Rat cardiac contractile dysfunction induced by Ca2+ overload: possible link to the proteolysis of alpha-fodrin.
The aim of the present study was to examine the mechanisms of Ca2+ overload-induced contractile dysfunction in rat hearts independent of ischemia and acidosis. Experiments were performed on 30 excised cross-circulated rat heart preparations. After hearts were exposed to high Ca2+, there was a contractile failure associated with a parallel downward shift of the linear relation between myocardial O(2) consumption per beat and systolic pressure-volume area (index of a total mechanical energy per beat) in left ventricles from all seven hearts that underwent the protocol. This result suggested a decrease in O(2) consumption for total Ca2+ handling in excitation-contraction coupling. In the hearts that underwent the high Ca2+ protocol and had contractile failure, we found marked proteolysis of a cytoskeleton protein, alpha-fodrin, whereas other proteins were unaffected. A calpain inhibitor suppressed the contractile failure by high Ca2+, the decrease in O(2) consumption for total Ca2+ handling, and membrane alpha-fodrin degradation. We conclude that the exposure to high Ca2+ may induce contractile dysfunction possibly by suppressing total Ca2+ handling in excitation-contraction coupling and degradation of membrane alpha-fodrin via activation of calpain.
Tsuji
T
T
Department of Surgery III, Nara Medical University, Kashihara, Nara 634-8521, Japan.
Ohga
Y
Y
Yoshikawa
Y
Y
Sakata
S
S
Abe
T
T
Tabayashi
N
N
Kobayashi
S
S
Kohzuki
H
H
Yoshida
K I
KI
Suga
H
H
Kitamura
S
S
Taniguchi
S
S
Takaki
M
M
D000818:Animals; D017487:Ankyrins / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology*; D002154:Calpain / Q000037:antagonists & inhibitors / Q000378:metabolism; D002306:Cardiac Volume / Q000187:drug effects; D002352:Carrier Proteins / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D018031:Connexin 43 / Q000378:metabolism; D004195:Disease Models, Animal; D004562:Electrocardiography; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism*; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects; D010447:Peptide Hydrolases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013599:Systole; D019210:Troponin I / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced* / Q000503:physiopathology; D013049:Spectrin
D017487:Ankyrins; D002118:Calcium; D002154:Calpain; D002352:Carrier Proteins; D018031:Connexin 43; D004791:Enzyme Inhibitors; D008840:Microfilament Proteins; D010447:Peptide Hydrolases; D019210:Troponin I; D013049:Spectrin