SISANews

Le HDL3 riducono la fibrinolisi

Le HDL sono considerate ateroprotettive principalmente a causa del loro ruolo nel trasporto inverso del colesterolo dai tessuti periferici al fegato. Sono implicate però anche in altre funzioni importanti come il rilasciamento vascolare, la sopravvivenza cellulare, l'adesività cellulare, l'angiogenesi e la produzione di ossido nitrico e prostaciclina. Queste funzioni sarebbero da attribuire alla sfingosina-1-fosfato, un liso-fosfolipide associato alle HDL, in particolare alle HDL3. Accanto a queste funzioni antiaterogene, la sfingosina-1-fosfato ne possederebbe anche di proaterogene, in parte legate al coinvolgimento nel processo infiammatorio ed in parte per un azione di stimolo alla produzione dell'inibitore dell'attivatore del plasminogeno da parte degli adipociti. Ne deriva una riduzione della fibrinolisi con le ovvie conseguenze sugli eventi ischemici cardiovascolari.

HDL3, but not HDL2, stimulates plasminogen activator inhibitor-1 release from adipocytes: the role of sphingosine-1-phosphate

Lee MH, Hammad SM, Semler AJ, Luttrell LM, Lopes-Virella MF, Klein RL.

J Lipid Res 2010;51:2619-28

Sphingosine-1-phosphate (S1P) is a bioactive lysophospholipid that regulates numerous key cardiovascular functions. High-density lipoproteins (HDLs) are the major plasma lipoprotein carriers of S1P. Fibrinolysis is a physiological process that allows fibrin clot dissolution, and decreased fibrinolytic capacity may result from increased circulating levels of plasminogen activator inhibitor-1 (PAI-1). We examined the effect of S1P associated with HDL subfractions on PAI-1 secretion from 3T3 adipocytes. S1P concentration in HDL3 averaged twice that in HDL2. Incubation of adipocytes with increasing concentrations of S1P in HDL3, but not HDL2, or with S1P complexed to albumin stimulated PAI-I secretion in a concentration-dependent manner. Quantitative RT-PCR revealed that S1P(1-3) are expressed in 3T3 adipocytes, with S1P(2) expressed in the greatest amount. Treatment of adipocytes with the S1P(1) and S1P(3) antagonist VPC23019 did not block PAI-1 secretion. Inhibiting S1P(2) with JTE-013 or reducing the expression of the gene coding for S1P(2) using silencing RNA (siRNA) technology blocked PAI-1 secretion, suggesting that the S1P(2) receptor mediates PAI-1 secretion from adipocytes exposed to HDL3 or S1P. Treatment with the phospholipase C (PLC) inhibitor U73122, the protein kinase C (PKC) inhibitor RO-318425, or the Rho-associated protein kinase (ROCK) inhibitor Y27632 all significantly inhibited HDL3- and S1P-mediated PAI-1 release, suggesting that HDL3- and/or S1P-stimulated PAI-1 secretion from 3T3 cells is mediated by activation of multiple, downstream signaling pathways of S1P(2).

J Lipid Res 2010;51:2619-28