Altered cardiac annexin mRNA and protein levels in the left ventricle of patients with end-stage heart failure.
Annexins are a unique family of membrane-associated, Ca2+ and phospholipid-binding proteins found in various tissues. Among the 12 isoforms, Annexin II, V and VI exist in heart tissue in the highest amounts. Annexin VI has been shown to affect intracellular Ca2+ cycling and contractility in isolated cardiomyocytes. Annexin V is present in both cardiomyocytes and non-myocyte cell types in the heart and may play a role in the regulation of cellular ion fluxes, organization and secretion, while the cardiac effects of annexin II are unclear. To identify changes in annexin II, V and VI isoforms that might occur in human heart failure, we measured mRNA and protein levels of these three annexins in transplanted left ventricular tissue of 12 patients with end-stage congestive heart failure due to coronary artery disease (CAD, n=6) or idiopathic dilated cardiomyopathy (DCM, n=6) who underwent cardiac transplantation. Normal heart tissue (C, n=6) was used as a control. Northern blot analyses showed a significant decrease (61%) in annexin VI mRNA levels in heart failure patients compared with controls (1.08+/-0.16 v 2.79+/-0.20 A.U.C. unit, determined by laser densitometry, mean+/-s.e.). In contrast, we found a 67% increase (2. 32+/-0.27 v 3.88+/-0.29) in annexin II mRNA levels and a two-fold increase (1.00+/-0.24 v 2.21+/-0.29) in annexin V mRNA levels in cardiomyopathic hearts as compared to normal hearts. Western blot analyses demonstrated a corresponding decrease (46.1%) in annexin VI protein levels in the heart failure group as compared to controls (2. 63+/-0.22 v 4.88+/-0.52), while annexin II protein levels showed a significant 40.7% increase in patients with heart failure compared to those in normal hearts (5.08+/-0.67 v 3.61+/-0.32). Annexin V protein levels were also significantly increased (45%) in heart failure patients compared with normal (2.14+/-0.19 v 1.48+/-0.11). No difference in either annexins II, V or VI mRNA and protein levels were found between CAD and DCM patients. We conclude that human end-stage heart failure is associated with a down regulation of annexin VI and up regulation of annexin II and V proteins. Coordinate changes were observed in steady-state mRNA levels. These results suggest that these annexin isoforms may contribute to the regulation of intracellular Ca2+ homeostasis in the cardiomyopathic heart.
Song
G
G
Division of Cardiology, University of Cincinnati, Cincinnati, OH, USA.
Campos
B
B
Wagoner
L E
LE
Dedman
J R
JR
Walsh
R A
RA
D000328:Adult; D017306:Annexin A2 / Q000235:genetics / Q000378:metabolism; D017304:Annexin A5 / Q000235:genetics / Q000378:metabolism; D017317:Annexin A6 / Q000235:genetics / Q000378:metabolism; D017302:Annexins / Q000235:genetics* / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D016022:Case-Control Studies; D015536:Down-Regulation; D006333:Heart Failure / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D006352:Heart Ventricles / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism*; D015854:Up-Regulation
D017306:Annexin A2; D017304:Annexin A5; D017317:Annexin A6; D017302:Annexins; D012333:RNA, Messenger; D002118:Calcium