A defective mechanosensing pathway affects fibroblast-to-myofibroblast transition in the old male mouse heart

Aude Angelini, Jo Ann Trial, Alexander B. Saltzman, Anna Malovannaya, Katarzyna A. Cieslik

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish (US)
Article number107283
JournaliScience
Volume26
Issue number8
DOIs
StatePublished - Aug 18 2023

Keywords

  • Cardiovascular medicine
  • Molecular microbiology
  • Pathophysiology

ASJC Scopus subject areas

  • General

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