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Preventing the Increase in Lysophosphatidic Acids: A New Therapeutic Target in Pulmonary Hypertension?
Thomas Duflot1, Ly Tu2,3, Matthieu Leuillier4
1UNIROUEN, INSERM U1096, CHU Rouen, Department of Pharmacology, Normandie University, F-76000 Rouen, France.
Insights
Circulating lysophosphatidic acids (LPA) show significant changes in pulmonary hypertension (PH), a cardiovascular disease. LPA may be a therapeutic target for PH, impacting pulmonary artery pressure and smooth muscle cell proliferation.
Area of Science:
- Biochemistry
- Cardiovascular Research
- Lipid Metabolism
Background:
- Cardiovascular diseases (CVD) are a major cause of mortality linked to lipid metabolism.
- Lysophospholipids (LPL), lysophosphatidic acids (LPA), and monoacylglycerols (MAG) are key lipid mediators.
- Therapeutic targets for CVD related to lipid signaling require further investigation.
Purpose of the Study:
- To evaluate circulating LPL, LPA, and MAG as potential therapeutic targets in CVD.
- To analyze plasma levels of these lipids in rat models of hypertension, heart failure, and pulmonary hypertension.
- To investigate the role of LPA in the pathophysiology of pulmonary hypertension.
Main Methods:
- Plasma levels of 22 lipid compounds (13 LPL, 6 LPA, 3 MAG) were measured using HPLC/MS².
- Studies were conducted in rat models of angiotensin-II-induced hypertension (HTN), ischemic chronic heart failure (CHF), and sugen/hypoxia (SuHx)-induced pulmonary hypertension (PH).
- In vitro experiments assessed the impact of LPA on human pulmonary artery smooth muscle cells (PA-SMCs).
Main Results:
- Modest, non-significant changes in monitored lipids were observed in HTN and CHF models.
- Significant increases in plasma LPA species (LPA 16:0, 18:1, 18:2, 20:4, 22:6) were found in the PH model.
- LPA increased PA-SMC proliferation, and plasma LPA(16:0) correlated with pulmonary artery systolic pressure in patients.
Conclusions:
- Circulating LPA levels are significantly altered in pulmonary hypertension.
- LPA contributes to the pathophysiology of PH by promoting PA-SMC proliferation.
- LPA signaling represents a potential therapeutic target for 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.
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