Mey Lilli, Bonaterra Gabriel A, Hoffmann Joy, Schwarzbach Hans, Schwarz Anja, Eiden Lee E, Weihe Eberhard, Kinscherf Ralf
Department of Medical Cell Biology, Institute for Anatomy and Cell Biology, Medical Faculty, Philipps-University of Marburg, Robert-Koch-Str. 8, 35037 Marburg, Germany.
Section on Molecular Neuroscience, National Institute of Mental Health Intramural Research Program, 49 Convent Drive, Room 5A38, Bethesda, MD 20892, USA.
Int J Mol Sci. 2024 Dec 10;25(24):13245. doi: 10.3390/ijms252413245.
A possible involvement of immune- and vasoregulatory PACAP signaling at the PAC1 receptor in atherogenesis and plaque-associated vascular inflammation has been suggested. Therefore, we tested the PAC1 receptor agonist Maxadilan and the PAC1 selective antagonist M65 on plaque development and lumen stenosis in the ApoE atherosclerosis model for possible effects on atherogenesis. Adult male ApoE mice were fed a cholesterol-enriched diet (CED) or standard chow (SC) treated with Maxadilan, M65 or Sham. Effects of treatment on atherosclerotic plaques, lumen stenosis, apoptosis and pro-inflammatory signatures were analyzed in the brachiocephalic trunk (BT). The percentage of Maxadilan treated mice exhibiting plaques under SC and CED was lower than that of Sham or M65 treatment indicating opposite effects of Maxadilan and M65. Maxadilan application inhibited lumen stenosis in SC and CED mice compared to the Sham mice. In spite of increased cholesterol levels, lumen stenosis of Maxadilan-treated mice was similar under CED and SC. In contrast, M65 under SC or CED did not reveal a significant influence on lumen stenosis. Maxadilan significantly reduced the TNF-α-immunoreactive (TNF-α) area in the plaques under CED, but not under SC. In contrast, the IL-1β area was reduced after Maxadilan treatment in SC mice but remained unchanged in CED mice compared to Sham mice. Maxadilan reduced caspase-3 immunoreactive (caspase-3) in the tunica media under both, SC and CED without affecting lipid content in plaques. Despite persistent hypercholesterolemia, Maxadilan reduces lumen stenosis, apoptosis and TNF-α driven inflammation. Our data suggest that Maxadilan provides atheroprotection by acting downstream of hypercholesterolemia-induced vascular inflammation. This implicates the potential of PAC1-specific agonist drugs against atherosclerosis even beyond statins and PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors.
有人提出，免疫和血管调节性垂体腺苷酸环化酶激活肽（PACAP）信号通过PAC1受体可能参与动脉粥样硬化的发生以及斑块相关的血管炎症。因此，我们在载脂蛋白E（ApoE）动脉粥样硬化模型中测试了PAC1受体激动剂Maxadilan和PAC1选择性拮抗剂M65对斑块形成和管腔狭窄的影响，以探究其对动脉粥样硬化发生的潜在作用。成年雄性ApoE小鼠喂食富含胆固醇的饮食（CED）或标准饲料（SC），分别用Maxadilan、M65处理或假处理。分析了在头臂干（BT）中治疗对动脉粥样硬化斑块、管腔狭窄、细胞凋亡和促炎信号的影响。与假处理或M65处理相比，在SC和CED条件下，接受Maxadilan处理且出现斑块的小鼠百分比更低，这表明Maxadilan和M65具有相反的作用。与假处理小鼠相比，应用Maxadilan可抑制SC和CED小鼠的管腔狭窄。尽管胆固醇水平升高，但在CED和SC条件下，接受Maxadilan处理的小鼠的管腔狭窄情况相似。相比之下，在SC或CED条件下，M65对管腔狭窄没有显著影响。在CED条件下，Maxadilan显著减少了斑块中肿瘤坏死因子-α（TNF-α）免疫反应阳性区域，但在SC条件下没有。相反，与假处理小鼠相比，Maxadilan处理后，SC小鼠的白细胞介素-1β区域减少，但CED小鼠保持不变。在SC和CED条件下，Maxadilan均降低了中膜中半胱天冬酶-3免疫反应阳性（caspase-3）水平，且不影响斑块中的脂质含量。尽管持续存在高胆固醇血症，但Maxadilan可减轻管腔狭窄、细胞凋亡和TNF-α驱动的炎症。我们的数据表明，Maxadilan通过在高胆固醇血症诱导的血管炎症下游发挥作用来提供动脉粥样硬化保护。这意味着PAC1特异性激动剂药物在抗动脉粥样硬化方面具有潜力，甚至超越他汀类药物和前蛋白转化酶枯草溶菌素/kexin 9型（PCSK9）抑制剂。
