MITF Regulates CFTR Expression to Participate in Myocardial Ischemia-Reperfusion Injury

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Gene Regulation

Background:

• Myocardial ischemia-reperfusion injury (MIRI) is a significant clinical challenge with incompletely understood regulatory mechanisms.
• Identifying key molecular targets and their functions is crucial for understanding and treating MIRI.

Purpose of the Study:

• To identify key genes involved in MIRI.
• To elucidate the regulatory role of microphthalmia-associated transcription factor (MITF) and cystic fibrosis transmembrane conductance regulator (CFTR) in MIRI.

Main Methods:

• Bioinformatic analysis of GEO datasets (GSE6381, GSE249812, GSE123342) to identify core MIRI-related genes.
• In vitro studies using oxygen-glucose deprivation/reoxygenation (OGD/OGR) models in AC16 cells to assess cell viability, apoptosis, and nitric oxide pathways.
• In vivo studies using a rat ischemia-reperfusion (I/R) model to evaluate cardiac function and injury markers.
• Investigation of the MITF-CFTR interaction using dual-luciferase and ChIP-qPCR assays.

Main Results:

• 42 core MIRI-related genes were identified, with CFTR consistently upregulated and linked to arginine biosynthesis.
• MITF was identified as a key transcription factor regulating CFTR expression in MIRI.
• In vitro and in vivo experiments demonstrated that MITF and CFTR play protective roles, with MITF knockdown or CFTR silencing exacerbating cardiac injury, while CFTR overexpression partially rescued damage.

Conclusions:

• The MITF-CFTR axis is a critical regulatory pathway in MIRI.
• Disruption of the MITF-CFTR interaction leads to aggravated cardiac injury.
• Targeting the MITF-CFTR pathway, particularly by restoring CFTR, holds therapeutic potential for MIRI.