(883.3) Lipid phosphate phosphatase-3 dysfunction exaggerates neointimal hyperplasia following diabetic vascular injury

Poster Board Number: E294

Utsab Subedi (LSU Health Sciences Center Shreveport), Susmita Bhattarai (LSU Health Sciences Center Shreveport), Sudha Sharma (LSU Health Sciences Center Shreveport), Hosne Ara (LSU Health Sciences Center Shreveport), Milena murov (LSU Health Sciences Center Shreveport), Md Shenuarin Bhuiyan (LSU Health Sciences Center Shreveport), Sumitra Miriyala (LSU Health Sciences Center Shreveport), Manikandan Panchatcharam (LSU Health Sciences Center Shreveport)

Introduction: Diabetes mellitus is a major risk factor for cardiovascular diseases and promotes neointimal hyperplasia characterized by occlusive disorders such as atherosclerosis and stenosis, caused by excessive proliferation and migration of vascular smooth muscle cells (VSMCs) following endovascular interventions such as balloon angioplasty and stent placement. Lipid phosphate phosphatase-3 (LPP3) is an enzyme that regulates the availability of lysophosphatidic acid (LPA) and has been reported to play a significant role in vascular genesis, cellular permeability, tumor progression, vascular remodeling, and myocardial infarction. However, the functional role and mechanism of LPP3 in diabetic neointimal hyperplasia is unclear. LPP3 dysfunction may lead to LPA accumulation at the vascular injury site, leading to vascular inflammation, proliferation, and migration, causing restenosis. Recently, the Receptor for Advanced Glycation End product (RAGE) has been presented as a potential receptor for LPA leading to downstream signaling in vascular smooth muscle cells (VSMCs).

Methods: In this study, we used a streptozocin-induced diabetes mice model. We made SM-22 specific LPP3 knock-out mice and performed endothelial denudation surgery in the carotid artery to induce neointima hyperplasia to tease out the role of LPP3 in restenosis. We isolated aortic VSMCs from LPP3 floxed and LPP3 knock-out mice and cultured them under normal or high glucose media. The immunoblotting was performed and probed with antibodies for total extracellular signal-regulated kinase (ERK) and phosphorylated-ERK. The cell proliferation and migration assay was performed using the Electric Cell substrate Impedance Sensing (ECIS) with or without LPP3 in VSMC under normal or high glucose conditions. Data are mean ± SEM; P-values were determined by Student t-test or one-way ANOVA with Tukeys post-hoc tests.

Result: We observed a significant increase in proliferation (Plt;0.01) and exaggerated migration (plt;0.01) of VSMC that lack LPP3 under the hyperglycemic condition in real-time using ECIS. These effects are at least partially a consequence of decreased lysophosphatidic acid hydrolysis due to lack of LPP3 activity. Furthermore, VSMC that lack LPP3 showed increased phospho-ERK expression (Plt;0.01) under hyperglycemic conditions.  The diabetic LPP3 knock-out mice exhibited exaggerated neo-intimal areas after the carotid injury compared to LPP3 floxed mice.

Conclusion: These findings implicate that LPP3 plays a vital role as a negative regulator of smooth muscle phenotypic modulation. We speculate that changes in LPP3 expression control the development of neo-intima by limiting smooth muscle cell proliferation, migration, and vascular inflammation in diabetic restenosis.

NIH-COBRE 1P20GM121307; HL141998; AA023610; AA025744; AA02574402S1; AA026708; HL141998S1