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Review
. 2009 Oct;19(7):238-42.
doi: 10.1016/j.tcm.2010.02.003.

A novel insight into the mechanism of pulmonary hypertension involving caveolin-1 deficiency and endothelial nitric oxide synthase activation

You-Yang Zhao  1 , Asrar B Malik
Affiliations
Review

A novel insight into the mechanism of pulmonary hypertension involving caveolin-1 deficiency and endothelial nitric oxide synthase activation

You-Yang Zhao et al. Trends Cardiovasc Med. 2009 Oct.

Abstract

Severe pulmonary hypertension (PH) is characterized by a progressive increase in pulmonary vascular resistance and vascular remodeling leading to right heart failure and early death. Our recent studies with the use of the novel mouse model with genetic deletions of caveolin-1 (Cav1) and endothelial nitric oxide synthase (eNOS) (NOS3) have demonstrated that persistent eNOS activation in Cav1(-/-) lungs results in tyrosine nitration of protein kinase G (PKG) and impairment of its activity, which thereby induces PH. The finding of eNOS activation and PKG nitration concomitant with Cav1 deficiency was recapitulated in lungs from patients with idiopathic pulmonary arterial hypertension. These data suggest targeting PKG nitration has potential value for the treatment of PH. Here, we will review the current knowledge about Cav1-regulated eNOS activity and its fundamental role in the pathogenesis of PH.

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Figures

Figure 1
Figure 1
Model of eNOS activation-induced PH. Cav1 is a scaffolding protein of caveolae and acts as a critical negative regulator of eNOS. Under physiological conditions, low-output eNOS-derived NO maintains normal pulmonary vascular resistance and pulmonary arterial pressure. Cav1 may also interact with other molecule(s) through its scaffolding domain and regulate ROS production. Accordingly, Cav1 deficiency (Cav1−/− mice or IPAH patients) results in persistent eNOS activation and formation of peroxynitrite in the pulmonary vasculature. The resultant increase of nitrative stress causes PKG tyrosine nitration and impairs its kinase activity. Impaired PKG signaling induces pulmonary vascular remodeling and vasoconstriction, and thereby pulmonary hypertension. PM, plasma membrane.
See this image and copyright information in PMC

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