Gene expression of the cardiac Na(+)-Ca2+ exchanger in end-stage human heart failure.

• DOI: 10.1161/01.res.75.3.443
• Publication Date: 2012-06-12T00:47:05Z
• Authors: R Studer; H Reinecke; J Bilger; T Eschenhagen; M Böhm; G Hasenfuss; H Just; J Holtz; H Drexler
• Keywords: Adult; Cardiomyopathy, Dilated; Male; Base Sequence; Myocardium; Blotting, Western; Guinea Pigs; Molecular Sequence Data; Gene Expression; Coronary Disease; Calcium-Transporting ATPases; Middle Aged; Myosins; 3. Good health; 03 medical and health sciences; 0302 clinical medicine; Animals; Humans; Calcium; Female; Carrier Proteins; Atrial Natriuretic Factor; Gene Library

The regulation of cytosolic Ca2+ concentration during excitation-contraction coupling is altered in the failing human heart. Previous studies have focused on disturbances in Ca2+ release and reuptake from the sarcoplasmic reticulum (SR), whereas functional studies of the cardiac Na(+)-Ca2+ exchanger, another important determinant of myocyte homeostasis, are lacking for the failing human heart. Using a cardiac Na(+)-Ca2+ exchanger cDNA recently cloned from a guinea pig cDNA library, we investigated the gene expression of the cardiac Na(+)-Ca2+ exchanger in relation to the SR Ca(2+)-ATPase. Expression of both genes was quantified in left ventricular myocardium from 24 failing human cardiac explants and 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 Ca(2+)-ATPase mRNA levels were decreased by 50% in DCM and by 45% in CAD (P < .05 for both versus control value). There was a positive correlation between Na(+)-Ca2+ exchanger and SR Ca(2+)-ATPase mRNA levels both in normal and failing human hearts, albeit with different slopes and intercepts of the regression line. The Na(+)-Ca2+ exchanger protein levels as assessed by Western blot analysis and normalized to beta-myosin heavy chain protein were increased in DCM and CAD (P < .05 and P < .01 versus control value, respectively), whereas SR Ca(2+)-ATPase protein 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 function with regard to diastolic Ca2+ removal.