Abstract 18746: SDPR/Cavin-2 Deficiency Exacerbates Hypoxia-induced Pulmonary Arterial Hypertension in Mice With an Increase in NOx Production and a Decrease in Caveolin-1

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Abstract

Introduction: Pulmonary arterial hypertension (PAH) is a poor prognosis disease even in recent years. However, the pathophysiology of PAH have remained obscure. Caveolin-1 gene, which encodes a membrane protein of caveolae and regulates its function, is identified as a causal gene of heritable PAH. Serum deprivation response (SDPR)/Cavin-2 is a member of the Cavin family, which also regulates caveolae function. Previous report showed that SDPR/Cavin-2 deficiency as well as Caveolin-1 deficiency led to loss of endothelial caveolae in the lung. However, the functional role of SDPR/Cavin-2 in lung remains unknown. Here, we present a detailed characterization of the lungs of SDPR/Cavin-2 knock-out (SDPR -/-) mice with hypoxia-induced PAH.

Methods and Results: To examine the role of SDPR/Cavin-2 in the development of PAH, we subjected wild-type (WT) and SDPR -/- mice to a model of PAH induced by hypoxia exposure. After four weeks exposure to 10% O2 hypoxia, right ventricular systolic pressure and weight ratio of right/left ventricular plus septum were significantly elevated in SDPR -/- mice compared with WT mice. Electron microscopy displayed reduction of the number of caveolae in pulmonary artery endothelial cells of SDPR-/- mice. Western blot analysis revealed that the expression of Caveolin-1 was increased in WT mouse lungs after hypoxia exposure, but not in SDPR -/- mouse lungs. Because Caveolin-1 regulates the activation of endothelial NO synthase (eNOS) and its deficiency aggravate PAH with excessive production of NO, we assessed the eNOS activity and the production quantity of NOx in the lung of SDPR -/- mice. The phosphorylation of eNOS and the quantity of NOx were significantly increased in hypoxia-exposed lungs of SDPR -/- mice compared with that of WT mice.

Conclusion: In the present study, we showed that SDPR/Cavin-2 deficiency exacerbated hypoxia-induced PAH with the hyperactivation of eNOS and an increase in NOx production. Our results suggest that this process is involved in Caveolin-1 reduction in pulmonary artery endothelial cells. SDPR/Cavin-2 might be a novel therapeutic target in the development of PAH.

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