Abstract 13228: Apoptosis Occurs in Late Stages of Unloading Related Ventricular Remodeling
Objective: As previously shown, myocardial unloading of a normal heart results in progressive atrophy associated with gradual loss of cardiomyocyte volume, shifted myocyte/connective tissue ratio, increase in myocardial stiffness and modifications of ventricular contractile capacity. Here, we examined effects of long-term unloading on gene expression with respect to remodeling of the contractile apparatus and/or myocardial apoptosis, which is an object of discussion with implications as to potential recovery mechanisms of an unloaded failing heart.
Methods: Heterotopically transplanted normal rat hearts were harvested at 3, 8, 15, 30 and 60 days. Total RNA was purified and 47 genes were analyzed using microfluid assay. Immunohistochemistry for cleaved Caspase (cCasp)-3 and TUNEL assay was utilized to corroborate findings regarding apoptosis.
Results: In parallel to marked atrophy (14 up to 63% ventricular volume loss at 3 resp. 60 days), genes involved in myocyte contractility (α-actin, α-MHC, SERCA2a, Troponin T) were significantly downregulated within 3 days, but partially recovered with duration of unloading. Fetal gene expression was upregulated to peak at 60 days (β-MHC (8-fold), ANF (3.8-fold), Troponin C (2.5-fold) and FGF-2 (3.2-fold), p<0.05). mRNA levels of apoptotic transcripts bax, bcl-2, bnip-3, cCasp-6 and -9 were not modified up to 30 days, but showed upregulation at 60 days (Figure). cCasp-3 was identified 3 days after transplantation surgery and again after 60 days, which also was the only time point showing TUNEL-positive apoptotic nuclei.
Conclusion: Our results suggest that unloading-induced atrophy is associated with rapid decline followed by early recovery of gene expression regulating the myocardial contractile apparatus. Signs of apoptosis occur only late after unloading at 60 days, indicating a time dependent mechanism that suggests the importance of reloading the heart to prevent excessive atrophy and possible cell death.
- © 2011 by American Heart Association, Inc.