LncRNA JPX targets SERCA2a to mitigate myocardial ischemia/reperfusion injury by binding to EZH2

Area of Science:

• Cardiovascular Biology
• Epigenetics
• Molecular Medicine

Background:

• Long non-coding RNAs (lncRNAs) play critical roles in cardiovascular diseases, including myocardial ischemia/reperfusion (I/R) injury.
• LncRNA just proximal to XIST (JPX) and Enhancer of zeste homolog 2 (EZH2) are implicated in cellular regulation.
• Understanding the interplay between JPX, EZH2, and cardiac function is crucial for developing novel therapeutic strategies.

Purpose of the Study:

• To investigate the mechanism by which JPX regulates Sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a (SERCA2a) expression.
• To explore the role of JPX in preventing cardiomyocyte I/R damage in vivo and in vitro.
• To determine if JPX can serve as a therapeutic target for I/R injury.

Main Methods:

• Construction of mouse myocardial I/R and HL1 cell hypoxia/reoxygenation models.
• Assessment of JPX expression levels and its impact on cardiomyocyte apoptosis and cardiac function.
• Fluorescence in situ hybridization (FISH), RNA immunoprecipitation (RIP), and chromatin immunoprecipitation (ChIP) assays to elucidate molecular interactions.

Main Results:

• JPX expression was significantly downregulated in myocardial I/R and hypoxia/reoxygenation models.
• Overexpression of JPX alleviated cardiomyocyte apoptosis, reduced infarct size, lowered serum cTnI, and improved cardiac systolic function.
• JPX directly binds to EZH2, reducing EZH2 enrichment and H3K27me3 levels at the SERCA2a promoter, thereby increasing SERCA2a expression.

Conclusions:

• LncRNA JPX directly binds to EZH2, inhibiting EZH2-mediated repression of SERCA2a.
• JPX protects the heart against acute myocardial I/R injury by modulating the EZH2/SERCA2a axis.
• JPX represents a promising therapeutic target for mitigating I/R-induced cardiac damage.