Division of Medical Physiology, Stellenbosch University, Cape Town, South Africa.
Department of Physiology and Otto Loewi Research Centre, Medical University of Graz, Austria.
FEBS J. 2019 Apr;286(7):1256-1270. doi: 10.1111/febs.14657. Epub 2018 Sep 28.
Mounting evidence points to increased rates of cardiovascular disease (CVD) among people living with HIV/AIDS (PLWHA). Endothelial dysfunction (loss of endothelium-dependent vascular relaxation in response to provasodilatory stimuli) constitutes an early pathophysiological event in atherogenesis and CVD. Both HIV-1 infection and antiretroviral therapy (ART) are implicated in the development of endothelial dysfunction; however, conclusions are frequently drawn from associations shown in epidemiological studies. In this narrative review of mainly in vitro and animal studies, we report on the current understanding of how various HIV-1 proteins, HIV-1-induced proinflammatory cytokines and common antiretroviral drugs directly impact vascular endothelial cells. Proposed cellular mechanisms underlying the switch to a dysfunctional state are discussed, including oxidative stress, impaired expression and regulation of endothelial nitric oxide (NO) synthase (eNOS) and increased expression of vascular adhesion molecules. From the literature, it appears that increased reactive oxygen species (ROS) production, linked to decreased NO bioavailability and ensuing endothelial dysfunction, may be proposed as a putative final common pathway afflicting the vascular endothelium in PLWHA. The HIV-1-proteins Tat, Gp120 and Nef in particular, the proinflammatory cytokine, TNF-α, and the antiretroviral drugs Efavirenz and Lopinavir, most commonly postulated to be primary causal agents of endothelial dysfunction, are also discussed. We conclude that, despite existing evidence from basic research papers, a significant gap remains in terms of the exact underlying cellular mechanisms involved in HIV-1 and ART induced endothelial dysfunction. Bridging this gap could help pave the way for future strategies to prevent and treat early cardiovascular changes in PLWHA.
越来越多的证据表明，艾滋病毒/艾滋病（PLWHA）患者的心血管疾病（CVD）发病率上升。内皮功能障碍（血管舒张刺激下内皮依赖性血管舒张反应丧失）是动脉粥样硬化和 CVD 的早期病理生理事件。HIV-1 感染和抗逆转录病毒治疗（ART）都与内皮功能障碍的发展有关；然而，结论通常是从流行病学研究中显示的相关性得出的。在这篇主要关于体外和动物研究的叙述性综述中，我们报告了目前对各种 HIV-1 蛋白、HIV-1 诱导的促炎细胞因子和常见抗逆转录病毒药物如何直接影响血管内皮细胞的理解。讨论了导致向功能障碍状态转变的潜在细胞机制，包括氧化应激、内皮一氧化氮（NO）合酶（eNOS）表达和调节受损以及血管黏附分子表达增加。从文献中可以看出，与内皮功能障碍相关的活性氧（ROS）产生增加，可能导致 NO 生物利用度降低，这可能被提出作为影响 PLWHA 血管内皮的一个潜在共同途径。特别是 HIV-1 蛋白 Tat、Gp120 和 Nef、促炎细胞因子 TNF-α 以及抗逆转录病毒药物依非韦伦和洛匹那韦，最常被推测为内皮功能障碍的主要原因，也在讨论之列。我们的结论是，尽管基础研究论文中有现有证据，但在 HIV-1 和 ART 诱导的内皮功能障碍的确切潜在细胞机制方面仍存在显著差距。弥合这一差距可能有助于为预防和治疗 PLWHA 的早期心血管变化铺平道路。
