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Role of PTEN in Hypoxic Pulmonary Vasoconstriction
Author(s) -
Krauszman Adrienn,
Kuebler Wolfgang
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.1031.3
Subject(s) - pten , hypoxic pulmonary vasoconstriction , tensin , caveolae , trpc6 , phosphatase , trpc , microbiology and biotechnology , hypoxia (environmental) , chemistry , pi3k/akt/mtor pathway , biology , cancer research , signal transduction , receptor , phosphorylation , vasoconstriction , endocrinology , transient receptor potential channel , biochemistry , organic chemistry , oxygen
Rationale Hypoxic pulmonary vasoconstriciton optimizes ventilation/perfusion matching in the lung, and critically depends on transient receptor potential canonical (TRPC) 6 activation and trafficking to caveolae. However, underlying regulatory mechanisms are yet unclear. In endothelial cells, phosphatase and tensin homolog (PTEN) has been shown to serve as a scaffold for TRPC6, enabling cell surface expression of the channel and subsequent Ca 2+ entry independent of its phosphatase activity. Based on these data we hypothesized that the interaction between PTEN and TRPC6 in PASMC may be required for TRPC6 transloaction to caveolae and an intact HPV response. Methods Interaction between PTEN and TRPC6 was tested by co‐immunoprecipitation in whole lung lysates, and by proximity ligation assay in pulmonary artery smooth muscle cells (PASMC). Caveolar recruitment of proteins was assessed in PASMC by sucrose density gradient ultracentrifugation. HPV was analyzed in isolated perfused lungs as hypoxia‐induced incresae in perfusion pressure. Results Hypoxia induced protein‐protein interaction between PTEN and TRPC6 in both whole lungs and PASMC. Hypoxia also translocated PTEN to caveolae (caveolin 1‐rich fraction) but inhibition of ROCK (Y27632; 5 µM) prevented this translocation. HPV response was significantly attenuated by Y27632, yet not by the PTEN phosphatase inhibitor VO‐OHpic (1‐50 µM). Conclusion Hypoxia induces PTEN interaction with TRPC6 in PASMC, and PTEN translocation to caveolae in a ROCK‐dependent manner. PTEN may play an important role in TRPC6 recruitment and activation downstream of ROCK and thus, mediate HPV in a manner that is independent of its phosphatase activity. Funded by a CIHR operational grant to WMK.