Heterogeneous transmural gene expression of calcium-handling proteins and natriuretic peptides in the failing human heart.
OBJECTIVE
Human heart failure is associated with a disturbed intracellular calcium (Ca2+) homeostasis. In this regard, ventricular wall stress is considered to be a determinant for expression of sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2a). In the present study, we analyzed the transmural protein and/or mRNA levels of SERCA2a, other Ca(2+)-handling proteins, and of atrial and brain natriuretic peptides (ANP and BNP) in the human heart.


METHODS
Subepicardial (epi), midmyocardial (mid), and subendocardial (endo) sections of the left ventricular free wall from end-stage failing (n = 17) and nonfailing (n = 5) human hearts were analyzed by Western blot for immunoreactive protein levels of SERCA2a, phospholamban (PLN), and calsequestrin (CS). Subepi- and subendocardial sections were analyzed by Northern blot for steady-state mRNA levels of SERCA2a, Na(+)-Ca2+ exchanger (NCX1), ANP, and BNP.


RESULTS
SERCA2a protein and mRNA levels were reduced by 40 +/- 5% (P < 0.01) and 25 +/- 7% (P < 0.05) in endo compared to epi in the failing heart and by 27 +/- 14% and 16 +/- 12% (non-significant) in the nonfailing heart, respectively. PLN protein levels were reduced by 23 +/- 6% (P < 0.05) in endo compared to epi in the failing heart and by 17 +/- 25% (non-significant) in the nonfailing heart, whereas CS protein levels and NCX1 mRNA levels were similar across the left ventricular wall. Strikingly, in the failing heart, both BNP and ANP mRNA levels were upregulated predominantly in endo.


CONCLUSIONS
In the failing human heart, SERCA2a and PLN, as well as natriuretic peptides but not CS and NCX1 are differentially expressed across the left ventricular wall, implicating (1) different susceptibility of subendocardium and subepicardium to factors affecting expression of these proteins and (2) differences in regulation of the distinct calcium-cycling proteins.
Prestle
J
J
Abteilung Kardiologie und Pneumologie, Georg-August-Universität Göttingen, Germany. jprestle@mdv.gwdg.de
Dieterich
S
S
Preuss
M
M
Bieligk
U
U
Hasenfuss
G
G
D000328:Adult; D000368:Aged; D009320:Atrial Natriuretic Factor / Q000032:analysis / Q000235:genetics*; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000032:analysis; D000252:Calcium-Transporting ATPases / Q000032:analysis / Q000235:genetics*; D002155:Calsequestrin / Q000032:analysis; D004699:Endocardium / Q000201:enzymology / Q000378:metabolism; D015870:Gene Expression; D006333:Heart Failure / Q000378:metabolism*; D006801:Humans; D008875:Middle Aged; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D020097:Natriuretic Peptide, Brain / Q000032:analysis / Q000235:genetics; D010496:Pericardium / Q000201:enzymology / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D012519:Sarcoplasmic Reticulum / Q000201:enzymology; D019831:Sodium-Calcium Exchanger / Q000235:genetics / Q000378:metabolism; D000099211:Phospholamban
D009320:Atrial Natriuretic Factor; D002118:Calcium; D002135:Calcium-Binding Proteins; D000252:Calcium-Transporting ATPases; D002155:Calsequestrin; D020097:Natriuretic Peptide, Brain; D012333:RNA, Messenger; D019831:Sodium-Calcium Exchanger; D000099211:Phospholamban