Mildly oxidised low density lipoprotein induces platelet shape change via Rho‐kinase‐dependent phosphorylation of myosin light chain and moesin

Retzer, Michaela; Siess, Wolfgang; Essler, Markus

doi:10.1016/s0014-5793(99)01762-7

Cited by 40 publications

(45 citation statements)

References 27 publications

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“…Preliminary experiments indicated that mouse liver expresses low levels of LPA receptors, 4 which would minimize the local effects of autotaxin/lysoPLD-mediated LPA generation on liver tissue. The A1AT promoter (Ϫ1206 -ϩ44) was amplified by PCR from a Yac clone obtained from ATCC.…”

Section: Enpp2-tg and Enpp2mentioning

confidence: 99%

“…The exposure of human platelets to LPA triggers shape change (3)(4)(5), fibronectin matrix assembly (6), and platelet-leukocyte interactions (7). LPA is also a weak activator of human platelet aggregation and potentiates the effects of other agonists such as ADP and epinephrine (3,8,9); although interestingly, platelets isolated from ϳ20% of normal donors are selectively unresponsive to LPA (10,11).…”

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confidence: 99%

“…LPA is also a weak activator of human platelet aggregation and potentiates the effects of other agonists such as ADP and epinephrine (3,8,9); although interestingly, platelets isolated from ϳ20% of normal donors are selectively unresponsive to LPA (10,11). LPA triggers several signaling pathways in human platelets that could account for its stimulatory effects (4,5,8,12). The majority of the biologic effects of LPA are thought to be mediated by G-protein-coupled receptors.…”

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confidence: 99%

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Autotaxin/Lysopholipase D and Lysophosphatidic Acid Regulate Murine Hemostasis and Thrombosis

Pamuklar

Federico

Liu

et al. 2009

Journal of Biological Chemistry

132

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The lipid mediator lysophosphatidic acid (LPA) is a potent regulator of vascular cell function in vitro, but its physiologic role in the cardiovasculature is largely unexplored. To address the role of LPA in regulating platelet function and thrombosis, we investigated the effects of LPA on isolated murine platelets. Although LPA activates platelets from the majority of human donors, we found that treatment of isolated murine platelets with physiologic concentrations of LPA attenuated agonist-induced aggregation. Transgenic overexpression of autotaxin/lysophospholipase D (Enpp2), the enzyme necessary for production of the bulk of biologically active LPA in plasma, elevated circulating LPA levels and induced a bleeding diathesis and attenuation of thrombosis in mice. Intravascular administration of exogenous LPA recapitulated the prolonged bleeding time observed in Enpp2-Tg mice. Enpp2 ؉/؊ mice, which have ϳ50% normal plasma LPA levels, were more prone to thrombosis. Plasma autotaxin associated with platelets during aggregation and concentrated in arterial thrombus, and activated but not resting platelets bound recombinant autotaxin/ lysoPLD in an integrin-dependent manner. These results identify a novel pathway in which LPA production by autotaxin/lysoPLD regulates murine hemostasis and thrombosis and suggest that binding of autotaxin/lysoPLD to activated platelets may provide a mechanism to localize LPA production.

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Section: Enpp2-tg and Enpp2mentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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Autotaxin/Lysopholipase D and Lysophosphatidic Acid Regulate Murine Hemostasis and Thrombosis

Pamuklar

Federico

Liu

et al. 2009

Journal of Biological Chemistry

132

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“…[4][5][6] Low nanomolar concentrations of LPA induce shape change of washed platelets through LPA receptor-linked signal transduction pathways that involve the small guanosine triphosphatase (GTPase) Rho and the Rho-kinase-mediated stimulation of myosin light-chain phosphorylation. [7][8][9] In contrast, high micromolar concentrations of LPA are required to induce aggregation of platelet-rich plasma. [10][11][12] In the present study we investigated whether and through which mechanism LPA could induce platelet shape change and aggregation in whole blood.…”

Section: Introductionmentioning

confidence: 99%

The plaque lipid lysophosphatidic acid stimulates platelet activation and platelet-monocyte aggregate formation in whole blood: involvement of P2Y1 and P2Y12 receptors

Haserück

Erl

Pandey

et al. 2004

Blood

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112

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Despite the fact that lysophosphatidic acid (LPA) has been identified as a main platelet-activating lipid of mildly oxidized low-density lipoprotein (LDL) and human atherosclerotic lesions, it remains unknown whether it is capable of activating platelets in blood. We found that LPA at concentrations slightly above plasma levels induces platelet shape change, aggregation, and platelet-monocyte aggregate formation in blood. 1-alkyl-LPA (16:0 fatty acid) was almost 20-fold more potent than 1-acyl-LPA (16:0). LPA directly induced platelet shape change in blood and platelet-rich plasma obtained from all blood donors. However, LPA-stimulated platelet aggregation in blood was donor dependent. It could be completely blocked by apyrase and antagonists of the platelet adenosine diphosphate (ADP) receptors P2Y 1 and P2Y 12 . These substances also inhibited LPA-induced aggregation of platelet-rich plasma and aggregation and serotonin secretion of washed platelets. These results indicate a central role for ADP-mediated P2Y 1 and P2Y 12 receptor activation in supporting LPA-induced platelet aggregation. Platelet aggregation and platelet-monocyte aggregate formation stimulated by LPA was insensitive to inhibition by aspirin. We conclude that LPA at concentrations approaching those found in vivo can induce platelet shape change, aggregation, and platelet-monocyte aggregate formation in whole blood and suggest that antagonists of platelet P2Y 1 and P2Y 12 receptors might be useful preventing LPA-elicited thrombus formation in patients with cardiovascular

