Abstract 16226: Mechanism of Caveolin and Plasma Membrane Repair in Daunorubicin-induced Heart Failure
Background: Anthracyclines, such as daunorubicin (Dau), are used as anticancer drugs but are associated with heart failure. Caveolin-3 (Cav-3), a structural protein in cell membranes, and membrane repair proteins, such as mitsugumin-53 (MG-53) and dysferlin, are involved in protection of the heart from cardiac stress. However, little is known about their roles in anthracycline-induced heart failure. We hypothesize that Dau alters caveolin and membrane repair proteins in the heart.
Methods and Results: New Zealand rabbits were administered Dau (3 mg/kg, intravenous) weekly for 9 weeks to induce heart failure. Dau treatment resulted in reduced left ventricle (LV) ejection fraction (Control; 69 % vs Dau; 38 %, n=8, p<0.001). LV samples from rabbits with Dau-induced heart failure showed increased Cav-3 protein expression compared to control tissues (2.8-fold vs. control, n=6, p<0.05), with no change in caveolin-1 (Cav-1). Sucrose density fractionation of LV samples from rabbits with Dau-induced heart failure showed that Cav-3, but not Cav-1, was increased (2.6-fold vs control, n=4, p<0.05). In addition, electron microscopy images show that Dau treatment increases formation of caveolae (1.9-fold vs control, n=10-12, p<0.01). Moreover, protein expression of MG-53 and dysferlin was increased in Dau-treated hearts (2.0 and 2.5-fold, n=6, p<0.05). Other membrane repair proteins such as affixin, calpain-3, and PTRF (polymerase-1 and transcriptase release factor) were unchanged. Immunomicroscopy revealed MG-53 and dysferlin were co-localized with Cav-3 in the Dau-treated LV. We have found similar changes in Cav-3 in failed human heart, suggesting the relevance of our rabbit model (1.3-fold vs. non failing human heart, n=5, p<0.05).
Conclusion: In rabbits with heart failure induced by Dau, caveolae, Cav-3, and membrane repair proteins are increased in LV. The results suggest a potential pathophysiologic role for Cav-3 and membrane repair proteins in daunorubicin-induced heart failure.
Author Disclosures: Y. Ichikawa: None. A. Zemlic-Harpf: None. M.D. McKirnan: None. Z. Zhang: None. A.M. Manso: None. R.S. Ross: None. H.K. Hammond: None. H.H. Patel: None. D.M. Roth: None.
- © 2016 by American Heart Association, Inc.