Preclinical Research
Connective Tissue Growth Factor Inhibition Enhances Cardiac Repair and Limits Fibrosis After Myocardial Infarction

https://doi.org/10.1016/j.jacbts.2018.10.007Get rights and content
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Highlights

  • To study the role of CTGF in post-MI cardiac repair and LV remodeling, we antagonized the function of CTGF with a mAb.

  • Treatment of mice with CTGF mAb during post-MI cardiac repair improved survival and resulted in better preserved LV systolic function.

  • Treatment with CTGF mAb during post-MI LV remodeling reduced the heart weight to body weight ratio, LV mass, cardiomyocyte hypertrophy, and fibrosis in the remote nonischemic myocardium.

  • CTGF mAb treatment induced c-Jun N-terminal kinase phosphorylation in ischemic hearts in vivo and in cultured human cardiac fibroblasts.

  • In conclusion, treatment of mice with CTGF mAb in a model of MI enhances cardiac repair and reduces adverse post-MI LV remodeling.

Summary

Myocardial infarction (MI)−induced cardiac fibrosis attenuates cardiac contractile function, and predisposes to arrhythmias and sudden cardiac death. Expression of connective tissue growth factor (CTGF) is elevated in affected organs in virtually every fibrotic disorder and in the diseased human myocardium. Mice were subjected to treatment with a CTGF monoclonal antibody (mAb) during infarct repair, post-MI left ventricular (LV) remodeling, or acute ischemia−reperfusion injury. CTGF mAb therapy during infarct repair improved survival and reduced LV dysfunction, and reduced post-MI LV hypertrophy and fibrosis. Mechanistically, CTGF mAb therapy induced expression of cardiac developmental and/or repair genes and attenuated expression of inflammatory and/or fibrotic genes.

Key Words

connective tissue growth factor monoclonal antibody
fibrosis
heart failure
ischemia−reperfusion injury
left ventricle
myocardial infarction

Abbreviations and Acronyms

CTGF
connective tissue growth factor
ECM
extracellular matrix
ERK
extracellular signal-regulated kinase
FB
fibroblast
I/R
ischemia−reperfusion
HF
heart failure
Ig
immunoglobulin
JNK
c-Jun N-terminal kinase
LV
left ventricular
mAb
monoclonal antibody
MI
myocardial infarction
TGF
transforming growth factor

Cited by (0)

Drs. Vainio, Magga, and Kerkelä were supported by the Finnish Foundation for Cardiovascular Research. Dr. Vainio was supported by the Finnish Medical Foundation. Dr. Magga was supported by grant 268505 from the Academy of Finland. Dr. Kerkelä was supported by grants 131020 and 297094 from the Academy of Finland, by the Sigrid Juselius Foundation, and by the Jane and Aatos Erkko Foundation. Drs. Fouse, Seeley, Signore, and Lipson hold stock in FibroGen. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

All authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Basic to Translational Science author instructions page.