Overexpression of TRPV6 Inhibits Coronary Atherosclerosis–Related Inflammatory Response and Cell Apoptosis via the PKA/UCP2 Pathway

IF 3.4 4区 医学 Q2 CARDIAC & CARDIOVASCULAR SYSTEMS
Lei Zheng, Huiying Zhang, Xuewen Li
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引用次数: 0

Abstract

Objective: This research is aimed at unravelling the intricate relationship between transient receptor potential vanilloid 6 (TRPV6), protein kinase A (PKA), uncoupling protein 2 (UCP2), and atherosclerosis. By shedding light on the role of the TRPV6/PKA/UCP2 pathway in inhibiting inflammatory response and cell apoptosis in coronary atherosclerotic plaques, this study provides valuable insights into potential therapeutic targets for treating coronary artery disease (CAD).

Methods: We established animal and cell models of atherosclerosis. The expression of TRPV6 was measured using immunohistochemistry and immunofluorescence. Cytokine levels were detected by enzyme-linked immunosorbent assay (ELISA). Cell viability and apoptosis ratio were measured using cell counting kit-8 (CCK-8) and flow cytometry. The binding relationship between TRPV6 and PKA was validated using chromatin immunoprecipitation (CHIP) and coimmunoprecipitation (CoIP). Finally, the expression of the TRPV6/PKA/UCP2 signaling pathway and apoptosis-related factors was detected using western blot (WB) and quantitative real-time polymerase chain reaction (qRT-PCR).

Results: TRPV6 was significantly decreased in atherosclerosis mouse and cell model. CHIP and CoIP assays indicated that TRPV6 binds to PKA and positively regulated its expression in oxidized low-density lipoprotein (ox-LDL)–treated human umbilical vein endothelial cells (HUVECs). Overexpression of TRPV6 significantly increased cell viability and inhibited apoptosis, whereas silencing TRPV6 had the opposite effect. Additionally, the overexpression of TRPV6 remarkably declined the expression of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1β). However, after silencing PKA, this effect was partially reversed, the cell viability and inflammatory response remarkably enhanced, and apoptosis significantly declined in oe-TRPV6 + si-PKA group.

Conclusions: In summary, our study demonstrated that TRPV6 inhibited apoptosis and inflammatory response in the atherosclerosis cell model through the regulation of the PKA/UCP2 pathway.

Abstract Image

过表达 TRPV6 可通过 PKA/UCP2 通路抑制冠状动脉粥样硬化相关炎症反应和细胞凋亡
研究目的本研究旨在揭示瞬时受体电位香草素 6(TRPV6)、蛋白激酶 A(PKA)、解偶联蛋白 2(UCP2)与动脉粥样硬化之间错综复杂的关系。通过揭示 TRPV6/PKA/UCP2 通路在抑制冠状动脉粥样硬化斑块炎症反应和细胞凋亡中的作用,本研究为治疗冠状动脉疾病(CAD)的潜在治疗靶点提供了有价值的见解:方法:我们建立了动脉粥样硬化动物模型和细胞模型。方法:我们建立了动脉粥样硬化动物模型和细胞模型,采用免疫组化和免疫荧光法测定 TRPV6 的表达。细胞因子水平通过酶联免疫吸附试验(ELISA)检测。使用细胞计数试剂盒-8(CCK-8)和流式细胞术测量细胞活力和凋亡率。使用染色质免疫沉淀(CHIP)和共免疫沉淀(CoIP)验证了 TRPV6 和 PKA 之间的结合关系。最后,利用 Western 印迹(WB)和实时定量聚合酶链反应(qRT-PCR)检测了 TRPV6/PKA/UCP2 信号通路和细胞凋亡相关因子的表达:结果:TRPV6在动脉粥样硬化小鼠和细胞模型中明显减少。CHIP和CoIP检测表明,TRPV6与PKA结合,并正向调节PKA在氧化低密度脂蛋白(ox-LDL)处理的人脐静脉内皮细胞(HUVECs)中的表达。过表达 TRPV6 能显著提高细胞活力并抑制细胞凋亡,而沉默 TRPV6 则效果相反。此外,过表达 TRPV6 还能明显降低肿瘤坏死因子-α(TNF-α)、白细胞介素-6(IL-6)和白细胞介素-1β(IL-1β)的表达。然而,沉默PKA后,这种效应被部分逆转,细胞活力和炎症反应明显增强,oe-TRPV6 + si-PKA 组的细胞凋亡显著下降:综上所述,我们的研究表明,TRPV6通过调控PKA/UCP2通路抑制动脉粥样硬化细胞模型中的细胞凋亡和炎症反应。
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来源期刊
Cardiovascular Therapeutics
Cardiovascular Therapeutics 医学-心血管系统
CiteScore
5.60
自引率
0.00%
发文量
55
审稿时长
6 months
期刊介绍: Cardiovascular Therapeutics (formerly Cardiovascular Drug Reviews) is a peer-reviewed, Open Access journal that publishes original research and review articles focusing on cardiovascular and clinical pharmacology, as well as clinical trials of new cardiovascular therapies. Articles on translational research, pharmacogenomics and personalized medicine, device, gene and cell therapies, and pharmacoepidemiology are also encouraged. Subject areas include (but are by no means limited to): Acute coronary syndrome Arrhythmias Atherosclerosis Basic cardiac electrophysiology Cardiac catheterization Cardiac remodeling Coagulation and thrombosis Diabetic cardiovascular disease Heart failure (systolic HF, HFrEF, diastolic HF, HFpEF) Hyperlipidemia Hypertension Ischemic heart disease Vascular biology Ventricular assist devices Molecular cardio-biology Myocardial regeneration Lipoprotein metabolism Radial artery access Percutaneous coronary intervention Transcatheter aortic and mitral valve replacement.
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