GENE-EXPRESSION OF THE CARDIAC NA-CA2+ EXCHANGER IN END-STAGE HUMAN HEART-FAILURE()

The regulation of cytosolic Ca2+ concentration during excitation-contr action coupling is altered in the failing human heart. Previous studie s have focused on disturbances in Cazt release and reuptake from the s arcoplasmic reticulum (SR), whereas functional studies of the cardiac Na+-Ca2+ exchanger, another important determinant of myocyte homeostas is, are lacking for the failing human heart. Using a cardiac Na+-Ca2exchanger cDNA recently cloned from a guinea pig cDNA library, we inve stigated the gene expression of the cardiac Na+-Ca2+ exchanger in rela tion to the SR Ca2+ ATPase. Expression of both genes was quantified in left ventricular myocardium from 24 failing human cardiac explants an d 7 control heart samples in relation to beta-myosin heavy chain mRNA by slot blot analysis. Compared with patients with nonfailing hearts, patients with dilated cardiomyopathy (DCM, n=13) showed a 55% increase in Na+-Ca2+ exchanger mRNA levels (P<.05 versus control value) and a 41% increase in patients with coronary artery disease (CAD, n=11). In the same hearts, SR Ca2+-ATPase mRNA levels were decreased by 50% in D CM and by 45% in CAD (P<.05 for both versus control value). There was a positive correlation between Na+-Ca2+ exchanger and SR Ca2+-ATPase m RNA levels both in normal and failing human hearts, albeit with differ ent slopes and intercepts of the regression line. The Na+-Ca+ exchange r protein levels as assessed by Western blot analysis and normalized t o P-myosin heavy chain protein were increased in DCM and CAD (P<.05 an d P<.01 versus control value, respectively), whereas SR Ca2+-ATPase pr otein levels were reduced (P<.05 for both groups versus control values ). Thus, the Na+-Ca2+ exchanger gene expression is enhanced in failing human hearts and may, in part, compensate for the depressed SR functi on with regard to diastolic Ca2+ removal.