Yun Qiu1, Yichen Wu1, Min Meng1, Man Luo1, Hongmei Zhao1, Hong Sun1, Sumin Gao2. 1. Department of Emergency Medicine, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, Jiangsu Province, China. 2. Department of Emergency Medicine, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, Jiangsu Province, China. Electronic address: gao666332@sina.com.
Abstract
BACKGROUND: This study explores the protective effects of a hydrogen sulfide donor, morpholin-4-ium 4-methoxyphenyl-morpholino-phosphinodithioate (GYY4137), in the hearts of diabetic mice that had been subjected to myocardial ischemia/reperfusion injury. Diabetes impairs the Akt pathway, in which the Akt protein is dephosphorylated and inactivated by PH domain leucine-rich repeat protein phosphatase-1 (PHLPP-1). However, the function of PHLPP-1 and molecular mechanism that underlies the cardiac protection exerted by GYY4137 remains unknown. METHODS: Diabetic or nondiabetic mice were subjected to 45 min of coronary artery occlusion followed by 2 h of reperfusion. H9c2 cells were cultured with normal or high glucose and then subjected to 3 h of hypoxia followed by 6 h of reoxygenation. Pretreatment with GYY4137 was performed in a randomized manner before ischemia/reperfusion or hypoxia/reoxygenation. The infarct size, cardiomyocyte apoptosis, and oxidative stress were measured. Western blotting was conducted to elucidate the protective mechanism. RESULTS: Diabetic mice or H9c2 cells exposed to high glucose displayed a larger infarct size, more severe cardiomyocyte apoptosis, lower cell viability, and increased oxidative stress, which were associated with increased levels of PHLPP-1 and reduced levels of p-Akt and nuclear factor-erythroid-2-related factor 2 (Nrf2) protein expression. These changes were prevented/reversed by GYYG4137 pretreatment. At the cellular level, PHLPP-1 siRNA attenuated cellular injury, and this was associated with increased p-Akt and nuclear Nrf2 protein, whereas the decrement of Akt phosphorylation induced by LY294002 augmented cellular injury and decreased nuclear Nrf2. CONCLUSIONS: GYY4137 activates the PHLPP-1/Akt/Nrf2 pathway to protect against diabetic myocardial ischemia/reperfusion injury.
BACKGROUND: This study explores the protective effects of a hydrogen sulfidedonor, morpholin-4-ium 4-methoxyphenyl-morpholino-phosphinodithioate (GYY4137), in the hearts of diabeticmice that had been subjected to myocardial ischemia/reperfusion injury. Diabetes impairs the Akt pathway, in which the Akt protein is dephosphorylated and inactivated by PH domain leucine-rich repeat protein phosphatase-1 (PHLPP-1). However, the function of PHLPP-1 and molecular mechanism that underlies the cardiac protection exerted by GYY4137 remains unknown. METHODS:Diabetic or nondiabetic mice were subjected to 45 min of coronary artery occlusion followed by 2 h of reperfusion. H9c2 cells were cultured with normal or high glucose and then subjected to 3 h of hypoxia followed by 6 h of reoxygenation. Pretreatment with GYY4137 was performed in a randomized manner before ischemia/reperfusion or hypoxia/reoxygenation. The infarct size, cardiomyocyte apoptosis, and oxidative stress were measured. Western blotting was conducted to elucidate the protective mechanism. RESULTS:Diabeticmice or H9c2 cells exposed to high glucose displayed a larger infarct size, more severe cardiomyocyte apoptosis, lower cell viability, and increased oxidative stress, which were associated with increased levels of PHLPP-1 and reduced levels of p-Akt and nuclear factor-erythroid-2-related factor 2 (Nrf2) protein expression. These changes were prevented/reversed by GYYG4137 pretreatment. At the cellular level, PHLPP-1 siRNA attenuated cellular injury, and this was associated with increased p-Akt and nuclear Nrf2 protein, whereas the decrement of Akt phosphorylation induced by LY294002 augmented cellular injury and decreased nuclear Nrf2. CONCLUSIONS:GYY4137 activates the PHLPP-1/Akt/Nrf2 pathway to protect against diabetic myocardial ischemia/reperfusion injury.
Authors: Claire L Allen; Katarzyna Wolanska; Naseeb K Malhi; Andrew V Benest; Mark E Wood; Winfried Amoaku; Roberta Torregrossa; Matthew Whiteman; David O Bates; Jacqueline L Whatmore Journal: Front Cell Dev Biol Date: 2021-09-07