Role of asymmetric methylarginine and connexin 43 in the regulation of pulmonary endothelial function

Tsang, H. et al. (2013) Role of asymmetric methylarginine and connexin 43 in the regulation of pulmonary endothelial function. Pulmonary Circulation, 3(3), pp. 675-691. (doi: 10.1086/674440) (PMID:24618552) (PMCID:PMC4070793)

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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.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Lang, Professor Ninian and Dowsett, Dr Laura and Leiper, Professor James
Authors: Tsang, H., Leiper, J., Lao, K. H., Dowsett, L., Delahaye, M. W., Barnes, G., Wharton, J., Howard, L., Iannone, L., Lang, N. N., Wilkins, M. R., and Wojciak-Stothard, B.
College/School:College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
Journal Name:Pulmonary Circulation
Publisher:Medknow Publications
ISSN (Online):2045-8940
Published Online:08 December 2016

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