Reduced platelet aggregation after fluvastatin therapy is associated with altered platelet lipid composition and drug binding to the platelets

Hussein, Osamah; Rosenblat, Mira; Schlezinger, Sorina; Keidar, Shlomo; Aviram, Michael

doi:10.1046/j.1365-2125.1997.00625.x

Cited by 94 publications

(47 citation statements)

References 12 publications

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Section: See Accompanying Article On Page 620mentioning

confidence: 99%

“…It is not known whether they are a consequence of lowering cholesterol or mediated via some other mechanism. 1,3,9 Here we show that statins and fibrates have rapid and direct inhibitory effects on platelet function in vitro and in vivo that cannot be attributed to effects on cholesterol levels.Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that are involved in many biological processes, including lipid and energy metabolism, 10,11 inflammation responses, and atherosclerotic plaque formation. 12,13 Three PPARs are known: ␣, ␤ (sometimes called ␦), and ␥.…”

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confidence: 99%

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Antiplatelet Actions of Statins and Fibrates Are Mediated by PPARs

Ali

Armstrong

Dhanji

et al. 2009

ATVB

116

109

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Objectives-Statins and fibrates are hypolipidemic drugs which decrease cardiac events in individuals without raised levels of cholesterol. These drugs inhibit platelet function, but the mechanisms by which this pleiotropic effect is exerted are not known. Methods and Results-We used a range of approaches to show statins inhibit human platelet activation in vitro while engaging PPAR␣ and PPAR␥. The effects of simvastatin were prevented by the PPAR␥ antagonist GW9662 or the PPAR␣ antagonist GW6471. In a small-scale human study fluvastatin activated PPAR␣ and PPAR␥ in platelets and reduced aggregation in response to arachidonic acid ex vivo. The effects of fenofibrate were prevented by PPAR␣ antagonism with GW6471. Fenofibrate increased bleeding time in wild-type, but not in PPAR␣ Ϫ/Ϫ mice. The inhibitory effect of fenofibrate, but not simvastatin, on aggregation was prevented by deletion of PPAR␣ in murine platelets. PKC␣, which influences platelet activation, associated and immune-precipitated with PPAR␥ in platelets stimulated with statins and with PPAR␣ in platelets stimulated with fenofibrate. Conclusions-This study is the first to provide a unifying explanation of how fibrates and statins reduce thrombotic and cardiovascular risk. Our findings that PPARs associate with PKC␣ in platelets also provide a mechanism by which these effects are mediated. Key Words: platelets Ⅲ statin Ⅲ fibrate Ⅲ PPAR␣, PPAR␥ S tatins are widely prescribed cholesterol-lowering drugs that are first-line treatments for the prevention of coronary artery disease and atherosclerosis, reducing the incidence of thrombotic events such as heart attack and stroke. 1 Statins inhibit the activity of a key enzyme in cholesterol synthesis within the body, 3-hydroxymethyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase, and so reduce cholesterol formation. 2 Statins are classified as natural (eg, pravastatin), synthetic (eg, fluvastatin), or semisynthetic (eg, simvastatin). Like the statins, the fibrates are widely used See accompanying article on page 620lipid-lowering drugs that reduce the incidence of heart attack and stroke. [3][4][5] Fibrates reduce triglycerides and increase high-density lipoprotein cholesterol. Importantly, statins and fibrates are preventative against heart attack and stroke, even in individuals with normal levels of circulating cholesterol. 1,2,6 However, the mechanisms by which statins or fibrates cause these noncholesterol related, or pleiotropic, protective effects are not completely understood.Interestingly both statins and fibrates inhibit platelet function, 3,7 which is, of course, a widely recognized property of drugs such as aspirin and clopidogrel that are used to reduce the incidence of heart attacks and strokes. 6,8 However, the mechanisms by which statins and fibrates inhibit platelets are unclear. It is not known whether they are a consequence of lowering cholesterol or mediated via some other mechanism. 1,3,9 Here we show that statins and fibrates have rapid and direct inhibitory effects on platelet function ...

