title: CaMKIIδ meditates phenylephrine induced cardiomyocyte hypertrophy through store-operated Ca2+entry.
abstract: Evidence suggests that store-operated Ca2+ entry (SOCE) is involved in the hypertrophy of cardiomyocytes. The signaling mechanisms of SOCE contributing to cardiac hypertrophy following phenylephrine (PE) stimulation are not fully understood. Ca2+/calmodulin-dependent protein kinase II δ (CaMKIIδ) plays an important role in regulating intracellular Ca2+hemostasis and function in the cardimyocytes. This study is aimed to determine the role of CaMKIIδ in regulating the PE-induced myocardial hypertrophy and the associated molecular signaling mechanisms. We used primary cultures of neonatal cardimyocytes isolated from the left ventricle of Sprague Dawley rats to investigate the effects of CaMKIIδ on myocardial hypertrophy and intracellular Ca2+mobilization. We found that the expression of CaMKIIδ was enhanced in PE-induced hypertrophic cardiomyocytes. CaMKIIδ siRNA, CaMKII inhibitor KN93, and SOCE blocker BTP2 attenuated the increase in the expression of CaMKIIδ and normalized the hypertrophic markers, atrial natriuretic peptide and brain natriuretic peptide, and size of cardiomyocytes induced by PE stimulation. The protein level of stromal interaction molecule 1 and Orai1, the essential components of the SOCE, is also enhanced in hypertrophic cardiomyocytes, which were normalized by CaMKIIδ siRNA and KN93 treatment. Hypertrophic cardiomyocytes showed an increase in the peak of Ca2+transient following store depletion, which was inhibited by SOCE blocker BTP2, CaMKIIδ siRNA, and KN93. The Ca2+currents through Ca2+release-activated Ca2+channels were increased in PE-treated cardiomyocytes and were attenuated by CaMKIIδ siRNA and KN93. These data indicate that PE-induced myocardial hypertrophy requires a complex signaling pathway that involves activation of both CaMKIIδ and SOCE. In conclusion, these studies reveal that up-regulation of CaMKIIδ may contribute to the PE-induced myocardial hypertrophy through the activation of SOCE expressed in the cardiomyocytes.
authors.affiliation: Department of Cardiology, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, PR China.
authors.forename: Yawei
authors.initials: Y
authors.lastname: Ji
authors.affiliation: Department of Urology, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, PR China.
authors.forename: Xin
authors.initials: X
authors.lastname: Guo
authors.affiliation: Department of Cardiology, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, PR China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, PR China.
authors.forename: Zhuyun
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Department of Cardiology, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, PR China.
authors.forename: Jianghua
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Kinesiology and Integrative Physiology, Michigan Technological University, Houghton, MI 49931, USA.
authors.forename: Qing-Hui
authors.initials: QH
authors.lastname: Chen
authors.affiliation: Department of Cardiology, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, PR China. Electronic address: lgui02@hotmail.com.
authors.forename: Le
authors.initials: L
authors.lastname: Gui
mesh_terms: D000818:Animals; D015153:Blotting, Western; D015220:Calcium Channels / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D006332:Cardiomegaly / Q000139:chemically induced / Q000378:metabolism*; D002316:Cardiotonic Agents / Q000633:toxicity*; D004195:Disease Models, Animal; D055785:Gene Knockdown Techniques; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010656:Phenylephrine / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D015854:Up-Regulation
chemical_list: D015220:Calcium Channels; D002316:Cardiotonic Agents; D010656:Phenylephrine; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; C517677:Camk2d protein, rat
keywords: Ca(2+) release activated Ca(2+) channel; Ca(2+)/calmodulin-dependent protein kinase II δ; Orai1; STIM1; Store-operated Ca(2+) entry