• Transl Res · May 2024

    Targeting a cardiac abundant and fibroblasts-specific piRNA (CFRPi) to attenuate and reverse cardiac fibrosis in pressure-overloaded heart failure.

    • Bo Chen, Bozhong Shi, Zijie Zhou, Yue Cui, Guowei Zeng, Lingyan Cheng, Xiaoyang Zhang, Kai Luo, Cong Li, Zhongqun Zhu, Zhifang Zhang, Jinghao Zheng, and Xiaomin He.
    • Department of Cardiothoracic Surgery, Shanghai Children's Medical Center, National Children's Medical Center, Shanghai Jiaotong University School of Medicine; 1678 Dongfang Road, Shanghai 200127, China.
    • Transl Res. 2024 May 1; 267: 102410-24.

    AbstractCardiac 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.Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.

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