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Section: See Accompanying Article On Page 620mentioning

confidence: 99%

mentioning

confidence: 99%

Antiplatelet Actions of Statins and Fibrates Are Mediated by PPARs

Ali

Armstrong

Dhanji

et al. 2009

ATVB

116

109

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“…[11][12][13][14] Studies to explore the molecular basis of the pleiotropic actions of statins on platelets have been limited to exploring the cholesterol content of platelet membranes, inhibition of thromboxane A 2 formation, and increase of nitric oxide (NO) bioavailability by upregulation of endothelial NO synthase with downregulation of markers of platelet reactivity. [15][16][17][18][19][20][21] The precise mechanisms of drug action, however, are not fully understood.…”

Section: Introductionmentioning

confidence: 99%

Antithrombotic actions of statins involve PECAM-1 signaling

Moraes

Vaiyapuri

Sasikumar

et al. 2013

Blood

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Key Points• The inhibitory effect of platelet function by statins results, at least in part, in action on PECAM-1.• Statins modulate Lyn activation and PECAM-1 tyrosine phosphorylation, resulting in the inhibition of downstream PI3K-dependent signaling.Statins are widely prescribed cholesterol-lowering drugs that are a first-line treatment of coronary artery disease and atherosclerosis, reducing the incidence of thrombotic events such as myocardial infarction and stroke. Statins have been shown to reduce platelet activation, although the mechanism(s) through which this occurs is unclear. Because several of the characteristic effects of statins on platelets are shared with those elicited by the inhibitory platelet adhesion receptor PECAM-1 (platelet endothelial cell adhesion molecule-1), we investigated a potential connection between the influence of statins on platelet function and PECAM-1 signaling. Statins were found to inhibit a range of platelet functional responses and thrombus formation in vitro and in vivo. Notably, these effects of statins on platelet function in vitro and in vivo were diminished in PECAM-1 2/2 platelets. Activation of PECAM-1 signaling results in its tyrosine phosphorylation, the recruitment and activation of tyrosine phosphatase SHP-2, the subsequent binding of phosphoinositol 3-kinase (PI3K), and diminished PI3K signaling. Statins resulted in the stimulation of these events, leading to the inhibition of Akt activation. Together, these data provide evidence for a fundamental role of PECAM-1 in the inhibitory effects of statins on platelet activation, which may explain some of the pleiotropic actions of these drugs. (Blood. 2013;122(18):3188-3196)

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“…Platelets from hypercholesterolemic humans have increased cholesterol content and hypersensitivity to endogenous aggregating agonists [9,21,25]. In familial hypercholesterolemic patients, cholesterol-lowering treatment with statin, an HMG-CoA reductase inhibitor, decreases the platelet cholesterol content and platelet sensitivity to the aggregating agonists such as ADP and collagen [9,17,18]. On the other hand, in vitro cholesterol depletion from the human platelet membrane decreases platelet sensitivity to the agonists such as ADP, collagen, and thrombin, and reduces the release of TXA 2 and ADP [1,7,20,30].…”

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confidence: 99%

Modulation of Rabbit Platelet Aggregation and Calcium Mobilization by Platelet Cholesterol Content

Shiraishi

Tani

Miyamoto

2010

The Journal of Veterinary Medical Science

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ABSTRACT. Hypercholesterolemia is one of the major contributing factors in atherosclerosis and the development of cardiovascular disease. Platelets from hypercholesterolemic rabbit have an increased cholesterol content and a hypersensitivity to endogenous aggregating agonists. Although rabbit has been widely used in studies of hypercholesterolemia, the precise role of platelet cholesterol in rabbit platelet activation has not been studied. In the present study, to determine the direct role of cholesterol on rabbit platelet activation, we examined the effect of in vitro modulation of cholesterol content on platelet activation. Cholesterol-depleted rabbit platelets by the treatment with methyl--cyclodextrin showed decreased platelet aggregation by physiological agonists such as thrombin, adenosine diphosphate, and collagen. The inhibition of thrombin-induced aggregation in cholesterol-depleted platelets was restored by cholesterol repletion in platelets. The cholesterol depletion also inhibited Ca 2+ mobilization, which plays a pivotal role in the platelet activation induced by physiological agonists. We showed that the Ca 2+ influx pathway is strongly suppressed by cholesterol depletion more than Ca 2+ release from intracellular Ca 2+ stores in platelets stimulated with thrombin. Furthermore, platelet aggregation induced by PMA, a potent protein kinase C activator, was also depressed by cholesterol depletion. On the other hand, cholesterol enrichment in platelets augmented thrombininduced aggregation and Ca 2+ mobilization. These findings suggest that cholesterol plays a critical role in regulating rabbit platelet activation, and provides fundamental information regarding hypercholesterolemia-mediated effects on cells in the rabbit model.

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Reduced platelet aggregation after fluvastatin therapy is associated with altered platelet lipid composition and drug binding to the platelets

Cited by 94 publications

References 12 publications

Antiplatelet Actions of Statins and Fibrates Are Mediated by PPARs

Antiplatelet Actions of Statins and Fibrates Are Mediated by PPARs

Antithrombotic actions of statins involve PECAM-1 signaling

Modulation of Rabbit Platelet Aggregation and Calcium Mobilization by Platelet Cholesterol Content

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