title: Impaired cardiac function and IGF-I response in myocytes from calmodulin-diabetic mice: role of Akt and RhoA.
abstract: This study characterized the cardiac contractile function and IGF-I response in a transgenic diabetic mouse model. Mechanical properties were evaluated in cardiac myocytes from OVE26 diabetic and FVB wild-type mice, including peak shortening (PS), time to PS (TPS), time to 90% relengthening (TR(90)) and maximal velocity of shortening/relengthening (+/-dL/dt). Intracellular Ca(2+) was evaluated as Ca(2+)-induced Ca(2+) release [difference in fura 2 fluorescent intensity (Delta FFI)] and fluorescence decay rate (tau). Sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA)2a, phospholamban (PLB), Na(+)-Ca(2+) exchanger (NCX), GLUT4, and the serine-threonine kinase Akt were assessed by Western blot. RhoA and IGF-I/IGF-I receptor mRNA levels were determined by RT-PCR and Northern blot. OVE26 myocytes displayed decreased PS, +/-dL/dt, and Delta FFI associated with prolonged TPS, TR(90), and tau. SERCA2a, NCX, and Akt activation were reduced, whereas PLB and RhoA were enhanced in OVE26 hearts. GLUT4 was unchanged. IGF-I enhanced PS and Delta FFI in FVB but not OVE26 myocytes. IGF-I mRNA was increased, but IGF-I receptor mRNA was reduced in OVE26 hearts and livers. These results validate diabetic cardiomyopathy in OVE26 mice due to reduced SERCA2, NCX, IGF-I response, and Akt activation associated with enhanced RhoA level, suggesting a therapeutic potential for Akt and RhoA.
authors.affiliation: Department of Pharmacology, Physiology, and Therapeutics, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota 58203.
authors.forename: Jinhong
authors.initials: J
authors.lastname: Duan
authors.forename: Hai-Ying
authors.initials: HY
authors.lastname: Zhang
authors.forename: Steven D
authors.initials: SD
authors.lastname: Adkins
authors.forename: Bonnie H
authors.initials: BH
authors.lastname: Ren
authors.forename: Faye L
authors.initials: FL
authors.lastname: Norby
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Zhang
authors.forename: Joseph N
authors.initials: JN
authors.lastname: Benoit
authors.forename: Paul N
authors.initials: PN
authors.lastname: Epstein
authors.forename: Jun
authors.initials: J
authors.lastname: Ren
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000032:analysis; D000252:Calcium-Transporting ATPases / Q000032:analysis; D002147:Calmodulin / Q000235:genetics*; D009202:Cardiomyopathies / Q000378:metabolism / Q000503:physiopathology*; D003925:Diabetic Angiopathies / Q000378:metabolism / Q000503:physiopathology*; D015870:Gene Expression; D051275:Glucose Transporter Type 4; D007334:Insulin-Like Growth Factor I / Q000235:genetics* / Q000494:pharmacology; D008099:Liver / Q000502:physiology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009004:Monosaccharide Transport Proteins / Q000032:analysis; D009124:Muscle Proteins; D009200:Myocardial Contraction / Q000502:physiology; D032383:Myocytes, Cardiac / Q000737:chemistry / Q000187:drug effects / Q000502:physiology; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger / Q000032:analysis; D017526:Receptor, IGF Type 1 / Q000235:genetics; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D019831:Sodium-Calcium Exchanger / Q000032:analysis; D020742:rhoA GTP-Binding Protein / Q000235:genetics*; D000099211:Phospholamban
chemical_list: D002118:Calcium; D002135:Calcium-Binding Proteins; D000252:Calcium-Transporting ATPases; D002147:Calmodulin; D051275:Glucose Transporter Type 4; D007334:Insulin-Like Growth Factor I; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D017526:Receptor, IGF Type 1; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D019831:Sodium-Calcium Exchanger; D020742:rhoA GTP-Binding Protein; D000099211:Phospholamban; C495693:Slc2a4 protein, mouse; C506947:Atp2a2 protein, mouse