Faculty Collaboration Database

FasL expression in cardiomyocytes activates the ERK1/2 pathway, leading to dilated cardiomyopathy and advanced heart failure. Clin Sci (Lond) 2016 Feb;130(4):289-99

Date

11/15/2015

Pubmed ID

26566650

DOI

10.1042/CS20150624

Scopus ID

2-s2.0-84958092902 (requires institutional sign-in at Scopus site)   11 Citations

Abstract

Increase in the apoptotic molecule Fas ligand (FasL) in serum and cardiomyocytes has been shown to be associated with progressive dilated cardiomyopathy (DCM) and congestive heart failure (CHF) in humans. However, the underlying mechanism(s) of FasL-related deterioration of heart function remain obscure. The aim of the present study is to determine roles of myocardial FasL in the activation of alternative pathways such as extracellular-signal-regulated kinase 1/2 (ERK1/2), inflammation or fibrosis and to identify effective treatments of progressive DCM and advanced CHF. Transgenic mice with cardiomyocyte-specific overexpression of FasL were investigated and treated with an ERK1/2 inhibitor (U-0126), losartan (los), prednisolone (pred) or placebo. Morpho-histological and molecular studies were subsequently performed. FasL mice showed significantly higher mortality compared with wild-type (WT) littermates due to DCM and advanced CHF. Prominent perivascular and interstitial fibrosis, increased interleukin secretion and diffuse CD3-positive cell infiltration were evident in FasL hearts. Up-regulation of the short form of Fas-associated death domain (FADD)-like interleukin 1β-converting enzyme (FLICE) inhibitory protein (s-FLIP), RIP (receptor-interacting protein) and ERK1/2 and down-regulation of transforming growth factor beta 1 (TGFβ1) and nuclear factor-κB (NF-κB) was determined in the myocardium, whereas expression of ERK1/2, periostin (Postn) and osteopontin increased in cardiac fibroblasts. U-0126 and los increased CHF survival by 75% compared with pred and placebo groups. U-0126 had both anti-fibrotic and anti-apoptotic effects, whereas los reduced fibrosis only. Myocardial FasL expression in mice activates differential robust fibrotic, apoptotic and inflammatory responses via ERK1/2 in cardiomyocytes and cardiac fibroblasts inducing DCM and CHF. Blocking the ERK1/2 pathway prevented progression of FasL-induced DCM and CHF by reducing fibrosis, inflammation and apoptosis in the myocardium.

Author List

Huby AC, Turdi S, James J, Towbin JA, Purevjav E

MESH terms used to index this publication - Major topics in bold

Angiotensin II Type 1 Receptor Blockers
Animals
Anti-Inflammatory Agents
Apoptosis
Apoptosis Regulatory Proteins
Cardiomyopathy, Dilated
Cells, Cultured
Disease Progression
Enzyme Activation
Fas Ligand Protein
Fibroblasts
Fibrosis
Genetic Predisposition to Disease
Heart Failure
Inflammation Mediators
Male
Mice, Inbred C57BL
Mice, Transgenic
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
Myocytes, Cardiac
Phenotype
Protein Kinase Inhibitors
Signal Transduction
Time Factors