Lu Jinhong, Wang Jianji, Liu Yu, Zhang Cuntai, Zhang Guojun, Ge Yipeng, Liu Lei
Department of Biochemistry and Molecular Biology School of Basic Medicine, Capital Medical University, Youanmen, Beijing, 100069, China.
Department of Cardiovascular Surgery, Beijing Anzhen Hospital, Capital Medical University, Anzhen Road 2#, Chaoyang District, Beijing, 10029, China.
Cardiovasc Diabetol. 2025 Nov 8;24(1):427. doi: 10.1186/s12933-025-02976-2.
Terazosin (TZ), a well-known antagonist of the α1-adrenergic receptor (α1-AR), has demonstrated protective effects on vascular endothelial cells (ECs) and reduced vascular stiffness in clinical studies. Endothelial dysfunction and oxidative stress are central drivers of cardiometabolic diseases such as diabetes, where sustained ROS burden accelerates EC senescence and barrier failure. These findings suggest its potential role in combating vascular aging and atherosclerosis; however, the underlying mechanisms remain partially understood. In this study, we investigated whether TZ can prevent atherosclerosis in ApoE mice fed a high-cholesterol diet and aimed to elucidate the mechanisms involved. Our results showed that TZ significantly reduced plaque size, EC senescence, vascular permeability, and reactive oxygen species (ROS) levels, effectively inhibiting atherosclerosis independently of α1-AR signaling. In cultured primary human umbilical vein ECs (HUVECs), TZ inhibited EC senescence via the Pgk1/Hsp90 pathway. It enhanced the interaction between Hsp90 and the antioxidant enzyme peroxiredoxin 1 (Prdx1), leading to lower ROS levels-a key driver of cellular senescence. These findings were confirmed in atherosclerotic ApoE mice. Furthermore, senescent ECs exhibited increased levels of vascular endothelial growth factor A (VEGFA) and decreased levels of angiostatin, contributing to higher vascular permeability and exacerbating atherosclerosis. TZ effectively reversed these changes. Overall, our study demonstrates that TZ primarily alleviates EC senescence and atherosclerosis through the Pgk1/Hsp90/Prdx1 pathway, highlighting Pgk1 activation as a strategy that may also mitigate endothelial dysfunction and oxidative stress in broader cardiometabolic contexts (e.g., diabetes), suggesting that TZ is a promising senomorphic agent for treating vascular aging and atherosclerosis in clinical settings and that Pgk1-targeted interventions could have implications beyond atherosclerosis.
特拉唑嗪（TZ）是一种著名的α1-肾上腺素能受体（α1-AR）拮抗剂，在临床研究中已证明对血管内皮细胞（ECs）具有保护作用，并降低了血管硬度。内皮功能障碍和氧化应激是糖尿病等心脏代谢疾病的核心驱动因素，其中持续的活性氧负担会加速EC衰老和屏障功能衰竭。这些发现表明其在对抗血管衰老和动脉粥样硬化方面具有潜在作用；然而，其潜在机制仍部分未明。在本研究中，我们调查了TZ是否能预防喂食高胆固醇饮食的载脂蛋白E（ApoE）小鼠的动脉粥样硬化，并旨在阐明其中涉及的机制。我们的结果表明，TZ显著减小了斑块大小、降低了EC衰老、血管通透性和活性氧（ROS）水平，有效地抑制了动脉粥样硬化，且独立于α1-AR信号传导。在原代培养的人脐静脉内皮细胞（HUVECs）中，TZ通过磷酸甘油酸激酶1（Pgk1）/热休克蛋白90（Hsp90）途径抑制EC衰老。它增强了Hsp90与抗氧化酶过氧化物还原酶1（Prdx1）之间的相互作用，导致较低的ROS水平——细胞衰老的关键驱动因素。这些发现在动脉粥样硬化的ApoE小鼠中得到了证实。此外，衰老的ECs表现出血管内皮生长因子A（VEGFA）水平升高和血管抑素水平降低，导致更高的血管通透性并加剧动脉粥样硬化。TZ有效地逆转了这些变化。总体而言，我们的研究表明，TZ主要通过Pgk1/Hsp90/Prdx1途径减轻EC衰老和动脉粥样硬化，突出了激活Pgk1作为一种策略，在更广泛的心脏代谢背景（如糖尿病）中也可能减轻内皮功能障碍和氧化应激，这表明TZ是一种有前景的衰老调节药物，可用于临床治疗血管衰老和动脉粥样硬化，且靶向Pgk1的干预措施可能具有超出动脉粥样硬化的意义。
