title: Dexmedetomidine-induced contraction involves phosphorylation of caldesmon by JNK in endothelium-denuded rat aortas.
abstract: Caldesmon, an inhibitory actin binding protein, binds to actin and inhibits actin-myosin interactions, whereas caldesmon phosphorylation reverses the inhibitory effect of caldesmon on actin-myosin interactions, potentially leading to enhanced contraction. The goal of this study was to investigate the cellular signaling pathway responsible for caldesmon phosphorylation, which is involved in the regulation of the contraction induced by dexmedetomidine (DMT), an alpha-2 adrenoceptor agonist, in endothelium-denuded rat aortas. SP600125 (a c-Jun NH2-terminal kinase [JNK] inhibitor) dose-response curves were generated in aortas that were pre-contracted with DMT or phorbol 12,13-dibutyrate (PDBu), a protein kinase C (PKC) activator. Dose-response curves to the PKC inhibitor chelerythrine were generated in rat aortas pre-contracted with DMT. The effects of SP600125 and rauwolscine (an alpha-2 adrenoceptor inhibitor) on DMT-induced caldesmon phosphorylation in rat aortic vascular smooth muscle cells (VSMCs) were investigated by western blot analysis. PDBu-induced caldesmon and DMT-induced PKC phosphorylation in rat aortic VSMCs was investigated by western blot analysis. The effects of GF109203X (a PKC inhibitor) on DMT- or PDBu-induced JNK phosphorylation in VSMCs were assessed. SP600125 resulted in the relaxation of aortas that were pre-contracted with DMT or PDBu, whereas rauwolscine attenuated DMT-induced contraction. Chelerythrine resulted in the vasodilation of aortas pre-contracted with DMT. SP600125 and rauwolscine inhibited DMT-induced caldesmon phosphorylation. Additionally, PDBu induced caldesmon phosphorylation, and GF109203X attenuated the JNK phosphorylation induced by DMT or PDBu. DMT induced PKC phosphorylation in rat aortic VSMCs. These results suggest that alpha-2 adrenoceptor-mediated, DMT-induced contraction involves caldesmon phosphorylation that is mediated by JNK phosphorylation by PKC.
authors.affiliation: 1. Department of Anesthesiology and Pain Medicine, Pusan National University Hospital, Biomed Research Institute, Pusan National University School of Medicine, Busan, Republic of Korea.
authors.forename: Jiseok
authors.initials: J
authors.lastname: Baik
authors.affiliation: 2. Department of Anesthesiology and Pain Medicine, Institute of Health Sciences, Gyeongsang National University School of Medicine, Gyeongsang National University Hospital, Jinju, Republic of Korea.
authors.forename: Seong-Ho
authors.initials: SH
authors.lastname: Ok
authors.affiliation: 3. Department of Anesthesiology and Pain Medicine, Gyeongsang National University Hospital, Jinju, Republic of Korea.
authors.forename: Hyunhoo
authors.initials: H
authors.lastname: Cho
authors.affiliation: 3. Department of Anesthesiology and Pain Medicine, Gyeongsang National University Hospital, Jinju, Republic of Korea.
authors.forename: Jongsun
authors.initials: J
authors.lastname: Yu
authors.affiliation: 3. Department of Anesthesiology and Pain Medicine, Gyeongsang National University Hospital, Jinju, Republic of Korea.
authors.forename: Woochan
authors.initials: W
authors.lastname: Kim
authors.affiliation: 3. Department of Anesthesiology and Pain Medicine, Gyeongsang National University Hospital, Jinju, Republic of Korea.
authors.forename: In-Koo
authors.initials: IK
authors.lastname: Nam
authors.affiliation: 4. Department of Oral and Maxillofacial Surgery, Gyeongsang National University Hospital, Jinju, Republic of Korea.
authors.forename: Mun-Jeoung
authors.initials: MJ
authors.lastname: Choi
authors.affiliation: 2. Department of Anesthesiology and Pain Medicine, Institute of Health Sciences, Gyeongsang National University School of Medicine, Gyeongsang National University Hospital, Jinju, Republic of Korea.
authors.forename: Heon-Keun
authors.initials: HK
authors.lastname: Lee
authors.affiliation: 2. Department of Anesthesiology and Pain Medicine, Institute of Health Sciences, Gyeongsang National University School of Medicine, Gyeongsang National University Hospital, Jinju, Republic of Korea.
authors.forename: Ju-Tae
authors.initials: JT
authors.lastname: Sohn
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D001011:Aorta / Q000378:metabolism / Q000502:physiology*; D053119:Benzophenanthridines / Q000494:pharmacology; D015153:Blotting, Western; D002148:Calmodulin-Binding Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D020927:Dexmedetomidine / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D009119:Muscle Contraction / Q000187:drug effects* / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D015016:Yohimbine / Q000494:pharmacology
chemical_list: D000873:Anthracenes; D053119:Benzophenanthridines; D002148:Calmodulin-Binding Proteins; D018341:Receptors, Adrenergic, alpha-2; C432165:pyrazolanthrone; D015016:Yohimbine; D020927:Dexmedetomidine; C016299:chelerythrine; D011493:Protein Kinase C
keywords: alpha-2 adrenoceptor; c-Jun NH2-terminal kinase; caldesmon; contraction; dexmedetomidine; protein kinase C; rat aorta.