Sestrin2 Attenuates Myocardial Endoplasmic Reticulum Stress and Cardiac Dysfunction During Ischemia/Reperfusion...

Area of Science:

• Cardiovascular Biology
• Cellular Stress Response
• Molecular Signaling

Background:

• Sestrin2 (Sesn2) is a stress-induced protein conferring protection against myocardial ischemia and reperfusion (I/R) injury.
• Endoplasmic reticulum (ER) stress is a key mediator in I/R injury pathogenesis.

Purpose of the Study:

• To investigate the role of Sesn2-mammalian target of rapamycin (mTOR) signaling in regulating ER stress during myocardial I/R.

Main Methods:

• Cardiac I/R was induced in wild-type (WT) and cardiac-specific Sesn2 knockout (Sesn2 KO) mice.
• Cardiac function, ER stress markers, and apoptosis were assessed post-I/R.
• Transmission electron microscopy evaluated ER lumen expansion.
• mTOR signaling was pharmacologically inhibited with rapamycin.

Main Results:

• I/R induced cardiac ER stress and upregulated Sesn2.
• Sesn2 KO hearts showed increased ER stress susceptibility and elevated mTOR signaling during I/R.
• ER lumen expansion and apoptosis were exacerbated in Sesn2-deficient hearts.
• Rapamycin treatment improved cardiac function and attenuated ER stress markers and apoptosis.

Conclusions:

• Sesn2 mitigates cardiac ER stress following I/R injury by modulating mTOR signaling.
• Targeting the Sesn2-mTOR pathway represents a potential strategy for maintaining cardiac ER homeostasis and protecting against I/R injury.