The AP-1 transcription factor c-Jun prevents stress-imposed maladaptive remodeling of the heart

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Transcriptional Regulation

Background:

• Systemic hypertension elevates cardiac workload, triggering signaling pathways for myocyte growth (hypertrophic response) to enhance contractility.
• Both adaptive and maladaptive cardiac growth can occur under increased workload conditions.
• Previous research identified AP-1 transcription factors junD and fra-1 in regulating cardiac hypertrophy.

Purpose of the Study:

• To investigate the specific roles of AP-1 transcription factors c-jun and c-fos in cardiac growth during pressure overload-induced hypertrophy.
• To determine if c-jun and c-fos are necessary for adaptive cardiac hypertrophy.

Main Methods:

• Utilized a mouse model of pressure overload-induced cardiac hypertrophy.
• Employed targeted deletion of Jun or Fos genes specifically in cardiomyocytes.
• Analyzed gene expression, sarcomere organization, cytoskeletal structure, fibrosis, and myocyte apoptosis.

Main Results:

• C-jun deficiency resulted in maladaptive hypertrophy, characterized by sarcomere disarray, actin cytoskeleton disorganization, pronounced cardiac fibrosis, and increased myocyte apoptosis.
• Jun-deficient hearts progressed to dilated cardiomyopathy following pressure overload.
• C-fos was found to be dispensable for adaptive cardiac hypertrophy in this model.

Conclusions:

• C-jun is critically required for adaptive cardiac hypertrophy, orchestrating a transcriptional program that supports sarcomere protein expression and suppresses extracellular matrix deposition.
• C-jun actively promotes sarcomere organization and maintains cytoskeletal integrity.
• C-fos does not contribute to the adaptive hypertrophic response to increased cardiac workload.