Impaired cardiac function and IGF-I response in myocytes from calmodulin-diabetic mice: Role of Akt and RhoA

Jinhong Duan, Hai-Ying Zhang, Steven D. Adkins, Bonnie H. Ren, Faye L. Norby, Xiaochun Zhang, Joseph N. Benoit, Paul N. Epstein, Jun Ren

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57 Scopus citations

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 (TR90) and maximal velocity of shortening/relengthening (textpmdL/dt). Intracellular Ca2+ was evaluated as Ca2+-induced Ca2+ release [difference in fura 2 fluorescent intensity (ΔFFI)] and fluorescence decay rate (τ). Sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)2a, phospholamban (PLB), Na+-Ca2+ 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, textpmdL/dt, and ΔFFI associated with prolonged TPS, TR90, and τ. SERCA2a, NCX, and Akt activation were reduced, whereas PLB and RhoA were enhanced in OVE26 hearts. GLUT4 was unchanged. IGF-I enhanced PS and ΔFFI 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.
Original languageEnglish (US)
Pages (from-to)E366-E376
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume284
Issue number2
DOIs
StatePublished - Feb 1 2003

Keywords

  • Diabetic mouse
  • Excitation-contraction coupling
  • Insulin-like growth factor I
  • Sarco(endo)plasmic reticulum Ca-ATPase
  • Sodium-calcium exchanger
  • Ventricular myocyte

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