HIV Protease Inhibitor Ritonavir Impairs Endothelial Function Via Reduction in Adipose Mass and Endothelial Leptin Receptor-Dependent Increases in NADPH Oxidase 1 (Nox1), C-C Chemokine Receptor Type 5 (CCR5), and Inflammation.
HIV Protease Inhibitor Ritonavir Impairs Endothelial Function Via Reduction in Adipose Mass and Endothelial Leptin Receptor-Dependent Increases in NADPH Oxidase 1 (Nox1), C-C Chemokine Receptor Type 5 (CCR5), and Inflammation.
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DOI：
10.1161/jaha.120.018074
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发表时间：
2020-10-20
影响因子：
5.4
通讯作者：
Belin de Chantemèle EJ
中科院分区：
文献类型：
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作者：
Bruder-Nascimento T;Kress TC;Kennard S;Belin de Chantemèle EJ
心血管疾病目前是接受抗逆转录病毒联合治疗的人类免疫缺陷病毒患者的主要死亡原因。尽管使用蛋白酶抑制剂利托那韦与心血管疾病的患病率增加有关，但其潜在机制仍不明确。在此，我们检验了利托那韦介导的脂肪萎缩通过减少内皮瘦素信号传导导致内皮功能障碍的假设。利托那韦长期（4周）但非短期（3天）治疗可降低小鼠体重、脂肪量和瘦素水平，并诱导内皮功能障碍。此外，利托那韦增加血管NADPH氧化酶1、主动脉H2 O2水平以及白细胞介素-1 β、GATA 3（加塔结合蛋白3）、巨噬细胞标志物（F4/80）和C-C趋化因子受体5型（CCR 5）表达。用tempol清除活性氧可以恢复内皮功能，并且小鼠中的NADPH氧化酶1和CCR 5缺失可以防止利托那韦介导的内皮功能障碍和血管炎症。值得注意的是，在利托那韦治疗的动物中，瘦素输注显著改善了内皮功能，并显著降低了血管NADPH氧化酶1、白细胞介素1β、GATA 3、F4/80和CCR 5水平。内皮细胞瘦素受体的选择性缺陷可取消输注瘦素对内皮功能的保护作用。相反，选择性增加内皮瘦素信号转导与蛋白酪氨酸磷酸酶缺失钝化利托那韦诱导的内皮功能障碍。总之，这些数据表明利托那韦相关的内皮功能障碍是肥胖和瘦素分泌减少的直接结果，这降低了内皮瘦素信号传导，并导致NADPH氧化酶1诱导的CCR 5介导的NO生物利用度降低。这些后者的数据还介绍了瘦素缺乏症作为心血管疾病的额外贡献者和瘦素作为CCR 5表达的负调节因子，这可能提供限制人类免疫缺陷病毒感染的有益途径。
Cardiovascular disease is currently the leading cause of death in patients with human immunodeficiency virus on combination antiretroviral therapy. Although the use of the protease inhibitor ritonavir has been associated with increased prevalence of cardiovascular disease, the underlying mechanisms remain ill‐defined. Herein, we tested the hypothesis that ritonavir‐mediated lipoatrophy causes endothelial dysfunction via reducing endothelial leptin signaling. Long‐term (4 weeks) but not short‐term (3 days) treatment with ritonavir reduced body weight, fat mass, and leptin levels and induced endothelial dysfunction in mice. Moreover, ritonavir increased vascular NADPH oxidase 1, aortic H2O2 levels as well as interleukin‐1β, GATA3 (GATA binding protein 3), the macrophage marker (F4/80), and C‐C chemokine receptor type 5 (CCR5) expression. Reactive oxygen species scavenging with tempol restored endothelial function, and both NADPH oxidase 1 and CCR5 deletion in mice protected from ritonavir‐mediated endothelial dysfunction and vascular inflammation. Remarkably, leptin infusion markedly improved endothelial function and significantly reduced vascular NADPH oxidase 1, interleukin‐1β, GATA3, F4/80, and CCR5 levels in ritonavir‐treated animals. Selective deficiency in endothelial leptin receptor abolished the protective effects of leptin infusion on endothelial function. Conversely, selective increases in endothelial leptin signaling with protein tyrosine phosphatase deletion blunted ritonavir‐induced endothelial dysfunction. All together, these data indicate that ritonavir‐associated endothelial dysfunction is a direct consequence of a reduction in adiposity and leptin secretion, which decreases endothelial leptin signaling and leads to a NADPH oxidase 1–induced, CCR5‐mediated reduction in NO bioavailability. These latter data also introduce leptin deficiency as an additional contributor to cardiovascular disease and leptin as a negative regulator of CCR5 expression, which may provide beneficial avenues for limiting human immunodeficiency virus infection.