Therapeutic impact of follistatin-like 1 on myocardial ischemic injury in preclinical models
Open accessAbstract
BACKGROUND: Acute coronary syndrome is a leading cause of death in developed countries. Follistatin-like 1 (FSTL1) is a myocyte-derived secreted protein that is upregulated in the heart in response to ischemic insult. Here, we investigated the therapeutic impact of FSTL1 on acute cardiac injury in small and large preclinical animal models of ischemia/reperfusion and dissected its molecular mechanism. METHODS AND RESULTS: Administration of human FSTL1 protein significantly attenuated myocardial infarct size in a mouse or pig model of ischemia/reperfusion, which was associated with a reduction of apoptosis and inflammatory responses in the ischemic heart. Administration of FSTL1 enhanced the phosphorylation of AMP-activated protein kinase in the ischemia/reperfusion-injured heart. In cultured cardiac myocytes, FSTL1 suppressed apoptosis in response to hypoxia/reoxygenation and lipopolysaccharide-stimulated expression of proinflammatory genes through its ability to activate AMP-activated protein kinase. Ischemia/reperfusion led to enhancement of bone morphogenetic protein-4 expression and Smad1/5/8 phosphorylation in the heart, and FSTL1 suppressed the increased phosphorylation of Smad1/5/8 in ischemic myocardium. Treating cardiac myocytes with FSTL1 abolished the bone morphogenetic protein-4-stimulated increase in apoptosis, Smad1/5/8 phosphorylation, and proinflammatory gene expression. In cultured macrophages, FSTL1 diminished lipopolysaccharide-stimulated expression of proinflammatory genes via activation of AMP-activated protein kinase and abolished bone morphogenetic protein-4-dependent induction of proinflammatory mediators. CONCLUSIONS: Our data indicate that FSTL1 can prevent myocardial ischemia/reperfusion injury by inhibiting apoptosis and inflammatory response through modulation of AMP-activated protein kinase- and bone morphogenetic protein-4-dependent mechanisms, suggesting that FSTL1 could represent a novel therapeutic target for post-myocardial infarction, acute coronary syndrome.
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Circulating levels of FSTL1 may work as a biomarker.
“Circulating levels of FSTL1 may work as a biomarker as high concentrations of FSTL1 are seen in patients with systolic and diastolic heart failure (196, 197), and as FSTL1 levels exhibit prognostic significance in the acute coronary syndrome (198).”
From Muscle–Organ Crosstalk: The Emerging Roles of Myokines (2020) · cites this paper as [198]
FSTL1 levels exhibit prognostic significance in acute coronary syndrome.
“FSTL1 levels exhibit prognostic significance in the acute coronary syndrome (198).”
From Muscle–Organ Crosstalk: The Emerging Roles of Myokines (2020) · cites this paper as [198]
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Muscle–Organ Crosstalk: The Emerging Roles of Myokines
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“Circulating levels of FSTL1 may work as a biomarker as high concentrations of FSTL1 are seen in patients with systolic and diastolic heart failure (196, 197), and as FSTL1 levels exhibit prognostic significance in the acute coronary syndrome (198).”
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- Authors
- Ogura, Y., Ouchi, N., Ohashi, K., Shibata, R., Kataoka, Y., Kambara, T., Kito, T., Maruyama, S., Yuasa, D., Matsuo, K., Enomoto, T., Uemura, Y., Miyabe, M., Ishii, M., Yamamoto, T., Shimizu, Y., Walsh, K., & Murohara, T.
- Affiliations
- Boston University (US)
- ORCID
- Venue
- Circulation
- Published
- 2012-10-02
- Volume
- 126
- Issue
- 14
- Pages
- 1728-1738
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- PMC
- PMC3548325
- OpenAlex
- W2146670463
- Cited by
- 183
- References
- 45
- Citations by year
- 2026: 8 · 2025: 13 · 2024: 12 · 2023: 12 · 2022: 12 · 2021: 10 · 2020: 20 · 2019: 15 · 2018: 11 · 2017: 17 · 2016: 15 · 2015: 16 · 2014: 14 · 2013: 7 · 2012: 1
- FWCI
- 8.77
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Boston Scientific Japan
- Japan Society for the Promotion of Science (24659384, 23390207)
- National Institute on Aging (R37AG015052, R01AG034972)
- National Heart, Lung, and Blood Institute (R01HL116591, P01HL081587, P01HL068758)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Acute Myocardial Infarction Research
- Keywords
- FSTL1, myocardial ischemia-reperfusion injury, acute coronary syndrome, myocardial infarction, AMPK, BMP4, Smad1/5/8 signaling, apoptosis, inflammation, macrophages, cardiomyocytes, hypoxia/reoxygenation, lipopolysaccharide, therapeutic target
- MeSH terms
- Animals, Cells, Cultured, Disease Models, Animal, Humans, Infusions, Intravenous, Mice, Inbred C57BL, Swine, Treatment Outcome, Myocardial Ischemia, Apoptosis, Follistatin-Related Proteins, Mice
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