Lipid Phosphate Phosphatase 3 regulates Lysophosphatidic Acid mediated vascular response in diabetic vascular injury

Abstract

Introduction Single nucleotide polymorphism in the PLPP3 gene is associated with the risk of coronary artery disease (CAD). PLPP3 encodes the lipid phosphate phosphatases (LPP) 3 that degrades and thereby attenuates lysophosphatidic acid (LPA) responsiveness of cells. Recently, LPA has been purposed to serve as a ligand for RAGE (Receptor for Advanced Glycation End Products), leading to diabetes associated with vascular dysfunction. However, a pathophysiologic role of LPP3 in diabetic vascular smooth muscle cells (VSMC) remains to be established. Objective To elucidate the role and mechanism of LPP3 in the regulation of diabetic VSMC. Methods and results Robust expression of LPP3 occurs following vascular injury, where SMC serves as the predominant source. The selective inactivation of LPP3 in SMC displays exaggerated neointimal formation in our diabetic mice model in response to carotid artery ligation injury. The primary function of LPP3 in SMC is to attenuate proliferation, ERK activity, and migration in response to LPA. These effects are, at least partially, a consequence of LPP3-catalysed LPA hydrolysis. We did not observe the systemic impact of SMC-deletion of LPP3 on either circulating LPA levels or hemodynamic parameters. This suggests the predominant effects of LPP3 on SMC are exerted in the local environment by regulating SMC response. Conclusion These findings implicate LPP3 as an important negative regulator of SMC phenotypic modulation and indicated that changes in LPP3 expression control the development of neointima by limiting SMC proliferation, migration and vascular inflammation diabetic restenosis.