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Newly identified caveolin‐1 mutation associated with heritable human pulmonary arterial hypertension mediates hyperproliferation via augmented calcium signaling (1089.10)
Author(s) -
Marsboom Glenn,
Theriault Kraig,
Debroy Auditi,
Mao Mao,
Baig Saqib,
Tiruppathi Chinnaswamy,
Bonini Marcelo,
Rehman Jalees,
Austin Eric,
Malik Asrar
Publication year - 2014
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.28.1_supplement.1089.10
Subject(s) - calcium , mutation , oxidative stress , thapsigargin , chemistry , serca , calcium signaling , fibroblast , endocrinology , medicine , microbiology and biotechnology , cancer research , biology , biochemistry , enzyme , gene , atpase , in vitro
Objective: Recently, a new mutation in Caveolin‐1 (Cav‐1) was identified in a family with heritable pulmonary arterial hypertension (hPAH), but the underlying molecular mechanisms by which the Cav‐1 mutation leads to hPAH are poorly understood. Methods: Human dermal fibroblasts were obtained from 3 healthy control subjects and 3 hPAH patients with the Caveolin‐1 mutation. Results: Patient fibroblasts had a markedly higher proliferative rate than those of control subjects (34±5 vs. 19±4%, P<0.05). Since calcium is an important regulator of cell proliferation, we compared maximal cytoplasmic calcium influx in response to the SERCA inhibitor thapsigargin. We found that calcium influx was higher in fibroblasts with a Cav‐1 mutation (2.38‐fold increase, P<0.005). Also, fibroblasts with a Cav‐1 mutation exhibited higher oxidative stress (2.5‐fold increase in H2O2 P<0.01, 4‐fold increase in peroxynitrite P<0.001). Conclusions: The newly identified Caveolin‐1 in hPAH patients as associated higher fibroblast proliferation, aberrant calcium signaling, and high levels of oxidative stress. These signaling pathways may be promising targets for novel therapies in hPAH and validate the role of Cav‐1 in clinical PAH. Since Cav‐1 is a disease modifier in experimental PAH, our findings may also prove valuable for understanding the pathophysiology of non‐heritable PAH.