- 作者: Ye-Ming Lee; Wei-Fan F Chen; Duen-Suey Chou; Thanasekaran Jayakumar; Suu-Yu Ho; Jie-Jen Lee; George Hsiao; Joen-Rong Sheu
- 作者服務機構: Department of Surgery, Hsinchu Mackay Memorial Hospital, Hsinchu; Mackay Medicine, Nursing and Management College, Taipei, Taiwan, R.O.C.
- 中文摘要: --
- 英文摘要:
Background: 3-Hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase
inhibitors (statins) have been widely used to reduce cardiovascular risk. These
statins (i.e., simvastatin) may exert other effects besides from their
cholesterol-lowering actions, including inhibition of platelet activation. Platelet
activation is relevant to a variety of coronary heart diseases. Although the
inhibitory effect of simvastatin in platelet activation has been studied; the
detailed signal transductions by which simvastatin inhibit platelet activation has
not yet been completely resolved.
Methods: The aim of this study was to systematically examine the detailed
mechanisms of simvastatin in preventing platelet activation. Platelet aggregation,
flow cytometric analysis, immunoblotting, and electron spin resonance studies
were used to assess the antiplatelet activity of simvastatin.
Results: Simvastatin (20-50 μM) exhibited more-potent activity of inhibiting
platelet aggregation stimulated by collagen than other agonists (i.e., thrombin).
Simvastatin inhibited collagen-stimulated platelet activation accompanied by
[Ca2+]i mobilization, thromboxane A2 (TxA2) formation, and phospholipase C
(PLC)γ2, protein kinase C (PKC), and mitogen-activated protein kinases (i.e.,
p38 MAPK, JNKs) phosphorylation in washed platelets. Simvastatin obviously
increased both cyclic AMP and cyclic GMP levels. Simvastatin markedly
increased NO release, vasodilator-stimulated phosphoprotein (VASP)
phosphorylation, and endothelial nitric oxide synthase (eNOS) expression.SQ22536, an inhibitor of adenylate cyclase, markedly reversed the
simvastatin-mediated inhibitory effects on platelet aggregation, PLCγ2 and p38
MAPK phosphorylation, and simvastatin-mediated stimulatory effects on VASP
and eNOS phosphorylation.
Conclusion: The most important findings of this study demonstrate for the first
time that inhibitory effect of simvastatin in platelet activation may involve
activation of the cyclic AMP-eNOS/NO-cyclic GMP pathway, resulting in
inhibition of the PLCγ2-PKC-p38 MAPK-TxA2 cascade, and finally inhibition
of platelet aggregation. - 中文關鍵字: --
- 英文關鍵字: --