Angiotensin-converting enzyme inhibitor preserves p21 and endothelial nitric oxide synthase expression in monocrotaline-induced pulmonary arterial hypertension in rats

Background-Pulmonary arterial hypertension (PAH) is associated with structu ral changes in the pulmonary vasculature characterized by the proliferation of cellular components of the vessels. ACE inhibitor (ACEI) may have benef icial effects in treating PAH, but its precise mechanism of action in the r emodeling process is unclear. p21 is a cyclin-dependent kinase inhibitor th at may have a protective role in this process by inhibiting cellular prolif eration. Endothelial nitric oxide synthase (eNOS) has also been shown to be protective by its vasodilatory effect. Therefore, we investigated whether expression of p21 and eNOS was modulated by ACEI treatment in a rat model. Methods and Results-Monocrotaline (MCT) was administered to 2 groups of Spr ague-Dawley rats fed a high-cholesterol diet, ie, one group received MCT co ncomitantly with enalapril treatment (MCT+/ACEI(+) rats), and the other gro up did not receive enalapril (MCT+/ACEI(-) rats). After 5 weeks, MRI showed right ventricular hypertrophy in MCT+/ACEI(-) rats. MCT+/ACEI(+) rats show ed a preserved right ventricular morphology. Isolated pulmonary perfusion s tudies showed that ACEI significantly upregulated NO production, as measure d by nitrite levels. Addition of N-methyl-D-glucamine dithiocarbamate-Fe so lution, an NO-trapping agent, reversed the basal vasodilatory effect of ACE I in the pulmonary vasculature. Immunoblot analysis showed decreased p21 an d eNOS expression in the lung in MCT+/ACEI(-) rats, whereas their expressio n was preserved with enalapril treatment. Conclusions-ACEI suppresses the development of MCT-induced PAH in rats. The mechanism of action might involve the preservation of p21 and eNOS express ion. Both p21 and endothelium-derived NO appear to have protective roles in the development of PAH.