Fibrotic
remodeling is an adverse consequence of
immune response-driven phenotypic modulation of cardiac
cells following
myocardial infarction (MI).
MicroRNA-146b (miR-146b) is an active regulator of
immunomodulation, but its function in the cardiac inflammatory cascade and its clinical implication in fibrotic
remodeling following MI remain largely unknown. Herein, miR-146b-5p was found to be upregulated in the infarcted
myocardium of
mice and the
serum of
myocardial ischemia patients. Gain- and loss-of-function experiments demonstrated that miR-146b-5p was a
hypoxia-induced regulator that governed the pro-fibrotic
phenotype transition of cardiac
cells. Overexpression of miR-146b-5p activated
fibroblast proliferation, migration, and
fibroblast-to-
myofibroblast transition, impaired
endothelial cell function and stress
survival, and disturbed
macrophage paracrine signaling. Interestingly, the opposite effects were observed when miR-146b-5p expression was inhibited.
Luciferase assays and rescue studies demonstrated that the miR-146b-5p target
genes mediating the above phenotypic modulations included
interleukin 1 receptor associated kinase 1 (IRAK1) and
carcinoembryonic antigen related cell adhesion molecule 1 (
CEACAM1). Local delivery of a miR-146b-5p
antagomir significantly reduced
fibrosis and
cell death, and upregulated
capillary and reparative
macrophages in the infarcted
myocardium to restore cardiac
remodeling and function in both
mouse and porcine MI models. Local inhibition of miR-146b-5p may represent a novel
therapeutic approach to treat cardiac fibrotic
remodeling and dysfunction following MI.