Abstract 14598: SDPR/Cavin-2 Deficiency Aggravates Hypoxia-induced Pulmonary Arterial Hypertension With ERK1/2 Hyperactivation and Caveolin-1 Reduction
Introduction: Pulmonary arterial hypertension (PAH) is a severe and fatal disease. However, the mechanisms of PAH have not been elucidated completely. Caveolin-1 gene, which encodes a membrane protein of caveolae and regulates its function, is recognized 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 & 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. Right ventricular systolic pressure (RVSP) was not elevated in SDPR-/- mice under normoxic conditions. After four weeks exposure to 10% O2 hypoxia, RVSP was 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 knockdown promotes p42/44 MAPK (ERK1/2) nuclear translocation and Caveolin-1 deletion-induced PAH shows the hyperactivation of ERK1/2, we assessed the ERK1/2 activity in the lung of SDPR -/- mice. The phosphorylation of ERK1/2 was significantly increased in hypoxia-exposed lungs of SDPR -/- mice compared with that of WT mice.
Conclusions: In the present study, we showed that SDPR/Cavin-2 deficiency aggravated hypoxia-induced PAH with the hyperactivation of ERK1/2. 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.
Author Disclosures: T. Kasahara: None. T. Ogata: None. N. Nakanishi: None. N. Maruyama: None. M. Nishi: None. Y. Higuchi: None. S. Matoba: None.
- © 2016 by American Heart Association, Inc.