Cardioprotective factors against myocardial infarction selected in vivo from an AAV secretome library
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Updated: Aug 30, 2025
A Simple and Efficient Method for In Vivo Cardiac-specific Gene Manipulation by Intramyocardial Injection in Mice
Published on: April 16, 2018
Giulia Ruozi1, Francesca Bortolotti1,2, Antonio Mura1
1Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB), 34139 Trieste, Italy.
Insights
Researchers discovered novel cardioactive proteins, Chordin-like 1 (Chrdl1), Fam3c, and Fam3b, that protect the heart after myocardial infarction. These factors offer potential new therapies for heart disease.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Regenerative Medicine
Background:
- Myocardial infarction and heart failure remain leading causes of morbidity and mortality worldwide.
- Current therapeutic strategies offer limited efficacy and lack curative potential for these conditions.
- There is an urgent need for novel, effective treatments to improve cardiac function and patient outcomes.
Purpose of the Study:
- To systematically identify previously unknown cardioactive biological factors using an unbiased in vivo screening approach.
- To discover novel therapeutic targets for myocardial infarction and heart failure.
- To validate the cardioprotective effects of identified factors and elucidate their underlying mechanisms.
Main Methods:
- Development and application of cardiac FunSel, a functional selection method using a library of 1198 barcoded adeno-associated virus (AAV) vectors encoding the mouse secretome.
- Pooled AAV vector injection into the mouse heart for in vivo screening.
- Iterative selection rounds to identify factors conferring cardioprotection against myocardial infarction.
- Biochemical assays to investigate the interaction of identified proteins with signaling pathways like BMP4 and TGF-β.
Main Results:
- Cardiac FunSel identified three key cardioprotective proteins: chordin-like 1 (Chrdl1), family with sequence similarity 3 member C (Fam3c), and Fam3b.
- Chrdl1 demonstrated significant protection by inhibiting BMP4, preventing cardiomyocyte death, and inducing autophagy post-myocardial infarction.
- Chrdl1 also mitigated cardiac fibrosis and pathological remodeling by inhibiting TGF-β and preventing fibroblast differentiation.
- Systemic delivery of Chrdl1, Fam3c, and Fam3b from the liver conferred cardiac protection, supporting their use as recombinant therapeutics.
Conclusions:
- Cardiac FunSel is a powerful platform for unbiased, in vivo discovery of tissue-protective factors.
- Chrdl1, Fam3c, and Fam3b represent promising novel therapeutic candidates for myocardial infarction and heart failure.
- Understanding the mechanisms of these proteins provides new insights into cardiac repair and regeneration.
- These findings pave the way for developing innovative biological therapies for cardiovascular diseases.
Abstract:
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.
