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OBJECTIVES: Although intracellular Ca2+ overload is believed to cause cardiac abnormalities and subcellular remodelling, its role in inducing alterations in cardiac gene expression has not been investigated.
METHODS: Intracellular Ca2+ overload was induced in isolated rat hearts on perfusion with Ca2+-free medium for 5 min followed by reperfusion with medium containing different concentrations of Ca2+ for 30 min (Ca2+paradox). Changes in messenger RNA levels for various subcellular proteins were monitored either by Northern blotting or real-time polymerase chain reaction techniques.
RESULTS: Marked depressions in gene expression for sarcolemma Na+- K+-ATPase and Na+-Ca2+ exchanger, sarcoplasmic reticulum Ca2+-pump ATPase, Ca2+ release channel and phospholamban, as well as myofibrillar α- and β-myosin heavy chain proteins were observed in hearts reperfused with 1.25 mM Ca2+ following perfusion with Ca2+-free medium. In contrast, messenger RNA levels for calpain-1 and -2 proteins were elevated in hearts subjected to Ca2+paradox. These changes were dependent on the concentration of Ca2+ in the reperfusion medium.
CONCLUSIONS: The results suggest that intracellular Ca2+ overload is an important factor in the induction of defects in gene expression, subcellular remodelling and cardiac dysfunction in heart disease.