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“…The precise composition of the solutions has been described elsewhere. 15,19 Ca 2ϩ was buffered using 10 mmol/L EGTA. Normal relaxing solution for the experiment with membrane-permeabilized strips was of the following composition (mmol/L): potassium methanesulphonate, 74.1; magnesium methanesulphonate, 2; MgATP, 4.5; EGTA, 1; creatine phosphate, 10; PIPES, 30.…”

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confidence: 99%

Cholesterol Primes Vascular Smooth Muscle to Induce Ca ² Sensitization Mediated by a Sphingosylphosphorylcholine–Rho-Kinase Pathway

Morikage

Kishi

Sato

et al. 2006

Circulation Research

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Abstract-Hypercholesterolemia is a major risk factor involved in abnormal cardiovascular events. Rho-kinase-mediated Ca 2ϩ sensitization of vascular smooth muscle (VSM) plays a critical role in vasospasm and hypertension. We recently identified sphingosylphosphorylcholine (SPC) and Src family tyrosine kinase (Src-TK) as upstream mediators for the Rho-kinase-mediated Ca 2ϩ sensitization. Here we report the strong linkage between cholesterol and the Ca 2ϩ sensitization of VSM mediated by a novel SPC/Src-TK/Rho-kinase pathway in both humans and rabbits. The extent of the sensitization correlated well with the total cholesterol or low-density lipoprotein cholesterol levels in serum.However, an inverse correlation with the serum level of high-density lipoprotein cholesterol was observed, and a correlation with other cardiovascular risk factors was nil. When cholesterol-lowering therapy was given to patients and rabbits with hypercholesterolemia, the SPC-induced contractions diminished. Depletion of VSM cholesterol by ␤-cyclodextrin resulted in a loss of membrane caveolin-1, a marker of cholesterol-enriched lipid raft, and inhibited the SPC-induced Ca 2ϩ sensitization and translocation of Rho-kinase from cytosol to the cell membrane. Vasocontractions induced by membrane depolarization and by an adrenergic agonist were cholesterol-independent. Our data support the previously unreported concept that cholesterol potentiates the Ca 2ϩ sensitization of VSM mediated by a SPC/Src-TK/ Rho-kinase pathway, and are also compatible with a role for cholesterol-enriched membrane microdomain, a lipid raft. This process may play an important role in the development of abnormal vascular contractions in patients with hypercholesterolemia. ( Key Words: Ca 2ϩ sensitization Ⅲ contraction Ⅲ membrane lipid raft Ⅲ Rho-kinase Ⅲ sphingosylphosphorylcholine Ⅲ vascular smooth muscle A bnormal vascular contraction as a result of Ca 2ϩ sensitization of vascular smooth muscles (VSMs) has attracted attention as a cause of hypertension and vasospasm. 1 Kureishi et al showed that constitutively active Rho-kinase applied to the cytosol of permeabilized VSM induced Ca 2ϩ sensitization and increased myosin light chain phosphorylation through a mechanism that is independent of a Ca 2ϩ -dependent myosin light chain kinase pathway. 2 In addition, the Rho-kinase blocker Y27632 cures hypertension in rats without affecting normal blood pressure, 3 and it also inhibits vasospasm of coronary arteries in a porcine model. 4 However, the mechanism by which Rho-kinase-mediated Ca 2ϩ sensitization of VSM is triggered in cardiovascular diseases has not been evident.Hyperlipidemia is a major risk factor for abnormal cardiovascular events. Evidence for this is provided by the J-shaped curve showing a strong relationship between serum cholesterol levels and the relative risk for coronary disease 5-7 (see also Figure I in the online data supplement, available at http://circres.ahajournals.org). Atheromatous plaques may be involved in cardiovascular events, 8,9 but the ext...

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Mildly oxidised low density lipoprotein induces platelet shape change via Rho‐kinase‐dependent phosphorylation of myosin light chain and moesin

Cited by 40 publications

References 27 publications

Autotaxin/Lysopholipase D and Lysophosphatidic Acid Regulate Murine Hemostasis and Thrombosis

Autotaxin/Lysopholipase D and Lysophosphatidic Acid Regulate Murine Hemostasis and Thrombosis

The plaque lipid lysophosphatidic acid stimulates platelet activation and platelet-monocyte aggregate formation in whole blood: involvement of P2Y1 and P2Y12 receptors

Cholesterol Primes Vascular Smooth Muscle to Induce Ca ² Sensitization Mediated by a Sphingosylphosphorylcholine–Rho-Kinase Pathway

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Mildly oxidised low density lipoprotein induces platelet shape change via Rho‐kinase‐dependent phosphorylation of myosin light chain and moesin

Cited by 40 publications

References 27 publications

Autotaxin/Lysopholipase D and Lysophosphatidic Acid Regulate Murine Hemostasis and Thrombosis

Autotaxin/Lysopholipase D and Lysophosphatidic Acid Regulate Murine Hemostasis and Thrombosis

The plaque lipid lysophosphatidic acid stimulates platelet activation and platelet-monocyte aggregate formation in whole blood: involvement of P2Y1 and P2Y12 receptors

Cholesterol Primes Vascular Smooth Muscle to Induce Ca 2 Sensitization Mediated by a Sphingosylphosphorylcholine–Rho-Kinase Pathway

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Cholesterol Primes Vascular Smooth Muscle to Induce Ca ² Sensitization Mediated by a Sphingosylphosphorylcholine–Rho-Kinase Pathway