Chronic infusion of ELABELA alleviates vascular remodeling in spontaneously hypertensive rats via anti-inflammatory, anti-oxidative and anti-proliferative effects
Chronic infusion of ELABELA alleviates vascular remodeling in spontaneously hypertensive rats via anti-inflammatory, anti-oxidative and anti-proliferative effects
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DOI：
10.1038/s41401-022-00875-w
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发表时间：
2022-03
影响因子：
8.2
通讯作者：
Chao Ye;Zhi Geng;Ling-li Zhang;Fen Zheng;Ye-Bo Zhou;G. Zhu;Xiao-Qing Xiong
中科院分区：
文献类型：
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作者：
Chao Ye;Zhi Geng;Ling-li Zhang;Fen Zheng;Ye-Bo Zhou;G. Zhu;Xiao-Qing Xiong
炎症激活和氧化应激促进血管平滑肌细胞（VSMCs）的增殖，这是高血压病理性血管重构的原因。ELABELA（ELA）是迄今为止发现的第二种血管紧张素受体样1（APJ）受体的内源性配体。在这项研究中，我们调查是否ELA调节VSMC增殖和血管重塑在自发性高血压大鼠（SHR）。我们发现，与Wistar-Kyoto大鼠（WKYs）相比，ELA在SHR VSMCs中的表达显著降低。外源性ELA-21显著抑制VSMC中炎性细胞因子和NADPH氧化酶1的表达、活性氧的产生和VSMC增殖，并增加核因子红细胞2相关因子（Nrf 2）的核转位。渗透压微泵输注外源性ELA-21 4周可显著降低SHR的舒张压，减轻血管重构，改善血管炎症和氧化应激。在WKY的VSMC中，血管紧张素II（Ang II）诱导的炎症激活，氧化应激和VSMC增殖减弱与外源性ELA-21预处理，但ELA敲低加剧。ELA-21可抑制SHR VSMCs和Ang Ⅱ处理的WKY VSMCs基质金属蛋白酶2和9的表达。我们进一步发现，外源性ELA-21诱导的增殖抑制和PI 3 K/Akt信号转导被PI 3 K/Akt抑制剂LY 294002放大，而APJ受体拮抗剂F13 A消除ELA-21诱导的VSMCs中PI 3 K/Akt抑制和Nrf 2激活。总之，我们证明ELA-21通过抗炎、抗氧化和抗增殖作用在SHR中促进血管重塑，表明ELA-21可能是治疗高血压的治疗剂。
Inflammatory activation and oxidative stress promote the proliferation of vascular smooth muscle cells (VSMCs), which accounts for pathological vascular remodeling in hypertension. ELABELA (ELA) is the second endogenous ligand for angiotensin receptor-like 1 (APJ) receptor that has been discovered thus far. In this study, we investigated whether ELA regulated VSMC proliferation and vascular remodeling in spontaneously hypertensive rats (SHRs). We showed that compared to that in Wistar-Kyoto rats (WKYs), ELA expression was markedly decreased in the VSMCs of SHRs. Exogenous ELA-21 significantly inhibited inflammatory cytokines and NADPH oxidase 1 expression, reactive oxygen species production and VSMC proliferation and increased the nuclear translocation of nuclear factor erythroid 2-related factor (Nrf2) in VSMCs. Osmotic minipump infusion of exogenous ELA-21 in SHRs for 4 weeks significantly decreased diastolic blood pressure, alleviated vascular remodeling and ameliorated vascular inflammation and oxidative stress in SHRs. In VSMCs of WKY, angiotensin II (Ang II)-induced inflammatory activation, oxidative stress and VSMC proliferation were attenuated by pretreatment with exogenous ELA-21 but were exacerbated by ELA knockdown. Moreover, ELA-21 inhibited the expression of matrix metalloproteinase 2 and 9 in both SHR-VSMCs and Ang II-treated WKY-VSMCs. We further revealed that exogenous ELA-21-induced inhibition of proliferation and PI3K/Akt signaling were amplified by the PI3K/Akt inhibitor LY294002, while the APJ receptor antagonist F13A abolished ELA-21-induced PI3K/Akt inhibition and Nrf2 activation in VSMCs. In conclusion, we demonstrate that ELA-21 alleviates vascular remodeling through anti-inflammatory, anti-oxidative and anti-proliferative effects in SHRs, indicating that ELA-21 may be a therapeutic agent for treating hypertension.