Wei-Hua Guo1, Xian Wang1, Mei-Sheng Shang2, Zhe Chen3, Qi Guo3, Li Li3, Hai-Ying Wang1, Rong-Hui Yu2, Chang-Sheng Ma4. 1. Department of Cardiology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China. 2. Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, No.2, Anzhen Road, Chaoyang District, Beijing, 100029, China. 3. Department of Cardiology, Beijing Tongren Hospital, Capital Medical University, Beijing, 100005, China. 4. Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, No.2, Anzhen Road, Chaoyang District, Beijing, 100029, China. csma_anzhen@126.com.
Abstract
OBJECTIVE: Atrial fibrillation (AF) is the most frequent form of cardiac arrhythmia and major cause of cardiac ischemia. Defective calcium homeostasis due to anomalous expression of ryanodine receptor type 2 (RyR2) or its hyperactivation by phosphorylation by serine threonine kinases has been implicated as a central mechanism of AF pathogenesis. Given the role of protein kinase C (PKC) isoforms in cardiac function we investigated role of PKC in AF using a rat model. RESULTS: PMA induced global increase in protein synthesis in cardiac fibroblasts isolated from AF rats, but not healthy controls, and the increase was inhibited by PKC inhibition. PMA mediated activation of both PKC and ERK and either inhibition of PKC by Go6983 or ERK by the MEK inhibitor Trametinib attenuated both P-ERK and P-PKC in both cardiac fibroblasts isolated from AF rats or from healthy rats but transduced with PKC-delta. The PKC and ERK mediated induction of global protein synthesis was found to be mediated by increased phosphorylation of the ribosomal protein S6. CONCLUSION: Our findings provide a foundation for future testing of PKC and MEK inhibitors to treat AF in pre-clinical models. It also needs to be determined if PKC and MAPK pathway activation is functioning via RyR2 or some yet undefined substrates.
OBJECTIVE:Atrial fibrillation (AF) is the most frequent form of cardiac arrhythmia and major cause of cardiac ischemia. Defective calcium homeostasis due to anomalous expression of ryanodine receptor type 2 (RyR2) or its hyperactivation by phosphorylation by serine threonine kinases has been implicated as a central mechanism of AF pathogenesis. Given the role of protein kinase C (PKC) isoforms in cardiac function we investigated role of PKC in AF using a rat model. RESULTS:PMA induced global increase in protein synthesis in cardiac fibroblasts isolated from AFrats, but not healthy controls, and the increase was inhibited by PKC inhibition. PMA mediated activation of both PKC and ERK and either inhibition of PKC by Go6983 or ERK by the MEK inhibitor Trametinib attenuated both P-ERK and P-PKC in both cardiac fibroblasts isolated from AFrats or from healthy rats but transduced with PKC-delta. The PKC and ERK mediated induction of global protein synthesis was found to be mediated by increased phosphorylation of the ribosomal protein S6. CONCLUSION: Our findings provide a foundation for future testing of PKC and MEK inhibitors to treat AF in pre-clinical models. It also needs to be determined if PKC and MAPK pathway activation is functioning via RyR2 or some yet undefined substrates.
Entities:
Keywords:
Atrial fibrillation; MAPK; PKC; Protein synthesis
Authors: Siarhei A Dabravolski; Nikolay K Sadykhov; Andrey G Kartuesov; Evgeny E Borisov; Vasily N Sukhorukov; Alexander N Orekhov Journal: Int J Mol Sci Date: 2022-06-21 Impact factor: 6.208