Hypertension is a major cause of heart attack and stroke. Our recent study revealed that gallic acid (GA) exerts protective effects on pressure overload-induced cardiac hypertrophy and dysfunction. However, the role of GA in angiotensin II (Ang II)-induced hypertension and vascular remodeling remains unknown. C57BL/6J mice were subjected to saline and Ang II infusion. Systolic blood pressure was measured using a tail-cuff system. Vascular remodeling and oxidative stress were examined by histopathological staining. Vasodilatory function was evaluated in the aortic ring. Our findings revealed that GA administration significantly ameliorated Ang II-induced hypertension, vascular inflammation, and fibrosis. GA also abolished vascular endothelial dysfunction and oxidative stress in Ang II-infused aortas. Mechanistically, GA treatment attenuated Ang II-induced upregulation of the immunoproteasome catalytic subunits β2i and β5i leading to reduction of the trypsin-like and chymotrypsin-like activity of the proteasome, which suppressed degradation of endothelial nitric oxide synthase (eNOS) and reduction of nitric oxide (NO) levels. Furthermore, blocking eNOS activity by using a specific inhibitor (_L-N^G-nitroarginine methyl ester) markedly abolished the GA-mediated beneficial effect. This study identifies GA as a novel immunoproteasome inhibitor that may be a potential therapeutic agent for hypertension and vascular dysfunction.

高血压是心脏病和中风的主要原因。我们最近的研究表明，没食子酸（GA）对压力超负荷引起的心脏肥大和功能障碍具有保护作用。但是，GA在血管紧张素II（Ang II）诱导的高血压和血管重塑中的作用仍然未知。C57BL / 6J小鼠接受盐水和Ang II输注。使用尾套系统测量收缩压。通过组织病理学染色检查血管重塑和氧化应激。在主动脉环中评估血管舒张功能。我们的发现表明，GA给药可显着改善Ang II引起的高血压，血管炎症和纤维化。GA还消除了注入Ang II的主动脉中的血管内皮功能障碍和氧化应激。机械上，GA处理减弱了Ang II诱导的免疫蛋白酶体催化亚基β2i和β5i的上调，从而导致蛋白酶体的胰蛋白酶样和胰凝乳蛋白酶样活性降低，从而抑制了内皮一氧化氮合酶（eNOS）的降解和一氧化氮的减少（否）级别。此外，通过使用特定的抑制剂来阻断eNOS活性（_大号-ñ^G-硝基精氨酸甲酯）显着消除了GA介导的有益作用。这项研究确定GA是一种新型的免疫蛋白酶体抑制剂，可能是高血压和血管功能障碍的潜在治疗剂。