RESUMO
OBJECTIVE: Cytomegalovirus (CMV) has been epidemiologically associated with multiple disease processes including coronary, carotid and cardiac graft atherosclerosis. An early initiating event in atherogenesis is the uptake by macrophages of oxidized low-density lipoproteins (OxLDL) via the scavenger receptor, CD36. Because CMV can activate host-cell gene transcription, we hypothesized that CMV may upregulate CD36 expression. METHODS AND RESULTS: THP-1 monocyte/macrophage cells were treated with Davis strain CMV and cell surface CD36 expression measured by flow cytometry. Virus challenge increased the percentage of cells expressing CD36 from 21.8 +/- 1.7 to 48.2 +/- 4.0% (mean +/- S.D. for three experiments, P=0.0005); CD36 mRNA accumulation was increased by CMV treatment as determined by reverse transcription-polymerase chain reaction. Viral challenge also upregulated the mitogen-activated protein kinase p38; further, the specific p38 inhibitor, SB203580, reversed the CMV-induced CD36 cell surface expression from 57.2% of cells to baseline levels (29.0 and 30.1% for SB203580 treated and control cells, respectively; P=0.001). Treatment with virus also stimulated uptake of OxLDL: microscopically, virus-treated cells had a mean of 32 +/- 4.0 lipid vacuoles compared with 20 +/- 1.3 for control cells (P=0.01). CONCLUSIONS: These findings suggest that CMV-induced CD36 expression is one mechanism through which CMV may promote atherosclerosis. Other CMV-associated atherogenic mechanisms may exist; additional investigation is necessary.
Assuntos
Membrana Celular/metabolismo , Citomegalovirus/fisiologia , RNA Mensageiro/metabolismo , Receptores Imunológicos/biossíntese , Receptores Imunológicos/genética , Antígenos CD36 , Células Cultivadas , Humanos , Receptores Depuradores , Regulação para CimaRESUMO
BACKGROUND: Cholesteryl ester transfer protein (CETP) regulates plasma lipid distribution. A polymorphism in the CETP gene (Taq1B) is associated with CETP activity, HDL concentration, atherosclerosis progression, and response to statins, and may influence cardiovascular (CV) events. We studied CETP Taq1B genotype, plasma HDL, and clinical events among all patients and patients stratified by statin treatment. METHODS: Consenting patients (n = 2531) with significant coronary artery disease (> or =1 lesion of > or =70% stenosis) undergoing coronary arteriography were genotyped, grouped by statin prescription at hospital discharge, and prospectively followed-up for the outcomes of all-cause mortality and myocardial infarction. RESULTS: CETP Taq1B genotype frequencies were: B1B1, 32.9%; B1B2, 50.3%; and B2B2 16.8%. Plasma HDL was reduced for B1B1 patients (33 +/- 12 mg/dL, vs 36 +/- 13 mg/dL and 36 +/- 13 mg/dL for B1B2 and B2B2, respectively, P for trend =.003). Overall, event rates did not differ between genotypes. Event rates were similar among untreated (24.8%) and statin-treated (24.2%) B1 homozygotes (P = NS); statins significantly reduced events for B1B2 subjects (28.0% vs 21.0%, P =.009) and for B2B2 subjects (26.4% vs 17.4%, P =.048). Therapeutic benefit for B2 carriers remained after adjustment for covariates, and regression interaction analysis showed that B2 carriers experienced reduced events (relative risk [RR] 0.62, 95% CI 0.45-0.86), but statins did not benefit those with B1B1 (RR 1.09, 95% CI 0.70-1.7; P for interaction =.02). Findings were similar for the end point of death alone, although a modest benefit was seen in B1B1 patients (RR 0.67, P =.10), in addition to the strong benefit for B1B2 (RR 0.53, P =.001) and B2B2 (RR 0.28, P =.001). CONCLUSIONS: The CETP Taq1B polymorphism is associated with differential HDL levels but no significant differential in CV risk in the absence of treatment. Importantly, however, CV event reduction by statin therapy is substantially enhanced in the presence of a B2 allele. Our findings suggest, for the first time, the potential of CETP Taq1B genotyping to enable more effective, pharmacogenetically directed therapy.
Assuntos
Proteínas de Transporte/genética , HDL-Colesterol/sangue , Doença da Artéria Coronariana/genética , Glicoproteínas , Polimorfismo Genético , Idoso , Análise de Variância , Proteínas de Transporte/fisiologia , Causas de Morte , Proteínas de Transferência de Ésteres de Colesterol , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/tratamento farmacológico , Estenose Coronária/sangue , Estenose Coronária/tratamento farmacológico , Estenose Coronária/genética , Feminino , Frequência do Gene , Genótipo , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Masculino , Infarto do Miocárdio/genética , Estudos ProspectivosRESUMO
BACKGROUND: Seropositivity to cytomegalovirus (CMV) and elevated C-reactive protein (CRP) may jointly predict increased mortality rates in patients with coronary artery disease (CAD). Therapy with statins reduces lipid levels but may also have other beneficial (eg, antiinflammatory) effects. This study prospectively evaluated the effect of statins on CMV-and CRP-associated death among patients with significant, angiographically defined CAD. METHODS AND RESULTS: We monitored 2315 patients with angiographically significant CAD (stenosis > or =70%) for an average of 2.4 years (maximum, 5.8 years). Anti-CMV IgG antibody levels and CRP concentrations were measured at baseline, and statin prescription was recorded. As previously reported, mortality rate was higher for CMV seropositivity (+) with high CRP (hazard ratio [HR], 2.0) and lower for statins (HR, 0.50). Compared with CMV(-)/low CRP (mortality rate, 5% with statin versus 4% without statin), the protective effect of statin therapy was markedly greater for CMV(+)/low CRP (mortality rate, 2% versus 7%; HR, 0.44; 95% CI, 0.16 to 1.3), CMV negative (-)/high CRP (mortality rate, 1% versus 8%; HR, 0.16), and CMV(+)/high CRP (mortality rate, 6% versus 17%; HR, 0.42; 95% CI, 0.25 to 0.70). After adjustment, interactions were found for statin therapy with CMV(+)/low CRP (P for interaction=0.065), CMV(-)/high CRP (P for interaction=0.051), and CMV(+)/high CRP (P for interaction=0.024). CONCLUSIONS: The survival benefit of statins interacted with CMV seropositivity and high CRP to significantly reduce mortality rates among patients with CAD. This finding supports the hypothesis that statins have beneficial, "lipid-independent," antiinflammatory effects. The mechanism of statin benefit associated with CMV seropositivity remains to be determined.