Abacavir increases platelet reactivity via competitive inhibition of soluble guanylyl cyclase

被引：60

作者：

Baum, Paul D. ^{[1
]}

Sullam, Paul M. ^{[2
]}

Stoddart, Cheryl A. ^{[1
]}

McCune, Joseph M. ^{[1
]}

机构：

[1] Univ Calif San Francisco, Div Expt Med, Dept Med, San Francisco, CA 94143 USA

[2] Univ Calif San Francisco, Vet Affairs Med Ctr, San Francisco, CA 94143 USA

来源：

AIDS | 2011年 / 25卷 / 18期

关键词：

abacavir; blood platelets; guanylate cyclase; myocardial infarction; P-selectin; REVERSE-TRANSCRIPTASE INHIBITORS; MYOCARDIAL-INFARCTION; SUPPRESSED HIV; RISK; BIOMARKERS; PHARMACOKINETICS; THERAPY;

D O I：

10.1097/QAD.0b013e32834d3cc3

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Objective: To provide a molecular mechanism that explains the association of the antiretroviral guanosine analogue, abacavir, with an increased risk of myocardial infarction. Design: Drug effects were studied with biochemical and cellular assays. Methods: Human platelets were incubated with nucleoside analogue drugs ex vivo. Platelet activation stimulated by ADP was studied by measuring surface P-selectin with flow cytometry. Inhibition of purified soluble guanylyl cyclase was quantified using an ELISA to measure cGMP production. Results: Pre-incubation of platelets in abacavir significantly increased activation in response to ADP in a time and dose-dependent manner. The active anabolite of abacavir, carbovir triphosphate, competitively inhibited soluble guanylyl cyclase activity with a K-i of 55 mu mol/l. Conclusion: Abacavir competitively inhibits guanylyl cyclase, leading to platelet hyper-reactivity. This may explain the observed increased risk of myocardial infarction in HIV patients taking abacavir. (C) 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins

引用

页码：2243 / 2248

页数：6

共 38 条

[1] PURIFICATION OF GUANYLATE CYCLASE FROM HUMAN PLATELETS AND EFFECT OF ARACHIDONIC-ACID PEROXIDE [J].

ASANO, T ;

HIDAKA, H .

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1977, 78 (03) :910-918

[2]

BRANDWEIN HJ, 1982, J BIOL CHEM, V257, P1309

[3] Risk of Myocardial Infarction and Abacavir Therapy: No Increased Risk Across 52 GlaxoSmithKline-Sponsored Clinical Trials in Adult Subjects [J].

Brothers, Cindy H. ;

Hernandez, Jaime E. ;

Cutrell, Amy G. ;

Curtis, Lloyd ;

Ait-Khaled, Mounir ;

Bowlin, Steve J. ;

Hughes, Sara H. ;

Yeo, Jane M. ;

Lapierre, Didier H. .

JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES, 2009, 51 (01) :20-28

[4] Cardiovascular risks associated with abacavir and tenofovir exposure in HIV-infected persons [J].

Choi, Andy I. ;

Vittinghoff, Eric ;

Deeks, Steven G. ;

Weekley, Cristin C. ;

Li, Yongmei ;

Shlipak, Michael G. .

AIDS, 2011, 25 (10) :1289-1298

[5] Abacavir use and cardiovascular disease events: a meta-analysis of published and unpublished data [J].

Cruciani, Mario ;

Zanichelli, Veronica ;

Serpelloni, Giovanni ;

Bosco, Oliviero ;

Malena, Marina ;

Mazzi, Romualdo ;

Mengoli, Carlo ;

Parisi, Saverio G. ;

Moyle, Graeme .

AIDS, 2011, 25 (16) :1993-2004

[6]

Cutrell A, 2008, LANCET, V371, P1413, DOI [10.1016/S0140-6736(08)60492-4, 10.1016/s0140-6736(08)60492-4]

[7] Nitric oxide-sensitive guanylyl cyclase is the only nitric oxide receptor mediating platelet inhibition [J].

Dangel, O. ;

Mergia, E. ;

Karlisch, K. ;

Groneberg, D. ;

Koesling, D. ;

Friebe, A. .

JOURNAL OF THROMBOSIS AND HAEMOSTASIS, 2010, 8 (06) :1343-1352

[8]

DAVIES MJ, 1985, BRIT HEART J, V53, P363

[9]

Ding X, 2011, C RETR OPP INF BOST

[10]

Francisci D, 2010, J INT AIDS SOC, V13, P1

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