Cardiac contractile dysfunction in J2N-k cardiomyopathic hamsters is associated with impaired SR function and regulation.
Although dilated cardiomyopathy (DCM) is known to result in cardiac contractile dysfunction, the underlying mechanisms are unclear. The sarcoplasmic reticulum (SR) is the main regulator of intracellular Ca2+ required for cardiac contraction and relaxation. We therefore hypothesized that abnormalities in both SR function and regulation will contribute to cardiac contractile dysfunction of the J2N-k cardiomyopathic hamster, an appropriate model of DCM. Echocardiographic assessment indicated contractile dysfunction, because the ejection fraction, fractional shortening, cardiac output, and heart rate were all significantly reduced in J2N-k hamsters compared with controls. Depressed cardiac function was associated with decreased cardiac SR Ca2+ uptake in the cardiomyopathic hamsters. Reduced SR Ca2+ uptake could be further linked to a decrease in the expression of the SR Ca(2+)-ATPase and cAMP-dependent protein kinase (PKA)-mediated phospholamban (PLB) phosphorylation at serine-16. Depressed PLB phosphorylation was paralleled with a reduction in the activity of SR-associated PKA, as well as an elevation in protein phosphatase activity in J2N-k hamster. The results of this study suggest that an alteration in SR function and its regulation contribute to cardiac contractile dysfunction in the J2N-k cardiomyopathic hamster.
Babick
Andrea P
AP
Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, Winnipeg, Manitoba, Canada R2H 2A6.
Cantor
Elliott J F
EJ
Babick
John T
JT
Takeda
Nobuakira
N
Dhalla
Naranjan S
NS
Netticadan
Thomas
T
D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000503:physiopathology*; D006224:Cricetinae; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004195:Disease Models, Animal; D004562:Electrocardiography; D008297:Male; D009119:Muscle Contraction / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000502:physiology; D010766:Phosphorylation; D012519:Sarcoplasmic Reticulum / Q000502:physiology*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000099211:Phospholamban
D002118:Calcium; D002135:Calcium-Binding Proteins; D000252:Calcium-Transporting ATPases; D017868:Cyclic AMP-Dependent Protein Kinases; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000099211:Phospholamban