Shukla Ashutosh M, Bose Chhanda, Karaduta Oleg K, Apostolov Eugene O, Kaushal Gur P, Fahmi Tariq, Segal Mark S, Shah Sudhir V
North Florida/South Georgia Veterans Healthcare System, Gainesville, Florida, United States of America; University of Florida, Gainesville, Florida, United States of America.
Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, United States of America; University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
PLoS One. 2015 Sep 28;10(9):e0139226. doi: 10.1371/journal.pone.0139226. eCollection 2015.
Cardiovascular disease is the largest cause of morbidity and mortality among patients with chronic kidney disease (CKD) and end-stage kidney disease, with nearly half of all deaths attributed to cardiovascular disease. Hydroxychloroquine (HCQ), an anti-inflammatory drug, has been shown to have multiple pleiotropic actions relevant to atherosclerosis. We conducted a proof-of-efficacy study to evaluate the effects of hydroxychloroquine in an animal model of atherosclerosis in ApoE knockout mice with and without chronic kidney disease. Forty male, 6-week-old mice were divided into four groups in a 2 x 2 design: sham placebo group; sham treatment group; CKD placebo group; and CKD treatment group. CKD was induced by a two-step surgical procedure. All mice received a high-fat diet through the study duration and were sacrificed after 16 weeks of therapy. Mice were monitored with ante-mortem ultrasonic echography (AUE) for atherosclerosis and vascular stiffness and with post-mortem histology studies for atherosclerosis. Therapy with HCQ significantly reduced the severity of atherosclerosis in CKD mice and sham treated mice. HCQ reduced the area of aortic atherosclerosis on en face examination by approximately 60% in HCQ treated groups compared to the non-treated groups. Additionally, therapy with HCQ resulted in significant reduction in vascular endothelial dysfunction with improvement in vascular elasticity and flow patterns and better-preserved vascular wall thickness across multiple vascular beds. More importantly, we found that presence of CKD had no mitigating effect on HCQ's anti-atherosclerotic and vasculoprotective effects. These beneficial effects were not due to any significant effect of HCQ on inflammation, renal function, or lipid profile at the end of 16 weeks of therapy. This study, which demonstrates structural and functional protection against atherosclerosis by HCQ, provides a rationale to evaluate its use in CKD patients. Further studies are needed to define the exact mechanisms through which HCQ confers these benefits.
心血管疾病是慢性肾脏病（CKD）和终末期肾病患者发病和死亡的主要原因，几乎一半的死亡都归因于心血管疾病。羟氯喹（HCQ）是一种抗炎药物，已被证明具有多种与动脉粥样硬化相关的多效性作用。我们进行了一项有效性验证研究，以评估羟氯喹在患有和未患有慢性肾脏病的载脂蛋白E基因敲除小鼠动脉粥样硬化动物模型中的作用。40只6周龄雄性小鼠按2×2设计分为四组：假手术安慰剂组；假手术治疗组；CKD安慰剂组；CKD治疗组。通过两步手术诱导CKD。在整个研究期间，所有小鼠均接受高脂饮食，并在治疗16周后处死。通过生前超声心动图（AUE）监测小鼠的动脉粥样硬化和血管僵硬度，并通过死后组织学研究监测动脉粥样硬化情况。HCQ治疗显著降低了CKD小鼠和假手术治疗小鼠的动脉粥样硬化严重程度。与未治疗组相比，HCQ治疗组在主动脉粥样硬化的正面检查中，动脉粥样硬化面积减少了约60%。此外，HCQ治疗导致血管内皮功能障碍显著减轻，血管弹性和血流模式得到改善，多个血管床的血管壁厚度得到更好的保留。更重要的是，我们发现CKD的存在对HCQ的抗动脉粥样硬化和血管保护作用没有减轻作用。这些有益作用并非由于HCQ在治疗16周结束时对炎症、肾功能或血脂谱有任何显著影响。这项研究证明了HCQ对动脉粥样硬化具有结构和功能保护作用，为评估其在CKD患者中的应用提供了理论依据。需要进一步研究来确定HCQ产生这些益处的确切机制。
