Cardioprotective factors against myocardial infarction selected in vivo from an AAV secretome library

心肌梗塞 心肌保护 体内 心力衰竭 医学 心功能曲线 生物 癌症研究 心脏病学 生物信息学 生物技术
作者
Giulia Ruozi,Francesca Bortolotti,Antonio Mura,Mateusz Tomczyk,Antonella Falcione,Valentina Martinelli,Simone Vodret,Luca Braga,Matteo Dal Ferro,Antonio Cannatà,Lorena Zentilin,Gianfranco Sinagra,Serena Zacchigna,Mauro Giacca
出处
期刊:Science Translational Medicine [American Association for the Advancement of Science]
卷期号:14 (660) 被引量:35
标识
DOI:10.1126/scitranslmed.abo0699
摘要

Therapies for patients with myocardial infarction and heart failure are urgently needed, in light of the breadth of these conditions and lack of curative treatments. To systematically identify previously unidentified cardioactive biologicals in an unbiased manner in vivo, we developed cardiac FunSel, a method for the systematic, functional selection of effective factors using a library of 1198 barcoded adeno-associated virus (AAV) vectors encoding for the mouse secretome. By pooled vector injection into the heart, this library was screened to functionally select for factors that confer cardioprotection against myocardial infarction. After two rounds of iterative selection in mice, cardiac FunSel identified three proteins [chordin-like 1 (Chrdl1), family with sequence similarity 3 member C (Fam3c), and Fam3b] that preserve cardiomyocyte viability, sustain cardiac function, and prevent pathological remodeling. In particular, Chrdl1 exerted its protective activity by binding and inhibiting extracellular bone morphogenetic protein 4 (BMP4), which resulted in protection against cardiomyocyte death and induction of autophagy in cardiomyocytes after myocardial infarction. Chrdl1 also inhibited fibrosis and maladaptive cardiac remodeling by binding transforming growth factor–β (TGF-β) and preventing cardiac fibroblast differentiation into myofibroblasts. Production of secreted and circulating Chrdl1, Fam3c, and Fam3b from the liver also protected the heart from myocardial infarction, thus supporting the use of the three proteins as recombinant factors. Together, these findings disclose a powerful method for the in vivo, unbiased selection of tissue-protective factors and describe potential cardiac therapeutics.
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