Dyslipidemia regulates thrombospondin-1-induced vascular smooth muscle cell chemotaxis.
Dyslipidemia is a risk factor for intimal hyperplasia (IH). Key to IH is vascular smooth muscle cell (VSMC) migration. Thrombospondin-1 (TSP-1) is a matricellular protein that stimulates VSMC migration.


OBJECTIVE
HDL will inhibit and LDL will augment TSP-1-induced VSMC chemotaxis. VSMC chemotaxis will be inhibited by the HDL moiety, S1P, through the S1PR1 receptor, and augmented by the LDL component, LPA, through the LPAR1 receptor. The goal of this study was to determine the effect of HDL and LDL and their receptors on TSP-1-induced VSMC chemotaxis. For VSMC chemotaxis to TSP-1 cells received the following pretreatments: low (25 µg/ml) or optimal (75 µg/ml) concentration of HDL, S1P, optimal (75 µg/ml) or high (175 µg/ml) concentration of LDL, or LPA. For the receptor studies, VSMCs were transfected with siRNA to S1PR1, S1PR3, LPAR1, LPAR2, LPAR3, or a S1PR2 receptor antagonist. The TSP-1-induced chemotaxis results were (1) HDL (25 µg/ml) or LDL (75 µg/ml) exhibited no effect on chemotaxis; (2) HDL (75 µg/ml) inhibited chemotaxis by 50.9 ± 8 % and S1P by 43.4 ± 11.6 %; (3) LDL (175 µg/ml) augmented chemotaxis by 30 ± 10.4 % and LPA by 25.6 ± 12.3 %; (4) S1PR1 and S1PR3 knockdown and S1PR2 antagonist-treated cells augmented chemotaxis; and (5) LPAR1 and LPAR2 knockdown inhibited and LPAR3 knockdown had no effect on chemotaxis. In conclusion, HDL/S1P inhibits, while LDL/LPA stimulates TSP-1-induced VSMC chemotaxis. The HDL/S1P effect is mediated by the S1PR1-3 receptors. The LDL/LPA effects are mediated by the LPAR1 and LPAR2 receptors, but not LPAR3. Therefore, lipids have significant effects on TSP-1-induced VSMC chemotaxis.
Department of Veterans Affairs Healthcare Network Upstate New York at Syracuse, Syracuse, NY, USA.
Pratik
P
Desai
Department of Surgery, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY, 13206, USA.|Department of Veterans Affairs Healthcare Network Upstate New York at Syracuse, Syracuse, NY, USA.
Jeffrey J
JJ
Stein
Department of Surgery, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY, 13206, USA.
Sufyan A
SA
Siddiqui
Department of Surgery, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY, 13206, USA.|Department of Veterans Affairs Healthcare Network Upstate New York at Syracuse, Syracuse, NY, USA.
Kristopher G
KG
Maier
Department of Surgery, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY, 13206, USA. gahtanv@upstate.edu.|Department of Veterans Affairs Healthcare Network Upstate New York at Syracuse, Syracuse, NY, USA. gahtanv@upstate.edu.
Vivian
V
Gahtan
D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects*; D050171:Dyslipidemias / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008075:Lipoproteins, HDL / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000494:pharmacology; D008246:Lysophospholipids / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D049368:Receptors, Lysophosphatidic Acid / Q000235:genetics / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000081025:Sphingosine-1-Phosphate Receptors; D019700:Thrombospondin 1 / Q000494:pharmacology*; D013997:Time Factors; D014162:Transfection
C000609549:LPAR1 protein, human; C000609550:LPAR2 protein, human; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D008246:Lysophospholipids; D049368:Receptors, Lysophosphatidic Acid; D049349:Receptors, Lysosphingolipid; C477362:S1PR1 protein, human; D000081025:Sphingosine-1-Phosphate Receptors; D019700:Thrombospondin 1; C577483:sphingosine-1-phosphate receptor-3, human; C060506:sphingosine 1-phosphate; D013110:Sphingosine; C032881:lysophosphatidic acid
Chemotaxis; Dyslipidemia; Lipoproteins; Muscle; Smooth; Thrombospondin-1