ALTERED CARDIAC ANNEXIN MESSENGER-RNA AND PROTEIN-LEVELS IN THE LEFT-VENTRICLE OF PATIENTS WITH END-STAGE HEART-FAILURE

Annexins are a unique family of membrane-associated, Ca2+ and phosphol ipid-binding proteins found in various tissues. Among the 12 isoforms, Annexin II, V and VI exist in heart tissue in the highest amounts. An nexin VI has been shown to affect intracellular Ca2+ cycling and contr actility in isolated cardiomyocytes. Annexin V is present in both card iomyocytes 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 chan ges in annexin II, V and VI isoforms that might occur in human heart f ailure, we measured mRNA and protein levels of these three annexins in transplanted left ventricular tissue of 12 patients with end-stage co ngestive heart failure due to coronary artery disease (CAD, n = 6) or idiopathic dilated cardiomyopathy (DCM, n = 6) who underwent cardiac t ransplantation. 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 n mRNA levels and a two-fold increase (1.0 0 +/- 0.24 v 2.21 +/- 0.29) in annexin V mRNA levels in cardiomyopathi c hearts as compared to normal hearts. Western blot analyses demonstra ted a corresponding decrease (46.1%) in annexin VI protein levels in t he heart failure group as compared to controls 12.63 +/- 0.22 v 4.88 /- 0.52), while annexin II protein levels showed a significant 40.7% i ncrease in patients with heart failure compared to those in normal hea rts (5.08 +/- 0.67 v, 3.61 +/- 0.32). Annexin V protein levels were al so significantly increased (45%) in heart failure patients compared wi th normal (2.14 +/- 0.19 v, 1.48 +/- 0.11). No difference in either an nexins II, V or VI mRNA and protein levels were found between CAD and DCM patients. We conclude that human end-stage heart failure is associ ated with a down regulation of annexin VI and up regulation of annexin II and V proteins. Coordinate changes were observed in steady-state m RNA levels. These results suggest that these annexin isoforms may cont ribute to the regulation of intracellular Ca2+ homeostasis in the card iomyopathic heart. (C) 1998 Academic Press Limited.