Abstract 17882: Cardiac Deletion of Brg1 Chromatin Remodeling Atpase Causes Dilated Cardiomyopathy
Background: Brahma-related gene 1 (Brg1) is the ATPase subunit of a large chromatin-remodeling complex. Chromatin changes mediated by this complex play essential roles in cell proliferation and differentiation. Mammalian cardiomyocytes (CMs) switch from proliferation to hypertrophy with concomitant transition from fetal to adult gene programming during neonatal development. Whether Brg1 is involved in the neonatal transition of CMs from a fetal to an adult phenotype remains unclear.
Methods: Using the Cre recombinase driven by alpha-myosin heavy chain promoter (MHC-Cre), we created a Brg1 loss-of-function by deleting 2 exons in the ATPase domain floxed by LoxP sites in the brg1 gene. Homozygous Brg1 deletion (KO) and wild-type (WT) mice were phenotyped by real-time RT-PCR, Western blotting, immunohistochemistry, and histology.
Results: Unlike global or SM22α-cre mediated Brg1 deletion, cardiac-specific homozygous deletion of Brg1 by MHC-Cre was compatible with neonatal viability, but caused increased mortality within 1 month after birth. Brg1 deficiency had no significant effect in cardiac cell cycle activity in 1, 4 and 8 day-old mice. However, the absence of Brg1 caused dilated cardiomyopathy during postnatal period. Body weight (BW) was similar between KO and WT mice. Heart weight (HW) was higher in KO than WT mice from 1 day (10.50±2.95 mg, KO vs. 9.41±1.58 mg, WT) to 8 days of age (62.67±7.37 mg, KO vs. 36.40±5.68 mg, WT). By 21 days of age, Brg1 KO mice developed chamber dilatation and congestive heart failure. Brg1 deletion did not delay the postnatal switch from a fetal to adult gene programming (downregulation of ANF and beta-MHC as well as upregulation of alpha-MHC). However, ANF was constantly higher in KO than in WT mice. Additionally, the postnatal decrease of ANF was reversed in KO, but not in WT mice at 8 days of age. Similarly, beta-MHC remained higher and alpha-MHC lower in KO than in WT mice at 8 days of age.
Conclusion: Brg1 is not required for CM proliferation in neonatal hearts. However, Brg1 deficiency caused dilated cardiomyopathy during postnatal heart development.
- © 2012 by American Heart Association, Inc.