CTRP1 prevents sepsis-induced cardiomyopathy via Sirt1-dependent pathways
CTRP1 prevents sepsis-induced cardiomyopathy via Sirt1-dependent pathways
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CTRP1 通过 Sirt1 依赖性途径预防脓毒症诱发的心肌病
DOI：
10.1016/j.freeradbiomed.2020.01.178
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发表时间：
2020-05-20
影响因子：
7.4
通讯作者：
Lan, Linhui
中科院分区：
文献类型：
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作者：
Jiang, Wanli;Li, Wen;Lan, Linhui
C1 q/肿瘤坏死因子相关蛋白1（CTRP 1）最近被确定为心脏代谢疾病的关键调节因子。有报道称CTRP 1可以抑制小鼠的肥大反应。然而，CTRP 1对脓毒症诱导的心肌病的影响仍然完全未知。使用腺相关病毒系统在小鼠中实现心肌细胞特异性CTRP 1过表达。CTRP 1缺陷小鼠也进行脂多糖（LPS）注射。我们发现CTRP 1过表达改善了LPS处理小鼠的存活率和心功能，并抑制了心肌炎症，氧化损伤和凋亡，而不影响代谢紊乱。CTRP 1缺失进一步降低了脓毒症小鼠的存活率和心功能，并促进了心肌炎症、氧化损伤和细胞凋亡。此外，我们发现CTRP 1在体外提供了对LPS诱导的细胞损伤的保护。CTRP 1激活sirtuin 1（Sirt 1）信号通路，并且Sirt 1抑制或缺陷在体内和体外阻断CTRP 1介导的心脏保护作用。更重要的是，我们的研究发现，重组人CTRP 1球形结构域输注也能够阻断脓毒症诱导的小鼠心肌病。结论：CTRP 1通过激活Sirt 1信号通路，提高了大鼠的存活率，减轻了LPS诱导的心肌损伤。
C1q/tumor necrosis factor-related protein 1 (CTRP1) has recently been identified as a key regulator of cardio-metabolic diseases. It has been reported that CTRP1 could inhibit the hypertrophic response in mice. However, the effect of CTRP1 on sepsis-induced cardiomyopathy remains completely unknown. Cardiomyocyte-specific CTRP1 overexpression was achieved using an adeno associated virus system in mice. CTRP1 deficiency mice were also subjected to lipopolysaccharide (LPS) injection. We found that CTRP1 overexpression improved survival rate and cardiac function, and suppressed myocardial inflammation, oxidative damage and apoptosis without affecting metabolic disturbance in LPS-treated mice. CTRP1 depletion further decreased survival rate and cardiac function, and promoting myocardial inflammation, oxidative damage and apoptosis in sepsis mice. In addition, we showed that CTRP1 provided protection against LPS-induced cell injury in vitro. CTRP1 activated sirtuin 1 (Sirt1) signaling pathway, and Sirt1 inhibition or deficiency blocked CTRP1-mediated cardioprotective effects in vivo and in vitro. More importantly, our study found that recombinant human globular domain of CTRP1 infusion was also capable of blocking sepsis-induced cardiomyopathy in mice. In conclusion, CTRP1 improved survival rate and attenuated LPS-induced cardiac injury via activating Sirt1 signaling pathway.