title: Deletion of Interleukin-6 Attenuates Pressure Overload-Induced Left Ventricular Hypertrophy and Dysfunction.
abstract: The role of interleukin (IL)-6 in the pathogenesis of cardiac myocyte hypertrophy remains controversial.
  
  
  
  To conclusively determine whether IL-6 signaling is essential for the development of pressure overload-induced left ventricular (LV) hypertrophy and to elucidate the underlying molecular pathways.
  
  
  
  Wild-type and IL-6 knockout (IL-6(-/-)) mice underwent sham surgery or transverse aortic constriction (TAC) to induce pressure overload. Serial echocardiograms and terminal hemodynamic studies revealed attenuated LV hypertrophy and superior preservation of LV function in IL-6(-/-) mice after TAC. The extents of LV remodeling, fibrosis, and apoptosis were reduced in IL-6(-/-) hearts after TAC. Transcriptional and protein assays of myocardial tissue identified Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and signal transducer and activator of transcription 3 (STAT3) activation as important underlying mechanisms during cardiac hypertrophy induced by TAC. The involvement of these pathways in myocyte hypertrophy was verified in isolated cardiac myocytes from wild-type and IL-6(-/-) mice exposed to prohypertrophy agents. Furthermore, overexpression of CaMKII in H9c2 cells increased STAT3 phosphorylation, and exposure of H9c2 cells to IL-6 resulted in STAT3 activation that was attenuated by CaMKII inhibition. Together, these results identify the importance of CaMKII-dependent activation of STAT3 during cardiac myocyte hypertrophy via IL-6 signaling.
  
  
  
  Genetic deletion of IL-6 attenuates TAC-induced LV hypertrophy and dysfunction, indicating a critical role played by IL-6 in the pathogenesis of LV hypertrophy in response to pressure overload. CaMKII plays an important role in IL-6-induced STAT3 activation and consequent cardiac myocyte hypertrophy. These findings may have significant therapeutic implications for LV hypertrophy and failure in patients with hypertension.
authors.affiliation: Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.|Division of Cardiovascular Diseases, Cardiovascular Research Institute, University of Kansas Medical Center, Kansas City, KS.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Division of Cardiovascular Diseases, Cardiovascular Research Institute, University of Kansas Medical Center, Kansas City, KS.
authors.forename: Guangming
authors.initials: G
authors.lastname: Cheng
authors.affiliation: Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Runming
authors.initials: R
authors.lastname: Jin
authors.affiliation: Division of Cardiovascular Diseases, Cardiovascular Research Institute, University of Kansas Medical Center, Kansas City, KS.
authors.forename: Muhammad R
authors.initials: MR
authors.lastname: Afzal
authors.affiliation: Division of Cardiovascular Diseases, Cardiovascular Research Institute, University of Kansas Medical Center, Kansas City, KS.
authors.forename: Anweshan
authors.initials: A
authors.lastname: Samanta
authors.affiliation: Division of Cardiovascular Diseases, Cardiovascular Research Institute, University of Kansas Medical Center, Kansas City, KS.
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Xuan
authors.affiliation: Division of Cardiovascular Diseases, Cardiovascular Research Institute, University of Kansas Medical Center, Kansas City, KS.
authors.forename: Magdy
authors.initials: M
authors.lastname: Girgis
authors.affiliation: Mount Sinai School of Medicine, New York, NY.
authors.forename: Harold K
authors.initials: HK
authors.lastname: Elias
authors.affiliation: Division of Cardiovascular Diseases, Cardiovascular Research Institute, University of Kansas Medical Center, Kansas City, KS.
authors.forename: Yanqing
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Division of Cardiovascular Diseases, Cardiovascular Research Institute, University of Kansas Medical Center, Kansas City, KS.
authors.forename: Arash
authors.initials: A
authors.lastname: Davani
authors.affiliation: Division of Cardiovascular Diseases, Cardiovascular Research Institute, University of Kansas Medical Center, Kansas City, KS.
authors.forename: Yanjuan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Division of Cardiovascular Diseases, Cardiovascular Research Institute, University of Kansas Medical Center, Kansas City, KS.
authors.forename: Xing
authors.initials: X
authors.lastname: Chen
authors.affiliation: Division of Cardiovascular Diseases, Cardiovascular Research Institute, University of Kansas Medical Center, Kansas City, KS.
authors.forename: Sheng
authors.initials: S
authors.lastname: Ye
authors.affiliation: Division of Cardiovascular Diseases, Cardiovascular Research Institute, University of Kansas Medical Center, Kansas City, KS.
authors.forename: Ou-Li
authors.initials: OL
authors.lastname: Wang
authors.affiliation: Division of Cardiovascular Diseases, Cardiovascular Research Institute, University of Kansas Medical Center, Kansas City, KS.
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.affiliation: Division of Cardiovascular Diseases, Cardiovascular Research Institute, University of Kansas Medical Center, Kansas City, KS.
authors.forename: Jeryl
authors.initials: J
authors.lastname: Hauptman
authors.affiliation: Division of Cardiovascular Diseases, Cardiovascular Research Institute, University of Kansas Medical Center, Kansas City, KS.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Vincent
authors.affiliation: Division of Cardiovascular Diseases, Cardiovascular Research Institute, University of Kansas Medical Center, Kansas City, KS.
authors.forename: Buddhadeb
authors.initials: B
authors.lastname: Dawn
mesh_terms: D000818:Animals; D017209:Apoptosis; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D005355:Fibrosis; D017353:Gene Deletion; D006352:Heart Ventricles / Q000378:metabolism* / Q000473:pathology; D017379:Hypertrophy, Left Ventricular / Q000235:genetics / Q000378:metabolism*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D018754:Ventricular Dysfunction
chemical_list: D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C577686:interleukin-6, mouse; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2
keywords: Ca2+/calmodulin-dependent protein kinase type II; cardiac myocyte; hypertension; interleukin-6; left ventricular hypertrophy; signal transducer and activator of transcription 3