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DUSP5 Functions in a Feedback Loop to Suppress Angiotensin‐Dependent Smooth Muscle Cell Proliferation and Pulmonary Arterial Hypertension
Author(s) -
Ferguson Bradley,
DemosDavies Kim,
Cavasin Maria,
Horita Henrick,
WeiserEvans Mary,
McKnight Robert,
Lane Robert,
McKinsey Timothy
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.724.11
Subject(s) - angiotensin ii , vascular smooth muscle , right ventricular hypertrophy , medicine , endocrinology , chemistry , renin–angiotensin system , kinase , cell growth , microbiology and biotechnology , pulmonary hypertension , biology , receptor , smooth muscle , blood pressure , biochemistry
Pulmonary arterial hypertension (PAH) is associated with marked remodeling of small pulmonary arteries (PAs) due to excess proliferation of fibroblasts, endothelial and smooth muscle cells (SMCs). Clinical and pre‐clinical studies have highlighted the renin‐angiotensin‐aldosterone system as a major contributor to pulmonary vascular remodeling in PAH. Indeed, angiotensin II (Ang II) is a potent stimulus for PASMC proliferation, in part through its ability to activate extracellular signal‐regulated kinase (ERK1/2). Here, we show that the ERK1/2 phosphatase, dual‐specificity phosphatase 5 (DUSP5), functions as a negative regulator of Ang II‐mediated SMC proliferation and PAH. DUSP5 is markedly upregulated in cultured SMCs in response to Ang II. Knockdown of DUSP5 leads to sustained ERK1/2 activation and enhanced cell proliferation in response to Ang II, and DUSP5 overexpression completely blocks Ang II‐mediated SMC proliferation. Remarkably, dusp5 null mice infused with Ang II develop profound PAH and right ventricular (RV) hypertrophy, in complete contrast to wild‐type mice exposed to Ang II. PAH in dusp5 null mice is associated with medial thickening of small PAs, stressing an in vivo role of DUSP5 as a negative regulator of Ang II‐dependent SMC proliferation. These data reveal a novel role for DUSP5 as an endogenous inhibitor of Ang II‐mediated ERK1/2 activation in SMCs, and demonstrate that disruption of this feedback loop leads to uncontrolled SMC proliferation and PAH.