JMJD2A mediates transcriptional activation of SFRP4 and regulates oxidative stress and mitochondrial dysfunction in heart failure

Area of Science:

• Cardiovascular Biology
• Mitochondrial Medicine
• Molecular Cardiology

Background:

• Mitochondrial dysfunction and oxidative stress are critical in heart failure (HF) progression.
• The precise molecular mechanisms driving these events in HF require further elucidation.
• Secreted frizzled-related protein 4 (SFRP4) is implicated, but its specific role remains unclear.

Purpose of the Study:

• To investigate the role of SFRP4 in mitochondrial dysfunction and oxidative stress during HF.
• To elucidate the underlying molecular mechanisms involving SFRP4 in HF pathogenesis.
• To explore potential therapeutic targets by examining the SFRP4 pathway.

Main Methods:

• Induction of HF in mice via transverse aortic constriction.
• Histopathological analysis (H&E, Masson's trichrome) and TUNEL assays for myocardial damage.
• In vitro studies using HL-1 cardiomyocytes treated with isoproterenol (ISO).
• Assessment of cell viability (CCK-8) and apoptosis (TUNEL assays).
• Analysis of SFRP4 and JMJD2A expression levels.

Main Results:

• SFRP4 and JMJD2A were upregulated in HF myocardial tissues.
• SFRP4 suppression attenuated myocardial apoptosis and fibrosis in HF mice.
• Inhibition of SFRP4 reduced mitochondrial dysfunction and oxidative stress in both mouse models and cardiomyocytes.
• JMJD2A was found to catalyze demethylation of the SFRP4 promoter, enhancing its transcription in HF.

Conclusions:

• SFRP4 plays a significant role in promoting mitochondrial dysfunction and oxidative stress in HF.
• JMJD2A directly promotes SFRP4 transcription, contributing to HF development.
• Targeting JMJD2A or SFRP4 presents a promising therapeutic avenue for managing HF progression.