Abstract
Decreased amplitude and slower kinetics of cardiomyocyte intracellular calcium (Cai2+) transients may underlie the diminished cardiac function observed in heart failure. These alterations occur in humans and animals with heart failure, including the TNF1.6 mouse model, in which heart failure arises from cardiac-specific overexpression of tumor necrosis factor α (TNFα). Objective: Since ablation of phospholamban expression (PLBKO) removes inhibition of the sarcoplasmic reticulum (SR) Ca2+ pump, enhances SR Ca2+ uptake and increases contractility, we assessed whether ablation of phospholamban expression could improve cardiac function, limit remodeling, and improve survival in the TNF1.6 model of heart failure. Methods: We bred PLBKO with TNF1.6 mice and characterized the progeny for survival, cardiac function (echocardiography), cardiac remodeling (hypertrophy, dilation, fibrosis), and Cai2+ transients and contractile function of isolated cardiomyocytes. Results: PLB ablation did not improve survival, cardiac function, or limit cardiac chamber dilation and hypertrophy in TNF1.6 mice (TKO mice). However, contractile function and Ca i2+ transients (amplitude and kinetics) of isolated TKO cardiomyocytes were markedly enhanced. This discordance between unimproved cardiac function, and enhanced Cai2+ cycling and cardiomyocyte contractile parameters may arise from a continued overexpression of collagen and decreased expression of gap junction proteins (connexin 43) in response to chronic TNFα stimulation. Conclusions: Enhancement of intrinsic cardiomyocyte Cai2+ cycling and contractile function may not be sufficient to overcome several parallel pathophysiologic processes present in the failing heart.
| Original language | English |
|---|---|
| Pages (from-to) | 468-480 |
| Number of pages | 13 |
| Journal | Cardiovascular research |
| Volume | 62 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - Jun 1 2004 |
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All Science Journal Classification (ASJC) codes
- Physiology
- Cardiology and Cardiovascular Medicine
- Physiology (medical)
Cite this
Phospholamban gene ablation improves calcium transients but not cardiac function in a heart failure model. / Janczewski, Andrzej M.; Zahid, Maliha; Lemster, Bonnie H.; Frye, Carol S.; Gibson, Gregory; Higuchi, Yoshihiro; Kranias, Evangelia G.; Feldman, Arthur M.; McTiernan, Charles F.
In: Cardiovascular research, Vol. 62, No. 3, 01.06.2004, p. 468-480.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Phospholamban gene ablation improves calcium transients but not cardiac function in a heart failure model
AU - Janczewski, Andrzej M.
AU - Zahid, Maliha
AU - Lemster, Bonnie H.
AU - Frye, Carol S.
AU - Gibson, Gregory
AU - Higuchi, Yoshihiro
AU - Kranias, Evangelia G.
AU - Feldman, Arthur M.
AU - McTiernan, Charles F.
PY - 2004/6/1
Y1 - 2004/6/1
N2 - Decreased amplitude and slower kinetics of cardiomyocyte intracellular calcium (Cai2+) transients may underlie the diminished cardiac function observed in heart failure. These alterations occur in humans and animals with heart failure, including the TNF1.6 mouse model, in which heart failure arises from cardiac-specific overexpression of tumor necrosis factor α (TNFα). Objective: Since ablation of phospholamban expression (PLBKO) removes inhibition of the sarcoplasmic reticulum (SR) Ca2+ pump, enhances SR Ca2+ uptake and increases contractility, we assessed whether ablation of phospholamban expression could improve cardiac function, limit remodeling, and improve survival in the TNF1.6 model of heart failure. Methods: We bred PLBKO with TNF1.6 mice and characterized the progeny for survival, cardiac function (echocardiography), cardiac remodeling (hypertrophy, dilation, fibrosis), and Cai2+ transients and contractile function of isolated cardiomyocytes. Results: PLB ablation did not improve survival, cardiac function, or limit cardiac chamber dilation and hypertrophy in TNF1.6 mice (TKO mice). However, contractile function and Ca i2+ transients (amplitude and kinetics) of isolated TKO cardiomyocytes were markedly enhanced. This discordance between unimproved cardiac function, and enhanced Cai2+ cycling and cardiomyocyte contractile parameters may arise from a continued overexpression of collagen and decreased expression of gap junction proteins (connexin 43) in response to chronic TNFα stimulation. Conclusions: Enhancement of intrinsic cardiomyocyte Cai2+ cycling and contractile function may not be sufficient to overcome several parallel pathophysiologic processes present in the failing heart.
AB - Decreased amplitude and slower kinetics of cardiomyocyte intracellular calcium (Cai2+) transients may underlie the diminished cardiac function observed in heart failure. These alterations occur in humans and animals with heart failure, including the TNF1.6 mouse model, in which heart failure arises from cardiac-specific overexpression of tumor necrosis factor α (TNFα). Objective: Since ablation of phospholamban expression (PLBKO) removes inhibition of the sarcoplasmic reticulum (SR) Ca2+ pump, enhances SR Ca2+ uptake and increases contractility, we assessed whether ablation of phospholamban expression could improve cardiac function, limit remodeling, and improve survival in the TNF1.6 model of heart failure. Methods: We bred PLBKO with TNF1.6 mice and characterized the progeny for survival, cardiac function (echocardiography), cardiac remodeling (hypertrophy, dilation, fibrosis), and Cai2+ transients and contractile function of isolated cardiomyocytes. Results: PLB ablation did not improve survival, cardiac function, or limit cardiac chamber dilation and hypertrophy in TNF1.6 mice (TKO mice). However, contractile function and Ca i2+ transients (amplitude and kinetics) of isolated TKO cardiomyocytes were markedly enhanced. This discordance between unimproved cardiac function, and enhanced Cai2+ cycling and cardiomyocyte contractile parameters may arise from a continued overexpression of collagen and decreased expression of gap junction proteins (connexin 43) in response to chronic TNFα stimulation. Conclusions: Enhancement of intrinsic cardiomyocyte Cai2+ cycling and contractile function may not be sufficient to overcome several parallel pathophysiologic processes present in the failing heart.
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UR - http://www.scopus.com/inward/citedby.url?scp=2442501143&partnerID=8YFLogxK
U2 - 10.1016/j.cardiores.2004.02.006
DO - 10.1016/j.cardiores.2004.02.006
M3 - Article
C2 - 15158139
AN - SCOPUS:2442501143
VL - 62
SP - 468
EP - 480
JO - Cardiovascular Research
JF - Cardiovascular Research
SN - 0008-6363
IS - 3
ER -