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

Pulmonary arterial hypertension (PAH) is associated with structural changes in the pulmonary vasculature characterized by the proliferation of cellular components of the vessels. ACE inhibitor (ACEI) may have beneficial effects in treating PAH, but its precise mechanism of action in the remodeling p...

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Published in:	Circulation (New York, N.Y.) N.Y.), 2001-08, Vol.104 (8), p.945-950
Main Authors:	KANNO, Shinichi, WU, Yi-Jen L, LEE, Paul C, BILLIAR, Timothy R, CHIEN HO
Format:	Article
Language:	eng
Subjects:	Angiotensin-Converting Enzyme Inhibitors - pharmacology Animals Biological and medical sciences Blood Pressure - drug effects Cells, Cultured Cyclin-Dependent Kinase Inhibitor p21 Cyclins - metabolism Dietary Fats Disease Models, Animal Enalapril - pharmacology Hypertension, Pulmonary - chemically induced Hypertension, Pulmonary - complications Hypertension, Pulmonary - drug therapy Hypertension, Pulmonary - physiopathology Hypertrophy, Right Ventricular - diagnosis Hypertrophy, Right Ventricular - etiology Hypertrophy, Right Ventricular - physiopathology In Vitro Techniques Lung - blood supply Lung - drug effects Lung - metabolism Lung - pathology Magnetic Resonance Imaging Male Medical sciences Monocrotaline Nitrates - metabolism Nitric Oxide Donors - pharmacology Nitric Oxide Synthase - biosynthesis Nitric Oxide Synthase Type III Nitrites - metabolism Perfusion Pneumology Pulmonary Artery - drug effects Pulmonary Artery - pathology Pulmonary Artery - physiopathology Pulmonary hypertension. Acute cor pulmonale. Pulmonary embolism. Pulmonary vascular diseases Rats Rats, Sprague-Dawley Signal Transduction - drug effects
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Summary:	Pulmonary arterial hypertension (PAH) is associated with structural changes in the pulmonary vasculature characterized by the proliferation of cellular components of the vessels. ACE inhibitor (ACEI) may have beneficial effects in treating PAH, but its precise mechanism of action in the remodeling process is unclear. p21 is a cyclin-dependent kinase inhibitor that may have a protective role in this process by inhibiting cellular proliferation. 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. Monocrotaline (MCT) was administered to 2 groups of Sprague-Dawley rats fed a high-cholesterol diet, ie, one group received MCT concomitantly with enalapril treatment (MCT(+)/ACEI(+) rats), and the other group did not receive enalapril (MCT(+)/ACEI(-) rats). After 5 weeks, MRI showed right ventricular hypertrophy in MCT(+)/ACEI(-) rats. MCT(+)/ACEI(+) rats showed a preserved right ventricular morphology. Isolated pulmonary perfusion studies showed that ACEI significantly upregulated NO production, as measured by nitrite levels. Addition of N-methyl-D-glucamine dithiocarbamate-Fe solution, an NO-trapping agent, reversed the basal vasodilatory effect of ACEI in the pulmonary vasculature. Immunoblot analysis showed decreased p21 and eNOS expression in the lung in MCT(+)/ACEI(-) rats, whereas their expression was preserved with enalapril treatment. ACEI suppresses the development of MCT-induced PAH in rats. The mechanism of action might involve the preservation of p21 and eNOS expression. Both p21 and endothelium-derived NO appear to have protective roles in the development of PAH.
ISSN:	0009-7322 1524-4539