Effects of HIV Protease Inhibitor Ritonavir on Vasomotor Function and Endothelial Nitric Oxide Synthase Expression
Effects of HIV Protease Inhibitor Ritonavir on Vasomotor Function and Endothelial Nitric Oxide Synthase Expression
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DOI：
10.1097/01.qai.0000153944.72641.34
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发表时间：
2005-06
期刊：
影响因子：
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通讯作者：
W. Fu;H. Chai;Q. Yao;Changyi J. Chen
中科院分区：
文献类型：
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作者：
W. Fu;H. Chai;Q. Yao;Changyi J. Chen
HIV蛋白酶抑制剂（PI）的使用可能与HIV感染患者的心血管疾病有关。本研究的目的是确定HIV PI利托那韦对血管功能和内皮型一氧化氮合酶（eNOS）表达的影响。猪冠状动脉环与利托那韦孵育24小时。血管功能研究与肌张力系统响应U46619（收缩），缓激肽（内皮依赖性舒张），硝普钠（SNP）（内皮非依赖性舒张）。15 μ M和30 μM利托那韦处理的血管环经U46619刺激后的收缩张力显著降低（P < 0.05）。与对照组相比，利托那韦（15 μ M和30 μM）对10 - 5 M缓激肽的反应分别降低了27%和78%（P < 0.05）。在SNP（10 - 6 M）存在下，未观察到舒张反应的改变。采用逆转录聚合酶链反应（RT-PCR）和免疫组织化学方法检测动脉环eNOS mRNA和蛋白水平。15 μ M和30 μM利托那韦处理组内皮型一氧化氮合酶mRNA表达分别降低54%和65%（P < 0.05）。eNOS蛋白水平在这些组中也显著降低。同时，研究了人冠状动脉内皮细胞（HCAECs）。利托那韦处理组内皮细胞eNOS mRNA和蛋白水平均显著降低（P < 0.05）。因此，利托那韦显着损害血管功能，并减少eNOS表达在猪冠状动脉内皮细胞以及HCAEC。这项研究表明，利托那韦可能有助于冠状动脉疾病的形成，在抗病毒治疗艾滋病病毒感染的患者。
The use of HIV protease inhibitors (PIs) may be associated with cardiovascular diseases in HIV-infected patients. The objective of this study was to determine the effects of the HIV PI ritonavir on vasomotor function and endothelial nitric oxide synthase (eNOS) expression. Porcine coronary artery rings were incubated with ritonavir for 24 hours. Vasomotor function was studied with a myograph tension system in response to U46619 (contraction), bradykinin (endothelium-dependent relaxation), and sodium nitroprusside (SNP) (endothelium-independent relaxation). The vessel tension contraction after challenge with U46619 showed a significant decrease in 15- and 30-μM ritonavir-treated rings (P < 0.05). In response to bradykinin at 10−5 M, ritonavir (15 and 30 μM) reduced the relaxation by 27% and 78%, respectively, as compared with controls (P < 0.05). No alterations in the relaxation response were observed in the presence of SNP (10−6 M). The mRNA and protein levels of eNOS of the artery rings were determined by reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry, respectively. The eNOS mRNA showed a 54% and 65% reduction for 15- and 30-μM ritonavir-treated rings, respectively (P < 0.05). The eNOS protein levels were also substantially decreased in these groups. In parallel, human coronary artery endothelial cells (HCAECs) were studied. HCAECs treated with ritonavir showed significant reductions in mRNA and protein levels of eNOS (P < 0.05). Thus, ritonavir significantly impairs vasomotor function and reduces eNOS expression in porcine coronary artery endothelial cells as well as HCAECs. This study suggests that ritonavir may contribute to coronary artery disease formation in antiviral therapy for HIV-infected patients.