Role of Sestrin2 in endoplasmic reticulum homeostasis and cardiac protection during ischemia/reperfusion injury
Description: Ischemic heart disease is a leading cause of death in the U.S. Despite increasing use and success of interventional coronary reperfusion, morbidity and mortality are still substantial and reperfusion injury itself is a major contributor to postoperative myocardial dysfunction. Intracellular calcium overload and excess free radicals, two important factors in ischemia reperfusion (I/R) injury, can exacerbate endoplasmic reticulum (ER) stress and mitochondrial dysfunction. The cellular adaptive responses to I/R, including unfolded protein response (UPR), may modulate these changes and attenuate cardiac injury. However, these cardiac adaptive responses are impaired in aging patients although the mechanisms involved remain unclear. Our preliminary data indicate that Sestrin2 (Sesn2), a stress-inducible protein, is downregulated in aging hearts and that Sesn2 deficiency in cardiomyocytes caused more severe cardiac dysfunction and larger myocardial infarction after I/R. Additionally, cardiac specific Sesn2 deficiency resulted in impaired calcium transients and excessive superoxide in cardiomyocytes after I/R. Therefore, we hypothesize that Sesn2 serves as an endogenous protective feedback mechanism in cardiomyocytes that attenuates ER stress and oxidative stress and protects against cardiac dysfunction after I/R. In Aim1, we will assess if Sesn2 deficiency in cardiomyocytes causes overactive and prolonged UPR and excessive reactive oxygen species (ROS) production in mitochondria during I/R. Since Sesn2 can regulate activity of AMP-activated protein kinase (AMPK) and the mammalian target of rapamycin complex 1 (mTORC1), in Aim2 we will determine whether Sesn2 attenuates ER stress and oxidative stress through AMPK/mTORC1 pathway. Also, we will determine whether restoration of Sesn2 in aging hearts can attenuate I/R injury. The innovation and significance of this proposal are 1) we will determine the role of Sesn2 as a key endogenous factor that protects cardiomyocytes against I/R injury, and 2) we will test a novel therapeutic strategy for I/R injury in aging hearts. The outcomes from this study will provide the foundation for developing a Sesn2 mimetic compound to improve cardiac adaptive responses and reduce I/R injury in older patients who have marked increases in morbidity and mortality after myocardial infarction, even after successful coronary reperfusion.
Funder: American Heart Association
Amount: $149,100
Funding type: fellowship
Funder scheme: Postdoctoral Fellowship
Start date: 2022-01-01
End date: 2023-12-31
Investigators: Xuan Li, Xuan Li
Institution: University of Mississippi Medical Center
Funded outputs count: 3
Funder award ID: 908950
OpenAlex ID: G7479218541