A Defective Mechanosensing Pathway Affects Fibroblast-to-Myofibroblast Transition in the Old Male Mouse Heart

Authors

Aude Angelini
JoAnn Trial
Alexander B Saltzman
Anna Malovannaya
Katarzyna A Cieslik

Publication Date

8-18-2023

Journal

iScience

DOI

10.1016/j.isci.2023.107283

PMID

37520701

PMCID

PMC10372839

PubMedCentral® Posted Date

7-14-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Cardiovascular medicine, Pathophysiology, Molecular microbiology

Abstract

The cardiac fibroblast interacts with an extracellular matrix (ECM), enabling myofibroblast maturation via a process called mechanosensing. Although in the aging male heart, ECM is stiffer than in the young mouse, myofibroblast development is impaired, as demonstrated in 2-D and 3-D experiments. In old male cardiac fibroblasts, we found a decrease in actin polymerization, α-smooth muscle actin (α-SMA), and Kindlin-2 expressions, the latter an effector of the mechanosensing. When Kindlin-2 levels were manipulated via siRNA interference, young fibroblasts developed an old-like fibroblast phenotype, whereas Kindlin-2 overexpression in old fibroblasts reversed the defective phenotype. Finally, inhibition of overactivated extracellular regulated kinases 1 and 2 (ERK1/2) in the old male fibroblasts rescued actin polymerization and α-SMA expression. Pathological ERK1/2 overactivation was also attenuated by Kindlin-2 overexpression. In contrast, old female cardiac fibroblasts retained an operant mechanosensing pathway. In conclusion, we identified defective components of the Kindlin/ERK/actin/α-SMA mechanosensing axis in aged male fibroblasts.

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