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Preventing the Increase in Lysophosphatidic Acids: A New Therapeutic Target in Pulmonary Hypertension?

ABSTRACT: Cardiovascular diseases (CVD) are the leading cause of premature death and disability in humans that are closely related to lipid metabolism and signaling. This study aimed to assess whether circulating lysophospholipids (LPL), lysophosphatidic acids (LPA) and monoacylglycerols (MAG) may be considered as potential therapeutic targets in CVD. For this objective, plasma levels of 22 compounds (13 LPL, 6 LPA and 3 MAG) were monitored by liquid chromatography coupled with tandem mass spectrometry (HPLC/MS²) in different rat models of CVD, i.e., angiotensin-II-induced hypertension (HTN), ischemic chronic heart failure (CHF) and sugen/hypoxia(SuHx)-induced pulmonary hypertension (PH). On one hand, there were modest changes on the monitored compounds in HTN (LPA 16:0, 18:1 and 20:4, LPC 16:1) and CHF (LPA 16:0, LPC 18:1 and LPE 16:0 and 18:0) models compared to control rats but these changes were no longer significant after multiple testing corrections. On the other hand, PH was associated with important changes in plasma LPA with a significant increase in LPA 16:0, 18:1, 18:2, 20:4 and 22:6 species. A deleterious impact of LPA was confirmed on cultured human pulmonary smooth muscle cells (PA-SMCs) with an increase in their proliferation. Finally, plasma level of LPA(16:0) was positively associated with the increase in pulmonary artery systolic pressure in patients with cardiac dysfunction. This study demonstrates that circulating LPA may contribute to the pathophysiology of PH. Additional experiments are needed to assess whether the modulation of LPA signaling in PH may be of interest.

SUBMITTER: Duflot T

PROVIDER: S-EPMC8621392 | biostudies-literature |

REPOSITORIES: biostudies-literature

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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.

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Preventing the Increase in Lysophosphatidic Acids: A New Therapeutic Target in Pulmonary Hypertension?

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