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Vascular repair and regeneration as a therapeutic target for pulmonary arterial hypertension.

ABSTRACT: The last decade has seen substantial changes in our understanding of the pathobiology of pulmonary arterial hypertension (PAH), a severe and devastating disease without curative treatment. It is now accepted that injury to the endothelial cells of the pulmonary arteries is central for the subsequent development of lumen-obliterative lung vascular lesions. A variety of circulating and lung-resident progenitor and stem cells likely contribute to vascular integrity, and evidence for the presence of cells expressing stem and progenitor cell markers is found inside and in the immediate vicinity of pulmonary vascular lesions in PAH. The currently available vasodilator therapies mainly target enhanced vasoconstriction in the lung circulation and help to maintain or improve right ventricular function, but do not treat pulmonary vascular remodeling, the underlying cause of the disease. Vascular gene therapy and cell therapy with progenitor and stem cells is a progressing field in the context of the development of novel treatment options for PAH, but the majority of the studies are currently performed at the level of preclinical studies in animal models. The current review provides an overview of the current knowledge on cell- and gene therapy-based approaches for vascular repair and regeneration in PAH.

SUBMITTER: Farkas L

PROVIDER: S-EPMC3688480 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Vascular repair and regeneration as a therapeutic target for pulmonary arterial hypertension.

Farkas Laszlo L Kolb Martin M

Respiration; international review of thoracic diseases 20130322 5

The last decade has seen substantial changes in our understanding of the pathobiology of pulmonary arterial hypertension (PAH), a severe and devastating disease without curative treatment. It is now accepted that injury to the endothelial cells of the pulmonary arteries is central for the subsequent development of lumen-obliterative lung vascular lesions. A variety of circulating and lung-resident progenitor and stem cells likely contribute to vascular integrity, and evidence for the presence of ...[more]

PMID: 23594605

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Project description:BackgroundPulmonary arterial hypertension is a severe and progressive disease, a hallmark of which is pulmonary vascular remodeling. Nicotinamide phosphoribosyltransferase (NAMPT) is a cytozyme that regulates intracellular nicotinamide adenine dinucleotide levels and cellular redox state, regulates histone deacetylases, promotes cell proliferation, and inhibits apoptosis. We hypothesized that NAMPT promotes pulmonary vascular remodeling and that inhibition of NAMPT could attenuate pulmonary hypertension.MethodsPlasma, mRNA, and protein levels of NAMPT were measured in the lungs and isolated pulmonary artery endothelial cells from patients with pulmonary arterial hypertension and in the lungs of rodent models of pulmonary hypertension. Nampt+/- mice were exposed to 10% hypoxia and room air for 4 weeks, and the preventive and therapeutic effects of NAMPT inhibition were tested in the monocrotaline and Sugen hypoxia models of pulmonary hypertension. The effects of NAMPT activity on proliferation, migration, apoptosis, and calcium signaling were tested in human pulmonary artery smooth muscle cells.ResultsPlasma and mRNA and protein levels of NAMPT were increased in the lungs and isolated pulmonary artery endothelial cells from patients with pulmonary arterial hypertension, as well as in lungs of rodent models of pulmonary hypertension. Nampt+/- mice were protected from hypoxia-mediated pulmonary hypertension. NAMPT activity promoted human pulmonary artery smooth muscle cell proliferation via a paracrine effect. In addition, recombinant NAMPT stimulated human pulmonary artery smooth muscle cell proliferation via enhancement of store-operated calcium entry by enhancing expression of Orai2 and STIM2. Last, inhibition of NAMPT activity attenuated monocrotaline and Sugen hypoxia-induced pulmonary hypertension in rats.ConclusionsOur data provide evidence that NAMPT plays a role in pulmonary vascular remodeling and that its inhibition could be a potential therapeutic target for pulmonary arterial hypertension.

Dataset Information

Vascular repair and regeneration as a therapeutic target for pulmonary arterial hypertension.

Publications

Vascular repair and regeneration as a therapeutic target for pulmonary arterial hypertension.

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