单磷酸环磷酸腺苷对心脏 GLP-1 受体的抗炎作用有重要调节作用。

IF 4.8 3区 医学 Q2 CELL BIOLOGY Inflammation Research Pub Date : 2024-11-01 Epub Date: 2024-09-21 DOI:10.1007/s00011-024-01950-0
Renee A Stoicovy, Natalie Cora, Arianna Perez, Deepika Nagliya, Giselle Del Calvo, Teresa Baggio Lopez, Emma C Weinstein, Jordana I Borges, Jennifer Maning, Anastasios Lymperopoulos
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引用次数: 0

摘要

背景:胰高血糖素样肽(GLP)-1 受体(GLP1R)激动剂除了控制血糖水平和减少肥胖外,还对心血管产生多种有益影响。它们还通过中枢和外周机制发挥抗炎作用。GLP1R 是一种 G 蛋白偶联受体(GPCR),与腺苷酸环化酶(AC)刺激性 Gs 蛋白偶联,以提高细胞中环 3`-5`- 腺苷酸单磷酸(cAMP)的水平。cAMP 通过其效应蛋白激酶 A(PKA)和直接由 cAMP 激活的交换蛋白(Epac)发挥各种抗凋亡和抗炎作用。然而,cAMP 在介导 GLP1R 抗炎作用(至少在心脏中)方面的确切作用和重要性仍有待确定。为此,我们测试了 GLP1R 激动剂利拉鲁肽对脂多糖(LPS)诱导的 H9c2 心脏细胞急性炎症损伤的影响,无论是在没有 cAMP 生成(AC 抑制)的情况下,还是在通过罗氟司特抑制磷酸二酯酶(PDE)-4 提高 cAMP 水平的情况下:利拉鲁肽剂量依赖性地抑制了LPS诱导的细胞凋亡,并提高了H9c2细胞中的cAMP水平,罗氟司特和PDE8抑制进一步增强了利拉鲁肽产生的cAMP。GLP1R刺激的cAMP明显抑制了LPS依赖性诱导的促炎性肿瘤坏死因子(TNF)-a、白细胞介素(IL)-1b和IL-6细胞因子的表达、诱导型一氧化氮合酶(iNOS)的表达和核因子(NF)-kB的活性、基质金属蛋白酶(MMP)-2和MMP-9的水平和活性以及H9c2心肌细胞的心肌损伤标志物。利拉鲁肽的作用是由 GLP1R 介导的,因为它们被 GLP1R 拮抗剂 exendin(9-39) 所取消。重要的是,AC抑制完全削弱了利拉鲁肽对LPS依赖性炎症损伤的抑制作用,而罗氟司特则显著增强了利拉鲁肽对LPS诱导的炎症的保护作用。最后,单独的 PKA 抑制或 Epac1/2 抑制只能部分阻断利拉鲁肽对 H9c2 心脏细胞中 LPS 诱导的炎症的抑制作用,但 PKA 和 Epac1/2 联合抑制可完全阻止利拉鲁肽减轻 LPS 依赖性炎症。结论:通过激活 PKA 和 Epac,cAMP 对 GLP1R 在心脏细胞中的抗炎信号转导至关重要,而且 cAMP 水平对 GLP1R 激动剂在心脏中的抗炎功效具有关键性调节作用。提高心脏 cAMP 水平的策略(如抑制 PDE4)可能会增强 GLP1R 激动剂药物对心血管(包括抗炎)的益处。
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Cyclic adenosine monophosphate critically modulates cardiac GLP-1 receptor's anti-inflammatory effects.

Background: Glucagon-like peptide (GLP)-1 receptor (GLP1R) agonists exert a multitude of beneficial cardiovascular effects beyond control of blood glucose levels and obesity reduction. They also have anti-inflammatory actions through both central and peripheral mechanisms. GLP1R is a G protein-coupled receptor (GPCR), coupling to adenylyl cyclase (AC)-stimulatory Gs proteins to raise cyclic 3`-5`-adenosine monophosphate (cAMP) levels in cells. cAMP exerts various anti-apoptotic and anti-inflammatory effects via its effectors protein kinase A (PKA) and Exchange protein directly activated by cAMP (Epac). However, the precise role and importance of cAMP in mediating GLP1R`s anti-inflammatory actions, at least in the heart, remains to be determined. To this end, we tested the effects of the GLP1R agonist liraglutide on lipopolysaccharide (LPS)-induced acute inflammatory injury in H9c2 cardiac cells, either in the absence of cAMP production (AC inhibition) or upon enhancement of cAMP levels via phosphodiesterase (PDE)-4 inhibition with roflumilast.

Methods & results: Liraglutide dose-dependently inhibited LPS-induced apoptosis and increased cAMP levels in H9c2 cells, with roflumilast but also PDE8 inhibition further enhancing cAMP production by liraglutide. GLP1R-stimulated cAMP markedly suppressed the LPS-dependent induction of pro-inflammatory tumor necrosis factor (TNF)-a, interleukin (IL)-1b, and IL-6 cytokine expression, of inducible nitric oxide synthase (iNOS) expression and nuclear factor (NF)-kB activity, of matrix metalloproteinases (MMP)-2 and MMP-9 levels and activities, and of myocardial injury markers in H9c2 cardiac cells. The effects of liraglutide were mediated by the GLP1R since they were abolished by the GLP1R antagonist exendin(9-39). Importantly, AC inhibition completely abrogated liraglutide`s suppression of LPS-dependent inflammatory injury, whereas roflumilast significantly enhanced the protective effects of liraglutide against LPS-induced inflammation. Finally, PKA inhibition or Epac1/2 inhibition alone only partially blocked liraglutide`s suppression of LPS-induced inflammation in H9c2 cardiac cells, but, together, PKA and Epac1/2 inhibition fully prevented liraglutide from reducing LPS-dependent inflammation.

Conclusions: cAMP, via activation of both PKA and Epac, is essential for GLP1R`s anti-inflammatory signaling in cardiac cells and that cAMP levels crucially regulate the anti-inflammatory efficacy of GLP1R agonists in the heart. Strategies that elevate cardiac cAMP levels, such as PDE4 inhibition, may potentiate the cardiovascular, including anti-inflammatory, benefits of GLP1R agonist drugs.

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来源期刊
Inflammation Research
Inflammation Research 医学-免疫学
CiteScore
9.90
自引率
1.50%
发文量
134
审稿时长
3-8 weeks
期刊介绍: Inflammation Research (IR) publishes peer-reviewed papers on all aspects of inflammation and related fields including histopathology, immunological mechanisms, gene expression, mediators, experimental models, clinical investigations and the effect of drugs. Related fields are broadly defined and include for instance, allergy and asthma, shock, pain, joint damage, skin disease as well as clinical trials of relevant drugs.
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