Heart Center and Beijing Key Laboratory of Hypertension, Beijing Institute of Respiratory Medicine and Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China.
Department of Cardiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China.
Apoptosis. 2024 Dec;29(11-12):2161-2182. doi: 10.1007/s10495-024-02021-9. Epub 2024 Oct 11.
Myocardial fibrosis is a typical pathological manifestation of hypertension. However, the exact role of sirtuin 7 (SIRT7) in myocardial remodeling remains largely unclear. Here, spontaneously hypertensive rats (SHRs) and angiotensin (Ang) II-induced hypertensive mice were pretreated with recombinant adeno-associated virus (rAAV)-SIRT7, copper chelator tetrathiomolybdate (TTM) or copper ionophore elesclomol, respectively. Compared with normotensive controls, reduced SIRT7 expression and augmented cuproptosis were observed in hearts of hypertensive rats and mice with decreased FDX1 levels and increased HSP70 levels. Notably, intervention with rAAV-SIRT7 and TTM strikingly prevented DLAT oligomers aggregation, and elevated ATP7A and TOM20 expressions, contributing to the alleviation of cuproptosis, mitochondrial injury, myocardial remodeling and heart dysfunction in spontaneously hypertensive rats and Ang II-induced hypertensive mice. In cultured rat primary cardiac fibroblasts (CFs), rhSIRT7 alleviated CuCl, Ang II or elesclomol-induced cuproptosis and fibroblast activation by blunting DLAT oligomers accumulation and downregulating α-SMA expression. Additionally, conditioned medium from rhSIRT7-pretreated CFs remarkably mitigated cellular hypertrophy and mitochondrial impairments of neonatal rat cardiomyocytes, as well as cell migration and polarization of RAW 264.7 macrophages. Importantly, verteporfin reduced CuCl-induced cuproptosis, mitochondrial injury and fibrotic activation in CFs. Knockdown of ATP7A with si-ATP7A blocked cellular protective effects of rhSIRT7 and verteporfin in CFs. In conclusion, SIRT7 attenuates cuproptosis, myocardial fibrosis and heart dysfunction in hypertension through the modulation of YAP/ATP7A signaling. Targeting SIRT7 is of vital importance for developing therapeutic strategies in hypertension and hypertensive heart disorders.
心肌纤维化是高血压的一种典型病理表现。然而，SIRT7（沉默信息调节因子 7）在心肌重构中的确切作用在很大程度上仍不清楚。在这里，自发性高血压大鼠（SHR）和血管紧张素（Ang）II 诱导的高血压小鼠分别用重组腺相关病毒（rAAV）-SIRT7、铜螯合剂四硫钼酸盐（TTM）或铜离子载体 elesclomol 预处理。与正常血压对照组相比，高血压大鼠和小鼠的 SIRT7 表达降低，FDX1 水平降低，HSP70 水平升高，观察到 cuproptosis 增加。值得注意的是，rAAV-SIRT7 和 TTM 的干预显著阻止了 DLAT 低聚物的聚集，并提高了 ATP7A 和 TOM20 的表达，有助于缓解自发性高血压大鼠和 Ang II 诱导的高血压小鼠的 cuproptosis、线粒体损伤、心肌重构和心功能障碍。在培养的大鼠原代心肌成纤维细胞（CFs）中，rhSIRT7 通过抑制 DLAT 低聚物的积累和下调α-SMA 的表达，减轻 CuCl、Ang II 或 elesclomol 诱导的 cuproptosis 和成纤维细胞激活。此外，rhSIRT7 预处理的 CFs 的条件培养基显著减轻了新生大鼠心肌细胞的细胞肥大和线粒体损伤，以及 RAW 264.7 巨噬细胞的细胞迁移和极化。重要的是，verteporfin 减少了 CuCl 诱导的 CFs 中的 cuproptosis、线粒体损伤和纤维化激活。用 si-ATP7A 敲低 ATP7A 阻断了 rhSIRT7 和 verteporfin 在 CFs 中的细胞保护作用。总之，SIRT7 通过调节 YAP/ATP7A 信号减轻高血压中的 cuproptosis、心肌纤维化和心功能障碍。靶向 SIRT7 对于开发高血压和高血压性心脏疾病的治疗策略至关重要。
