artery occlusion (BCCAO) method. The cerebral infarction area and volume were assessed and analyzed by 2,3,5-triphenyltetrazolium chloride (TTC) staining. p38 MAPK and caspase-3 were detected by western blotting. Neuronal apoptosis was measured using TUNEL staining. Neurological deficits were detected by behavioral testing. Furthermore, to assess whether these neuroprotective effects occurred when p38 MAPK was inhibited, p38 heterozygous knockdown (p38KI/+) mice were used. We found that p38 MAPK endogenous inhibition rescued hippocampal cell apoptosis, reduced ischemic penumbra, and improved neurological behavioral deficits. These findings showed that p38 MAPK endogenous inhibition had a neuroprotective effect on IRI and that p38 MAPK may be a potential therapeutic target for cerebral IRI.

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