Review ArticleA Novel Insight Into the Mechanism of Pulmonary Hypertension Involving Caveolin-1 Deficiency and Endothelial Nitric Oxide Synthase Activation
Introduction
Pulmonary hypertension (PH) is defined as a mean pulmonary arterial pressure greater than 25 mm Hg at rest or 30 mm Hg with exercise (Farber and Loscalzo 2004). Pulmonary hypertension of different etiologies share several features: endothelial dysfunction, worsening vasoconstriction, remodeling of pulmonary microvessels, and intravascular thrombosis (Farber and Loscalzo, 2004, Rabinovitch, 1997, Rubin, 1997). These changes typically result in increased medial thickness, microvascular occlusion, and formation of plexiform lesions, all of which contribute to the mechanism of increased pulmonary vascular resistance (PVR) and PH. As the molecular mechanisms responsible for pulmonary vascular remodeling and vasoconstriction remain elusive, there are limited options available for the prevention and treatment of progressive PH, including idiopathic pulmonary arterial hypertension (IPAH) (Farber, 2008, Puri et al., 2007). Idiopathic pulmonary arterial hypertension is the most severe form of PH, which without treatment leads to right heart failure and premature death (Farber and Loscalzo, 2004, Rabinovitch, 1997, Rubin, 1997, Runo and Loyd, 2003). Studies have described mutations of bone morphogenetic protein receptor type II in patients with familial PAH and IPAH (Lane et al., 2000, Machado et al., 2006). Given that only 10% to 15% of these individuals go on to develop severe disease (Humbert et al., 2006, Machado et al., 2006), other genetic and environmental factors are likely to be important. One important factor may be oxidative/nitrative stress (Bowers et al., 2004, Hoshikawa et al., 2001, Nozik-Grayck and Stenmark, 2007). Tissue hypoxia, ischemia, and inflammation all contribute to the production of reactive oxygen species (ROS) in the lung tissue of patients with severe PH (Bowers et al., 2004, Hoshikawa et al., 2001). The reaction between ROS and nitric oxide (NO) results in not only low bioavailability of NO but also formation of peroxynitrite and resultant nitrative stress (Beckman et al., 1990, Hurst, 2002). Although increased oxidative/nitrative stress has been demonstrated in lung tissues of patients with severe PH, including IPAH (Bowers et al., 2004, Cracowski et al., 2001), the mechanistic role of oxidative/nitrative stress in the pathogenesis of PH has not been fully elucidated. Here, we discuss the critical role of endothelial NO synthase (eNOS) activation secondary to caveolin-1 (Cav1) deficiency in the pathogenesis of PH through tyrosine nitration-mediated impairment of protein kinase G (PKG) activity.
Section snippets
Caveolin-1 Regulation of Endothelial Nitric Oxide Synthase Activity
Caveolae, 50 to 100-nm vesicular invaginations of the cell plasma membrane, have emerged as the site of the important events at the plasma membrane such as vesicular trafficking as well as signal transduction (Galbiati et al., 2001, Rothberg et al., 1992. Three isoforms of caveolins (Cav1, Cav2, and Cav3), the structural proteins of caveolae, have been identified. Caveolins are shown to act as scaffolding proteins to concentrate and orchestrate many signaling molecules, including eNOS,
Pathogenic Role of Caveolin-1 Deficiency in Pulmonary Hypertension
The critical role of Cav1 deficiency in the pathogenesis of PH was first identified by Zhao et al. (Zhao et al. 2002). Cav1-deficient mice exhibit pulmonary hypertension and right ventricle hypertrophy. Hemodynamic measurements also reveal a significant increase of right ventricular contractility and diastolic function at baseline in Cav1−/− mice compared with age- and sex-matched wild-type (WT) mice. Our recent studies further demonstrate that Cav1−/− lungs exhibit increased pulmonary vascular
Causal Role of Endothelial Nitric Oxide Synthase Activation Secondary to Caveolin-1 Deficiency in the Pathogenesis of Pulmonary Hypertension
To determine the consequences of chronic activation of eNOS in Cav1−/− lungs, our recent studies have used a mouse model with genetic deletions of both Cav1 and NOS3 (double knockout, DKO) (Zhao et al. 2009). Surprisingly, DKO mice do not develop pulmonary hypertension. In contrast to Cav1−/− mice, DKO mice have the same right ventricular systolic pressure (RVSP) as WT mice. The ratio of right ventricle weight/left ventricle plus septum weight is normal in DKO mice and PVR in DKO mice is
Mechanistic Role of Protein Kinase G Nitration in the Pathogenesis of Pulmonary Hypertension
Our recent studies provide additional insights into the molecular basis of eNOS activation-induced PH in Cav1−/− mice. Given that NO reacts with superoxide to form the damaging ROS peroxynitrite, which modifies proteins and may interfere with their function through tyrosine nitration, we have detected a significant increase in nitrotyrosine expression, a surrogate measure of peroxynitrite in Cav1−/− lungs. Prominent nitrotyrosine immunostaining is also evident in Cav1−/− pulmonary vasculature,
Conclusions and Future Perspectives
Severe PH (including IPAH) is a fatal disease characterized by a progressive increase in PVR and vascular remodeling leading to right heart failure and early death. Despite recent advances in our understanding of the mechanisms and genetic determinants of PH, there are limited options available for the prevention and treatment of severe PH. Prominent oxidative/nitrative stress is a hallmark of the pathology of severe PH. Our recent studies have now provided a mechanistic insight into the
Acknowledgments
The authors apologize to the many authors whose significant works were not cited owing to the space limitations. This work was supported by National Institutes of Health grants R01 HL085462 to Y.Y. Zhao and P01 HL060678 to A.B. Malik.
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2016, Vascular PharmacologyCitation Excerpt :A mutation in the Cav-1 gene, which is associated with a reduction in Cav-1 expression in pulmonary endothelial cells, had been identified in IPAH patients [53]. It was proposed that the loss or reduction of endothelial Cav-1 leads to dysregulation of eNOS activity and subsequently vascular remodeling and PH [54–57]. However, much less attention has been paid to caveolae and Cav-1 of PASMCs in PH. A previous study showed substantial increase in Cav-1 expression in PASMCs of IPAH patients [31], and another study found a progressive increase in Cav-1 in PASMCs of MCT-induced PH rats [58].