Cardiovascular Risk of Antiretroviral Therapy Drugs in HIV

HIV 抗逆转录病毒治疗药物的心血管风险

• 批准号: 10700275
• 负责人: Jasimuddin Ahamed
• 金额: $ 70.11万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10700275
• 关键词: Acceleration; Acetylcysteine; Antiplatelet Drugs; Autopsy; Blood Platelets; Cells; Clinical; Communicable Diseases; Data; Dose; Etiology; Exhibits; Fibrosis; Foundations; Functional disorder; Goals; HIV; HIV antiretroviral; Heart; Heart failure; Human; In Vitro; Individual; Injections; Intervention; Investigation; Knock-out; Life Expectancy; Link; LoxP-flanked allele; Macrophage; Magnetic Resonance Imaging; Measures; Mediating; Membrane Transport Proteins; Mesenchymal; Mus; Myeloid Cells; Myocardial dysfunction; Organ; Patients; Persons; Pharmaceutical Preparations; Phenotype; Pilot Projects; Pirfenidone; Plasma; Platelet Activation; Play; Population; Prevention strategy; Process; Protease Inhibitor; Proteins; Publishing; Quality of life; Regimen; Research; Risk; Ritonavir; Role; Signal Transduction; Source; Sudden Death; Techniques; Tenofovir; Testing; Transforming Growth Factor beta; Transforming Growth Factors; Transgenic Mice; Transgenic Organisms; Xenograft procedure; antifibrotic treatment; antiretroviral therapy; cardiovascular disorder risk; cardiovascular risk factor; cell type; comorbidity; coronary fibrosis; effective intervention; improved; in vivo; inhibitor; innovation; mouse model; novel strategies; patient population; pharmacologic; potential biomarker; prevent; profibrotic cytokine; receptor; recruit; translational potential

PROJECT SUMMARY Although antiretroviral therapy drugs (ART) have prevented HIV propagation and increased life expectancy of people with HIV (PWH), the rate of sudden death in this population is 2-4-times higher than people without HIV. Autopsies have revealed cardiac fibrosis in half of this HIV patient population, a likely etiology for sudden death. The protease inhibitor class ART (PI-ART) is linked to cardiovascular risk in PWH, and it is plausible that ART can exacerbate the risk by inducing cardiac fibrosis. Our long-term goals are to determine the mechanism and the impact of ART-induced cardiac fibrosis in PWH, and to explore preventive strategies. Transforming growth factor β1 (TGFβ1) is a strong profibrotic cytokine and platelets contain ~100 times more TGFβ1 than other cells and are a major source of plasma TGFβ1 contributing to organ fibrosis. Higher plasma TGFβ1 levels and cardiac fibrosis are observed in HIV+ individuals, but whether ART further increases plasma TGFβ1 and cardiac fibrosis in PWH is not clear. In pilot studies, we observed that newer ART regimens, including PI-boosted dose of ritonavir (RTV) and tenofovir, activated platelets to release TGFβ1, which can be blocked by Ceefourin-1, a specific inhibitor of MRP4, a membrane transporter highly expressed in platelets from HIV patients. Injection of a PI-boosted dose of RTV in transgenic Tg26 HIV mice (which exhibit multiple HIV-associated comorbidities) increased cardiac fibrosis and diastolic dysfunction associated with the accumulation of CD206+ cells expressing αSMA in the heart, presumably macrophages. These results led to our central hypothesis that ART may activate platelets to release TGFβ1 via MRP4, which stimulates macrophages to undergo mesenchymal transition, inducing cardiac fibrosis. The objective of this application is to determine the mechanism by which different classes of ART induce platelet TGFβ1 release and identify the cell types to which TGFβ1 signals, leading to cardiac fibrosis. The following Specific Aims will address the objective: 1) Screen a panel of different classes of ART, alone and in combination, for induction of platelet release of TGFβ1 and identify the mechanisms of this process; 2) Determine whether contemporary ART-mediated TGFβ1 release via MRP4 induces cardiac fibrosis in vivo; 3) Determine whether TGFβ1 signaling in macrophages leads to mesenchymal transition and cardiac fibrosis. Our studies will clarify the mechanism of ART-induced TGFβ1 release from platelets and the cell types on which TGFβ1 signals, leading to cardiac fibrosis. We will use innovative techniques to evaluate platelet activation, measure plasma TGFβ1 levels, and assess cellular signaling and cardiac fibrosis in two murine models of HIV. Furthermore, our research will explore the translational potential for mitigating ART-induced cardiac fibrosis in HIV mice with anti-TGFβ1 and anti-fibrotic agents, such as Galunisertib or Pirfenidone. Our studies may also elucidate whether TGFβ1 could be a potential biomarker of underlying organ fibrosis in PWH. It may also lay the foundation for better mechanistic understanding and novel strategies for preventing comorbidities in PWH and fibrosis in other infectious diseases.

项目摘要 尽管抗逆转录病毒疗法药物（ART）已防止HIV传播并提高预期寿命 患有艾滋病毒（PWH）的人，该人群的猝死率比没有艾滋病毒的人高2-4倍。 尸检显示了一半的HIV患者人群的心脏纤维化，这可能是猝死的病因。 蛋白酶抑制剂类艺术（PI-ART）与PWH中的心血管风险有关，这是合理的。 可以通过诱导的心脏纤维化来加剧风险。我们的长期目标是确定机制和 转化生长因子β1 （TGFβ1）是一种强的纤维化细胞因子，血小板含有比其他细胞的TGFβ1高约100倍，并且是A 血浆TGFβ1的主要来源导致器官纤维化。较高的血浆TGFβ1水平和心脏纤维化是 在HIV+个体中观察到，但是ART是否进一步增加了PWH中的血浆TGFβ1和心脏纤维化 不清楚。在试点研究中，我们观察到，较新的艺术方案，包括Ritonavir（RTV）和 Tenofovir，激活的血小板释放TGFβ1，可以通过MRP4的特定抑制剂Ceefourin-1封闭，MRP4， 来自HIV患者的血小板高度表达的膜转运蛋白。注射促进pi剂量的RTV 在转基因TG26 HIV小鼠（暴露了多种HIV相关的合并症）中，心脏纤维化和 与表达αSMA的CD206+细胞的积累相关的舒张功能障碍， 大概是巨噬细胞。这些结果导致我们的中心假设，即艺术可能激活血小板以释放 TGFβ1通过MRP4刺激巨噬细胞进行间充质转变，诱导心脏纤维化。 该应用的目的是确定不同类别诱导血小板的机制 TGFβ1释放并确定TGFβ1信号的细胞类型，导致心脏纤维化。以下特定 目的将解决目标：1）单独和联合组合的不同类别的艺术面板屏幕 诱导TGFβ1的血小板释放并确定此过程的机制； 2）确定是否 通过MRP4释放当代艺术介导的TGFβ1在体内诱导心脏纤维化； 3）确定是否 巨噬细胞中的TGFβ1信号传导导致间充质转变和心脏纤维化。我们的研究将澄清 ART诱导的TGFβ1从血小板释放的机理和TGFβ1信号的细胞类型（领先） 我们将使用创新技术评估血小板激活，测量血浆TGFβ1 水平，并评估两个HIV鼠模型中的细胞信号传导和心脏纤维化。此外，我们的研究 将探索用抗TGFβ1和 抗纤维化剂，例如甘霉菌或吡啶酮。我们的研究还可以阐明TGFβ1是否可以 成为PWH中潜在器官纤维化的潜在生物标志物。它也可能为更好的机理奠定基础 理解和新的策略可预防其他传染病中PWH合并症和纤维化的合并症。