心力衰竭
心脏纤维化
纤维化
医学
压力过载
心脏病学
内科学
生物
心肌肥大
作者
Bingqiu Chen,Bozhong Shi,Zijie Zhou,Yue Cui,Guowei Zeng,Lu Cheng,Xiaoyang Zhang,Kai Luo,Cong Liu,Zhenan Zhu,Zhifang Zhang,Jinghao Zheng,Xiaoxiao He
标识
DOI:10.1016/j.trsl.2024.01.003
摘要
Cardiac fibrosis under chronic pressure overload is an end-stage adverse remodeling of heart. However, current heart failure treatments barely focus on anti-fibrosis and the effects are limited. We aimed to seek for a cardiac abundant and cardiac fibrosis specific piRNA, exploring its underlying mechanism and therapeutic potential. Whole transcriptome sequencing and the following verification experiments identified a highly upregulated piRNA (piRNA-000691) in transverse aortic constriction (TAC) mice, TAC pig, and heart failure human samples, which was abundant in heart and specifically expressed in cardiac fibroblasts. CFRPi was gradually increased along with the progression of heart failure, which was illustrated to promote cardiac fibrosis by gain- and loss-of-function experiments in vitro and in vivo. Knockdown of CFRPi in mice alleviated cardiac fibrosis, reversed decline of systolic and diastolic functions from TAC 6 weeks to 8 weeks. Mechanistically, CFRPi inhibited APLN, a protective peptide that increased in early response and became exhausted at late stage. Knockdown of APLN in vitro notably aggravated cardiac fibroblasts activation and proliferation. In vitro and in vivo evidence both indicated Pi3k-AKT-mTOR as the downstream effector pathway of CFRPi-APLN interaction. Collectively, we here identified CFPPi as a heart abundant and cardiac fibrosis specific piRNA. Targeting CFRPi resulted in a sustainable increase of APLN and showed promising therapeutical prospect to alleviate fibrosis, rescue late-stage cardiac dysfunction, and prevent heart failure.
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