Cui Xiuru, Wang Yawei, Lu Hanlin, Wang Lei, Xie Xianwei, Zhang Shenghao, Kovarik Pavel, Li Shuijie, Liu Shanshan, Zhang Qunye, Yang Jianmin, Zhang Cheng, Tian Jinwei, Liu Yan, Zhang Wencheng
State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, 250012, China.
Department of Cardiology, Second Affiliated Hospital of Harbin Medical University, Heilongjiang Provincial Key Laboratory of Panvascular Disease, The Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin, 150086, China.
Adv Sci (Weinh). 2025 Jan;12(3):e2408811. doi: 10.1002/advs.202408811. Epub 2024 Nov 26.
Hypertension remains a major risk factor for cardiovascular diseases, but the underlying mechanisms are not well understood. Zinc finger protein 36 (ZFP36) is an RNA-binding protein that regulates mRNA stability by binding to adenylate-uridylate-rich elements in the mRNA 3'-untranslated region. This study reveals that ZFP36 expression is highly elevated in the arteries of hypertensive patients and rodents. In cultured vascular smooth muscle cell (VSMC), angiotensin II (AngII) activates poly (ADP-ribose) polymerases1 (PARP1) to stimulate Zfp36 expression at the transcriptional level. VSMC-specific ZFP36 deletion reduces vessel contractility and blood pressure levels in mice. Mechanistically, ZFP36 regulates G protein-coupled receptors (GPCRs)-mediated increases in intracellular calcium levels through impairing the mRNA stability of regulator of G protein signaling 2 (RGS2). Moreover, the VSMC-specific ZFP36 deficiency attenuates AngII-induced hypertension and vascular remodeling in mice. AAV-mediated ZFP36 knockdown ameliorates spontaneous hypertension in rats. These findings elucidate that ZFP36 plays an important role in the regulation of smooth muscle contraction and blood pressure through modulating RGS2 expression. ZFP36 inhibition may represent a new therapeutic strategy for the treatment of hypertension.
高血压仍然是心血管疾病的主要危险因素，但其潜在机制尚未完全明确。锌指蛋白36（ZFP36）是一种RNA结合蛋白，通过与mRNA 3'非翻译区富含腺苷酸 - 尿苷酸的元件结合来调节mRNA稳定性。本研究表明，ZFP36在高血压患者和啮齿动物的动脉中表达显著升高。在培养的血管平滑肌细胞（VSMC）中，血管紧张素II（AngII）激活聚（ADP - 核糖）聚合酶1（PARP1），在转录水平刺激Zfp36表达。VSMC特异性ZFP36缺失可降低小鼠的血管收缩性和血压水平。机制上，ZFP36通过损害G蛋白信号调节因子2（RGS2）的mRNA稳定性来调节G蛋白偶联受体（GPCR）介导的细胞内钙水平升高。此外，VSMC特异性ZFP36缺乏可减轻小鼠AngII诱导的高血压和血管重塑。腺相关病毒介导的ZFP36敲低可改善大鼠的自发性高血压。这些发现阐明了ZFP36通过调节RGS2表达在平滑肌收缩和血压调节中起重要作用。抑制ZFP36可能代表一种治疗高血压的新策略。
