title: ROS-Induced Nuclear Translocation of Calpain-2 Facilitates Cardiomyocyte Apoptosis in Tail-Suspended Rats.
abstract: Isoproterenol (ISO) induced nuclear translocation of calpain-2 which further increased susceptibility of cardiomyocyte apoptosis in tail-suspended rats. The underlying mechanisms remain elusive. In the present study, the results showed that ISO (10 nM) significantly elevated NADPH oxidases (NOXs) activity and NOXs-derived ROS productions which induced nuclear translocation of calpain-2 in cardiomyocytes of tail-suspended rats. In contrast, the inhibition of NADPH oxidase or cleavage of ROS not only reduced ROS productions, but also resisted nuclear translocation of calpain-2 and decreased ISO-induced apoptosis of cardiomyocyte in tail-suspended rats. ISO also increased the constitutive binding between calpain-2 and Ca(2+)/calmodulin-dependent protein kinase II δB (CaMK II δB) in nuclei, concomitant with the promotion of CaMK II δB degradation and subsequent down-regulation of Bcl-2 mRNA expression and the ratio of Bcl-2 to Bax protein in tail-suspended rat cardiomyocytes. These effects of ISO on cardiomyocytes were abolished by a calpain inhibitor PD150606. Inhibition of calpain significantly reduced ISO-induced loss of the mitochondrial membrane potential, cytochrome c release into the cytoplasm, as well as the activation of caspase-3 and caspase-9 in mitochondrial apoptotic pathway. In summary, the above results suggest that ISO increased NOXs-derived ROS which activated nuclear translocation of calpain-2, subsequently nuclear calpain-2 degraded CaMK II δB which reduced the ratio of Bcl-2 to Bax, and finally the mitochondria apoptosis pathway was triggered in tail-suspended rat cardiomyocytes. Therefore, calpain-2 may represent a potentially therapeutic target for prevention of oxidative stress-associated cardiomyocyte apoptosis.
authors.affiliation: Department of Aerospace Physiology, Fourth Military Medical University, 169 Changlexi Road, Xi'an, 710032,, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Chang
authors.affiliation: Department of Aerospace Physiology, Fourth Military Medical University, 169 Changlexi Road, Xi'an, 710032,, China.
authors.forename: Juan-Juan
authors.initials: JJ
authors.lastname: Sheng
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Aerospace Physiology, Fourth Military Medical University, 169 Changlexi Road, Xi'an, 710032,, China.
authors.forename: Zhi-Jie
authors.initials: ZJ
authors.lastname: Yue
authors.forename: Bo
authors.initials: B
authors.lastname: Jiao
authors.affiliation: Department of Aerospace Physiology, Fourth Military Medical University, 169 Changlexi Road, Xi'an, 710032,, China.
authors.forename: Jin-Sheng
authors.initials: JS
authors.lastname: Li
authors.affiliation: Department of Aerospace Physiology, Fourth Military Medical University, 169 Changlexi Road, Xi'an, 710032,, China.
authors.forename: Zhi-Bin
authors.initials: ZB
authors.lastname: Yu
mesh_terms: D000179:Acrylates / Q000008:administration & dosage; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000096:biosynthesis* / Q000378:metabolism; D002154:Calpain / Q000096:biosynthesis* / Q000378:metabolism; D053148:Caspase 3 / Q000096:biosynthesis; D053453:Caspase 9 / Q000096:biosynthesis; D002466:Cell Nucleolus / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D007545:Isoproterenol / Q000008:administration & dosage; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000096:biosynthesis* / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis* / Q000378:metabolism
chemical_list: D000179:Acrylates; C494828:Bax protein, rat; C100442:PD 150606; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; D009247:NADH, NADPH Oxidoreductases; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; C517677:Camk2d protein, rat; D002154:Calpain; D053148:Caspase 3; D053453:Caspase 9; C000594975:Capn2 protein, rat; D007545:Isoproterenol
keywords: APOPTOSIS; CALPAIN-2; CARDIOMYOCYTE; NADPH OXIDASE; NUCLEAR TRANSLOCATION