Gene expression of the cardiac Na(+)-Ca2+ exchanger in end-stage human heart failure.
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.
Studer
R
R
Arbeitsgruppe Molekulare Kardiologie, Universitat Freiburg, Germany.
Reinecke
H
H
Bilger
J
J
Eschenhagen
T
T
Böhm
M
M
Hasenfuss
G
G
Just
H
H
Holtz
J
J
Drexler
H
H
D000328:Adult; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000096:biosynthesis*; D001483:Base Sequence; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000096:biosynthesis; D002311:Cardiomyopathy, Dilated / Q000378:metabolism*; D002352:Carrier Proteins / Q000096:biosynthesis*; D003327:Coronary Disease / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D015723:Gene Library; D006168:Guinea Pigs; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009206:Myocardium / Q000378:metabolism*; D009218:Myosins / Q000096:biosynthesis; D009838:Oligodeoxyribonucleotides; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D051381:Rats; D012016:Reference Values; D015183:Restriction Mapping; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D019831:Sodium-Calcium Exchanger
D002352:Carrier Proteins; D009838:Oligodeoxyribonucleotides; D012333:RNA, Messenger; D019831:Sodium-Calcium Exchanger; D009320:Atrial Natriuretic Factor; D012964:Sodium; D009218:Myosins; D000252:Calcium-Transporting ATPases; D002118:Calcium