Abstract 17600: Lipid Phosphate Phosphatase 3 Negatively Regulates Smooth Muscle Cell Phenotypic Modulation and Limits Neotimal Hyperplasia
Rationale: A common SNP in PPAP2b associates with risk of coronary artery disease (CAD). PPAP2b encodes the lipid phosphate phosphatases (LPP) 3 that degrades and thereby may attenuate lysophosphatidic acid (LPA) responsiveness of cells. However, a pathophysiologic role for LPP3 in vascular cells remains to be established.
Objective: To determine the role and mechanisms by which LPP3 regulates vascular SMC responses.
Methods and Results: Robust expression of LPP3 occurs in experimental atherosclerosis and following arterial injury, where SMC serve as the predominant source. Mice with selective inactivation of LPP3 in SMC display an exaggerated neointimal response to carotid ligation injury. Gain- and loss-of-function approaches establish that a major function of LPP3 in isolated SMC cells is to attenuate proliferation, ERK activity, Rho activation and migration in response to serum and LPA. These effects are, at least partially, a consequence of LPP3-catalyzed LPA hydrolysis. We did not observe systemic effects of SMC-deletion of LPP3 on either circulating LPA levels or hemodynamic parameters, suggesting that the predominate effects of LPP3 on SMCs are exerted in the local environment by regulating SMC responses.
Conclusions: These findings implicate LPP3 as an important negative regulator of SMC phenotypic modulation and indicate that changes in LPP3 expression control the development of neointima by limiting SMC proliferation, migration, and vascular inflammation.
- © 2011 by American Heart Association, Inc.