Heart failure is one of the leading causes of death worldwide. A stimulated heart
undergoes either adaptive physiological hypertrophy, which can maintain a normal heart
function, or maladaptive pathological remodeling, which can deteriorate heart function.
These 2 kinds of remodeling often co-occur at the early stages of many heart diseases
and have important effects on cardiac function. The Bcl2-associated athanogene 3 (BAG3)
protein is highly expressed in the heart and has many functions. However, it is unknown
how BAG3 is regulated and what its function is during physiological hypertrophy and
pathological remodeling. We generated tamoxifen-induced, heart-specific heterozygous
and homozygous BAG3 knockout mouse models (BAG3 protein level decreased by approximately
40% and 80% in the hearts after tamoxifen administration). BAG3 knockout models were
subjected to swimming training or phenylephrine (PE) infusion to induce cardiac physiological
hypertrophy and pathological remodeling. Neonatal rat ventricular cardiomyocytes (NRVCs)
were used to study BAG3 functions and mechanisms in vitro. We found that BAG3 was
upregulated in physiological hypertrophy and in pathological remodeling both in vivo
and in vitro. Heterozygous or homozygous knockout BAG3 in mouse hearts and knockdown
of BAG3 in the NRVCs blunted physiological hypertrophy and aggravated pathological
remodeling, while overexpression of BAG3 promoted physiological hypertrophy and inhibited
pathological remodeling in NRVCs. Mechanistically, BAG3 overexpression in NRVCs promoted
physiological hypertrophy by activating the protein kinase B (AKT)/mammalian (or mechanistic)
target of rapamycin (mTOR) pathway. BAG3 knockdown in NRVCs aggravated pathological
remodeling through activation of the calcineurin/nuclear factor of activated T cells
2 (NFATc2) pathway. Because BAG3 has a dual role in cardiac remodeling, heart-specific
regulation of BAG3 may be an effective therapeutic strategy to protect against deterioration
of heart function and heart failure caused by many heart diseases.
Abbreviations:
ACTA1 (skeletal α-actin), AKT (protein kinase B), α-MHC (α-myosin heavy chain), ANP (atrial natriuretic peptide), BAG3 (Bcl2-associated athanogene 3), β-MHC (Myh7, β-myosin heavy chain), Cre+Bag3+/+ (α-MHC-MerCreMer+Bag3+/+), Cre+Bag3+/f (α-MHC-MerCreMer+Bag3+/flox), Cre+Bag3f/f (α-MHC-MerCreMer+Bag3flox/flox), CM (Cardiomyocyte), 4E-BP1 (eukaryotic translation initiation factor 4E-binding protein 1), HE (heterozygous), HO (homozygous), IGF1 (insulin-like growth factor 1), KO (knockout), MerCreMer (tamoxifen-inducible Cre recombinase), mTOR (mammalian (mechanistic) target of rapamycin), NC (negative control), NFATC2 (nuclear factor of activated T cells 2), NRVC (neonatal rat ventricular cardiomyocyte), PE (phenylephrine), PI3K (phosphoinositide 3-kinase), SERCA (sarco/endoplasmic reticulum Ca2+-ATPase), TMX (tamoxifen)To read this article in full you will need to make a payment
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Article info
Publication history
Published online: February 08, 2021
Accepted:
February 4,
2021
Received in revised form:
February 2,
2021
Received:
June 15,
2020
Identification
Copyright
© 2021 Elsevier Inc. All rights reserved.
