Open AccessRole of Asymmetric Methylarginine and Connexin 43 in the Regulation of Pulmonary Endothelial Function
Author(s) -
Tsang Hilda,
Leiper James,
Lao Ka Hou,
Dowsett Laura,
Delahaye Matthew W.,
Barnes Gareth,
Wharton John,
Howard Luke,
Ian Lucio,
Lang Ninian N.,
Wilkins Martin R.,
WojciakStothard Beata
Publication year - 2013
Publication title -
pulmonary circulation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.791
H-Index - 40
ISSN - 2045-8940
DOI - 10.1086/674440
Subject(s) - angiogenesis , connexin , medicine , asymmetric dimethylarginine , endothelial dysfunction , endothelium , nitric oxide synthase type iii , gap junction , endothelial stem cell , nitric oxide , endocrinology , nitric oxide synthase , microbiology and biotechnology , enos , biology , biochemistry , arginine , in vitro , intracellular , amino acid
Circulating levels of asymmetric dimethylarginine (ADMA), a nitric oxide synthase inhibitor, are increased in patients with idiopathic pulmonary hypertension (IPAH). We hypothesized that ADMA abrogates gap junctional communication, required for the coordinated regulation of endothelial barrier function and angiogenesis, and so contributes to pulmonary endothelial dysfunction. The effects of ADMA on expression and function of gap junctional proteins were studied in human pulmonary artery endothelial cells; pulmonary endothelial microvascular cells from mice deficient in an enzyme metabolizing ADMA, dimethylarginine dimethylaminohydrolase I (DDAHI); and blood‐derived endothelial‐like cells from patients with IPAH. Exogenous and endogenous ADMA inhibited protein expression and membrane localization of connexin 43 (Cx43) in a nitric oxide/soluble guanosine monophosphate/c‐jun‐dependent manner in pulmonary endothelial cells, resulting in the inhibition of gap junctional communication, increased permeability, and decreased angiogenesis. The effects of ADMA were prevented by overexpression of DDAHI or Cx43 and by treatment with rotigaptide. Blood‐derived endothelial‐like cells from IPAH patients displayed a distinct disease‐related phenotype compared to cells from healthy controls, characterized by reduced DDAHI expression, increased ADMA production, and abnormal angiogenesis. In summary, we show that ADMA induces pulmonary endothelial dysfunction via changes in expression and activity of Cx43. Cells from IPAH patients exhibit abnormal DDAHI/Cx43 signaling as well as differences in gap junctional communication, barrier function, and angiogenesis. Strategies that promote DDAHI/Cx43 signaling may have an endothelium‐protective effect and be beneficial in pulmonary vascular disease.