title: No contribution of IP3-R(2) to disease phenotype in models of dilated cardiomyopathy or pressure overload hypertrophy.
abstract: BACKGROUND
  We investigated the contribution of inositol(1,4,5)-trisphosphate (Ins(1,4,5)P3 [IP3]) receptors (IP3-R) to disease progression in mouse models of dilated cardiomyopathy (DCM) and pressure overload hypertrophy. Mice expressing mammalian sterile 20-like kinase and dominant-negative phosphatidylinositol-3-kinase in heart (Mst1×dn-PI3K-2Tg; DCM-2Tg) develop severe DCM and conduction block, associated with increased expression of type 2 IP3-R (IP3-R(2)) and heightened generation of Ins(1,4,5)P3. Similar increases in Ins(1,4,5)P3 and IP3-R(2) are caused by transverse aortic constriction.
  
  
  RESULTS
  To evaluate the contribution of IP3-R(2) to disease progression, the DCM-2Tg mice were further crossed with mice in which the type 2 IP3-R (IP3-R(2)-/-) had been deleted (DCM-2Tg×IP3-R(2)-/-) and transverse aortic constriction was performed on IP3-R(2)-/- mice. Hearts from DCM-2Tg mice and DCM-2Tg×IP3-R(2)-/- were similar in terms of chamber dilatation, atrial enlargement, and ventricular wall thinning. Electrophysiological changes were also similar in the DCM-2Tg mice, with and without IP3-R(2). Deletion of IP3-R(2) did not alter the progression of heart failure, because DCM-2Tg mice with and without IP3-R(2) had similarly reduced contractility, increased lung congestion, and atrial thrombus, and both strains died between 10 and 12 weeks of age. Loss of IP3-R(2) did not alter the progression of hypertrophy after transverse aortic constriction.
  
  
  CONCLUSIONS
  We conclude that IP3-R(2) do not contribute to the progression of DCM or pressure overload hypertrophy, despite increased expression and heightened generation of the ligand, Ins(1,4,5)P3.
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
authors.forename: Nicola
authors.initials: N
authors.lastname: Cooley
authors.forename: Kunfu
authors.initials: K
authors.lastname: Ouyang
authors.forename: Julie R
authors.initials: JR
authors.lastname: McMullen
authors.forename: Helen
authors.initials: H
authors.lastname: Kiriazis
authors.forename: Farah
authors.initials: F
authors.lastname: Sheikh
authors.forename: Wei
authors.initials: W
authors.lastname: Wu
authors.forename: Yongxin
authors.initials: Y
authors.lastname: Mu
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Du
authors.forename: Ju
authors.initials: J
authors.lastname: Chen
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Woodcock
mesh_terms: D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D018450:Disease Progression; D004562:Electrocardiography; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005838:Genotype; D006327:Heart Block / Q000378:metabolism / Q000503:physiopathology; D006333:Heart Failure / Q000378:metabolism / Q000503:physiopathology; D017379:Hypertrophy, Left Ventricular / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D058539:Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D016277:Ventricular Function, Left; D017725:Ventricular Pressure; D020257:Ventricular Remodeling
chemical_list: D053496:Inositol 1,4,5-Trisphosphate Receptors; D015544:Inositol 1,4,5-Trisphosphate; D058539:Phosphatidylinositol 3-Kinase; D017346:Protein Serine-Threonine Kinases