1. Major contribution of the 3/6/7 class of TRPC channels to myocardial ischemia/reperfusion and cellular hypoxia/reoxygenation injuries
- Author
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Lutz Birnbaumer, Yanhong Liao, Karina Formoso, Sebastian Susperreguy, Jinsong Kang, Xiju He, Benju Liu, Jinghong Yao, Shoutian Li, and Anbing Shi
- Subjects
0301 basic medicine ,Male ,Apoptosis ,Transient receptor potential channel ,Mice ,0302 clinical medicine ,TRPC3 ,MUERTE CELULAR ,Hipoxia ,TRPC ,Mice, Knockout ,Multidisciplinary ,Imidazoles ,Models, Cardiovascular ,Anatomy ,Bioquímica y Biología Molecular ,Calcium Channel Blockers ,Cell Hypoxia ,APOPTOSIS ,Medicina Básica ,PNAS Plus ,Myoblasts, Cardiac ,Signal Transduction ,medicine.medical_specialty ,Mice, 129 Strain ,CIENCIAS MÉDICAS Y DE LA SALUD ,Ischemia ,chemistry.chemical_element ,Myocardial Reperfusion Injury ,INFARTO DEL MIOCARDIO ,Calcium ,Biology ,Cell Line ,03 medical and health sciences ,Internal medicine ,medicine ,TRPC6 Cation Channel ,Animals ,Calcium Signaling ,Protein kinase B ,TRPC Cation Channels ,Trpc ,CALCIO ,medicine.disease ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,Endocrinology ,Mitochondrial permeability transition pore ,chemistry ,Reperfusion ,Cardiac Infarct ,030217 neurology & neurosurgery - Abstract
Fil: He, Xiju. Huazhong University of Science and Technology. Tongji Medical College. Department of Anatomy; China Fil: He, Xiju. Huazhong University of Science and Technology. Tongji Medical College. Institute of Brain Research; China Fil: He, Xiju. Hubei University of Medicine. Department of Anatomy; China Fil: Li, Shoutian. Huazhong University of Science and Technology. Tongji Medical College. Department of Anatomy; China Fil: Li, Shoutian. Huazhong University of Science and Technology. Tongji Medical College. Institute of Brain Research; China Fil: Liu, Benju. Huazhong University of Science and Technology. Tongji Medical College. Department of Anatomy; China Fil: Liu, Benju. Huazhong University of Science and Technology. Tongji Medical College. Institute of Brain Research; China Fil: Susperreguy, Sebastian. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina Fil: Formoso, Karina. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina Fil: Yao, Jinghong. Huazhong University of Science and Technology. Tongji Medical College. Union Hospital. Department of Infectious Disease; China Fil: Kang, Jinsong. Huazhong University of Science and Technology. Tongji Medical College. Tongji Hospital. Department of Surgery; China Fil: Anbing, Shi. Huazhong University of Science and Technology. Tongji Medical College. Department of Biochemistry and Molecular Biology; China Fil: Birnbaumer, Lutz. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina Fil: Birnbaumer, Lutz. Research Triangle Park. National Institute of Environmental Health Sciences. Neurobiology Laboratory; Estados Unidos Fil: Liao, Yanhong. Huazhong University of Science and Technology. Tongji Medical College. Department of Anatomy; China Fil: Liao, Yanhong. Huazhong University of Science and Technology. Tongji Medical College. Institute of Brain Research; China Abstract: The injury phase after myocardial infarcts occurs during reperfusion and is a consequence of calcium release from internal stores combined with calcium entry, leading to cell death by apoptopic and necrotic processes. The mechanism(s) by which calcium enters cells has(ve) not been identified. Here, we identify canonical transient receptor potential channels (TRPC) 3 and 6 as the cation channels through which most of the damaging calcium enters cells to trigger their death, and we describe mechanisms activated during the injury phase. Working in vitro with H9c2 cardiomyoblasts subjected to 9-h hypoxia followed by 6-h reoxygenation (H/R), and analyzing changes occurring in areas-at-risk (AARs) of murine hearts subjected to a 30-min ischemia followed by 24-h reperfusion (I/R) protocol, we found: (i) that blocking TRPCwith SKF96365 significantly ameliorated damage induced by H/R, including development of the mitochondrial permeability transition and proapoptotic changes in Bcl2/BAX ratios; and (ii) that AAR tissues had increased TUNEL+ cells, augmented Bcl2/BAX ratios, and increased p(S240)NFATc3, p(S473) AKT, p(S9)GSK3β, and TRPC3 and -6 proteins, consistent with activation of a positive-feedback loop in which calcium entering through TRPCs activates calcineurin-mediated NFATc3-directed transcription of TRPC genes, leading to more Ca2+ entry. All these changes were markedly reduced in mice lacking TRPC3, -6, and -7. The changes caused by I/R in AAR tissues were matched by those seen after H/R in cardiomyoblasts in all aspects except for p-AKT and p-GSK3β, which were decreased after H/R in cardiomyoblasts instead of increased. TRPC should be promising targets for pharmacologic intervention after cardiac infarcts.
- Published
- 2017