Atorvastatin Reduces the Proadhesive and Prothrombotic Endothelial Cell Phenotype Induced by Cocaine and Plasma From Cocaine Consumers In Vitro

Abstract

Objective-Cocaine consumption is a risk factor for vascular ischemic complications. Although endothelial dysfunction and accelerated atherosclerosis have been observed in cocaine consumers, the mechanisms underlying their pathogenesis are not fully understood. This study aimed at identifying the effects of atorvastatin in relation to a proadhesive and prothrombotic phenotype induced by cocaine and plasma from chronic cocaine users on endothelial cells. Approach and Results-Human umbilical vein endothelial cells were exposed to either cocaine or platelet-free plasma (PFP) from chronic cocaine consumers in the presence or absence of 10 μmol/L of atorvastatin. Atorvastatin significantly reduced the enhanced platelet adhesion that was induced by cocaine and PFP from chronic cocaine consumers, as well as the release of the von Willebrand factor. Atorvastatin also avoided striking alterations on cell monolayer structure triggered by both stimuli and enhanced NO reduction because of cocaine stimulation through disrupting interactions between endothelial nitric oxide synthase (eNOS) and caveolin-1, thus increasing eNOS bioavailability. Cocaineincreased tissue factor-dependent procoagulant activity and reactive oxygen species generation were not counteracted by atorvastatin. Although monocyte chemoattractant protein-1 levels were not significantly higher than controls either under cocaine or PFP stimulation, atorvastatin completely avoided monocyte chemoattractant protein-1 release in both conditions. Platelets stimulated with cocaine or PFP did not express P-selectin, glycoprotein IIb/IIIa, or CD40L and failed to adhere to resting human umbilical vein endothelial cell. Conclusions-Cocaine

Vascular disease in cocaine addiction

“…1, upper box) [10,23,24] center on the loss of the endothelium's protective functions, a common denominator in the pathogenesis of ischemic vascular disease [35,36]. Cocaine releases endothelin-1 45 , which is found to be elevated in CUD and declines with detoxification [36,46,47].…”

“…Cocaine releases endothelin-1 45 , which is found to be elevated in CUD and declines with detoxification [36,46,47]. When vessels are stressed, endothelin-1 (a vasoconstrictor protein produced by vascular endothelial cells) is elevated and nitric oxide (a blood vessel dilator) decreases, leading to vasoconstriction [35,36]. It was recently demonstrated that cocaine elicits autophagy involving nitric oxide and glyceraldehyde-3-phosphate dehydrogenase signaling cascade [48].…”

Endothelium

“…Endothelial cells exposed to cocaine or plasma from chronic cocaine consumers were more proadhesive, with increased von Willebrand deposition, enhancing platelet binding, an effect prevented by statin treatment. 50 Atherosclerotic stimuli increase Arginase-2 expression, leading to eNOS uncoupling. The specific HDAC2 is a critical regulator of endothelial Arginase2 transcription.…”

Immune-mediated and lipid-mediated platelet function in atherosclerosis

“…In addition, atorvastatin can inhibit platelet CD40-mediated and CD40L-mediated thrombin generation, independently of its cholesterol-lowering effect [112]. Notably atorvastatin reduces the proadhesive and prothrombotic endothelial cell phenotype caused by cocaine consumption [113]. Atorvastatin enhances interactions between endothelial nitric oxide synthase (eNOS) and caveolin-1, thus increasing endothelial cell nitric oxide production [113].…”

“…Notably atorvastatin reduces the proadhesive and prothrombotic endothelial cell phenotype caused by cocaine consumption [113]. Atorvastatin enhances interactions between endothelial nitric oxide synthase (eNOS) and caveolin-1, thus increasing endothelial cell nitric oxide production [113]. In addition, statins can directly increase platelet nitric oxide production by upregulating platelet eNOS in turn inhibiting platelet recruitment.…”