cFLIP_L Alleviates Myocardial Ischemia-Reperfusion Injury by Inhibiting Endoplasmic Reticulum Stress

Area of Science:

• Cardiovascular Biology
• Cellular Stress Response
• Molecular Medicine

Background:

• Endoplasmic reticulum stress (ERS) is a key factor in myocardial ischemia-reperfusion injury (MIRI).
• Cellular FLICE-inhibitory protein (cFLIP) regulates apoptosis and ERS.
• The long isoform of cFLIP (cFLIP_L) role in MIRI is not fully understood.

Purpose of the Study:

• To investigate the effect of cFLIP_L on apoptosis and ERS in MIRI.
• To elucidate the underlying molecular mechanisms of cFLIP_L in MIRI.

Main Methods:

• Established MIRI models in Sprague-Dawley rats and H9c2 cells using ischemia/reperfusion (I/R) and hypoxia/reoxygenation (H/R) protocols.
• Utilized cFLIP_L recombinant adenovirus for overexpression in vivo and in vitro.
• Assessed cardiomyocyte viability, apoptosis, ERS markers (GRP78, IRE-1, PERK), and p38 MAPK activation via coimmunoprecipitation.

Main Results:

• cFLIP_L expression was decreased in I/R and H/R injury models.
• Overexpression of cFLIP_L reduced myocardial infarction and enhanced H9c2 cell viability.
• cFLIP_L overexpression inhibited ERS and apoptosis, an effect reversed by an ERS agonist.
• cFLIP_L attenuated ERS by inhibiting p38 MAPK activation.

Conclusions:

• cFLIP_L expression is downregulated in MIRI, correlating with increased ERS and apoptosis.
• Upregulating cFLIP_L mitigates MIRI by suppressing ERS and myocardial apoptosis.
• The protective mechanism involves the inhibition of p38 MAPK activity.
• cFLIP_L represents a potential therapeutic target for MIRI.