Ji Deng-Ren, Chang Rui, Liu Shi-Meng, Zhang Ya-Rong, Zhao Jie, Yu Yan-Rong, Jia Mo-Zhi, Wu Ning, Tang Hui-Fang, Tang Chao-Shu, Zhou Ye-Bo, Qi Yong-Fen
Laboratory of Cardiovascular Bioactive Molecule, School of Basic Medical Sciences, Peking University, Beijing 100083, China; State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100083, China; Department of Pathogen Biology, School of Basic Medical Sciences, Peking University, Beijing 100083, China.
Department of Physiology, Nanjing Medical University, Nanjing 211166, Jiangsu, China.
J Mol Cell Cardiol. 2025 Aug;205:86-98. doi: 10.1016/j.yjmcc.2025.06.011. Epub 2025 Jun 30.
The aging-associated cardiac remodeling (AACR) is characterized by myocardial hypertrophy, fibrosis and cardiac dysfunction, which could be further aggravated by angiotensin II (Ang II) and pressure-overload in aged people. In this study, we aimed to investigate the roles and mechanisms of intermedin (IMD), an endogenous peptide, in AACR in aged mice (18 months) with subcutaneous Ang II infusion (1000 ng/kg/min) for 2 weeks via osmotic pump or transverse abdominal aorta constriction (AAC) surgery for 4 weeks. In aged mice undergoing Ang II infusion or AAC surgery, the results showed that the mRNA and protein levels of IMD were significantly reduced, but the protein levels of its receptor complex components were increased; blood pressure (BP), myocardial hypertrophy, fibrosis, and cardiac dysfunction were notably aggravated; mitochondrial Sirtuin 3 (SIRT3) protein level, superoxide dismutase 2 (SOD2) activity and ATP production were remarkably decreased, but acetylated SOD2 (acSOD2) protein level was markedly increased when compared with the old mice. The above alterations could be effectively alleviated by the subcutaneous IMD administration (5 ng/kg/min) for 2 or 4 weeks. In Ang II-stimulated cardiomyocytes, IMD treatment improved Ang II-induced mitochondrial dysfunction and oxidative distress, up-regulated SIRT3 protein expression, and reduced acSOD2 protein level, which were notably weakened by SIRT3 knockdown. Moreover, SIRT3 deletion attenuated the protective effects of IMD on myocardial hypertrophy, fibrosis, and cardiac dysfunction in aged mice undergoing Ang II infusion. In addition, the effect of IMD on up-regulating SIRT3 expression was effectively inhibited by the antagonism of IMD receptor or blocking PI3K/Akt, cAMP/PKA and AMPK signaling pathways in vitro. Taken together, IMD alleviated AACR and cardiac dysfunction aggravated by Ang II or pressure-overload involving the improvement of mitochondrial oxidative distress through SIRT3-medaiated SOD2 deacetylation.
衰老相关的心脏重塑（AACR）的特征是心肌肥大、纤维化和心脏功能障碍，在老年人中，血管紧张素II（Ang II）和压力超负荷会进一步加重这些症状。在本研究中，我们旨在研究内介素（IMD）这一内源性肽在18月龄老年小鼠AACR中的作用及机制。这些老年小鼠通过渗透泵皮下输注Ang II（1000 ng/kg/分钟）持续2周，或通过横断腹主动脉缩窄（AAC）手术持续4周。在接受Ang II输注或AAC手术的老年小鼠中，结果显示IMD的mRNA和蛋白水平显著降低，但其受体复合物成分的蛋白水平升高；血压（BP）、心肌肥大、纤维化和心脏功能障碍明显加重；线粒体沉默调节蛋白3（SIRT3）蛋白水平、超氧化物歧化酶2（SOD2）活性和ATP生成显著降低，但与老年小鼠相比，乙酰化SOD2（acSOD2）蛋白水平显著升高。皮下给予IMD（5 ng/kg/分钟）2周或4周可有效缓解上述改变。在Ang II刺激的心肌细胞中，IMD处理改善了Ang II诱导的线粒体功能障碍和氧化应激，上调了SIRT3蛋白表达，并降低了acSOD2蛋白水平，而SIRT3基因敲低显著削弱了这些作用。此外，SIRT3基因缺失减弱了IMD对接受Ang II输注的老年小鼠心肌肥大、纤维化和心脏功能障碍的保护作用。此外，在体外，IMD受体拮抗剂或阻断PI3K/Akt、cAMP/PKA和AMPK信号通路可有效抑制IMD上调SIRT3表达的作用。综上所述，IMD通过SIRT3介导的SOD2去乙酰化改善线粒体氧化应激，从而减轻了由Ang II或压力超负荷加重的AACR和心脏功能障碍。
