Related Experiment Video
Updated: Aug 24, 2026
Analysis of Cardiac Contractile Dysfunction and Ca2+ Transients in Rodent Myocytes
Published on: May 25, 2022
Phospholamban gene ablation improves calcium transients but not cardiac function in a heart failure model
Andrzej M Janczewski1, Maliha Zahid, Bonnie H Lemster
1Cardiovascular Institute, University of Pittsburgh, 200 Lothrop Street, 1744.1 BST, Pittsburgh, PA 15213, USA.
Insights
Ablating phospholamban did not improve heart failure in mice, despite enhancing cardiomyocyte function. This suggests other factors in heart failure prevent recovery even with improved calcium handling.
Area of Science:
- Cardiology
- Molecular Biology
- Physiology
Background:
- Diminished cardiomyocyte intracellular calcium (Ca(i)(2+)) transients impair cardiac function in heart failure.
- This is observed in human and animal models, including the TNF1.6 mouse model with cardiac-specific tumor necrosis factor alpha (TNF alpha) overexpression.
Purpose of the Study:
- To investigate if ablating phospholamban (PLB) expression improves cardiac function, limits remodeling, and enhances survival in the TNF1.6 heart failure mouse model.
- Phospholamban ablation enhances sarcoplasmic reticulum (SR) Ca(2+) uptake and contractility by removing SR Ca(2+) pump inhibition.
Main Methods:
- Breeding PLB knockout (PLBKO) mice with TNF1.6 mice to create TNF1.6/PLBKO (TKO) mice.
- Assessing survival, cardiac function (echocardiography), cardiac remodeling (hypertrophy, dilation, fibrosis), and cardiomyocyte Ca(2+)(i) transients and contractile function.
Main Results:
- PLB ablation did not improve survival, cardiac function, or limit cardiac remodeling in TNF1.6 mice.
- However, isolated TKO cardiomyocytes showed markedly enhanced contractile function and Ca(2+)(i) transients (amplitude and kinetics).
- Discordance may stem from continued collagen overexpression and decreased connexin 43 in response to chronic TNF alpha.
Conclusions:
- Enhancing intrinsic cardiomyocyte Ca(2+)(i) cycling and contractile function alone may be insufficient to overcome parallel pathophysiologic processes in heart failure.
- Further research is needed to address the complex mechanisms underlying heart failure progression.
Unlabelled:
Decreased amplitude and slower kinetics of cardiomyocyte intracellular calcium (Ca(i)(2+)) 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 alpha (TNF alpha).
Objective:
Since ablation of phospholamban expression (PLBKO) removes inhibition of the sarcoplasmic reticulum (SR) Ca(2+) pump, enhances SR Ca(2+) 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 Ca(2+)(i) 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(2+)(i) transients (amplitude and kinetics) of isolated TKO cardiomyocytes were markedly enhanced. This discordance between unimproved cardiac function, and enhanced Ca(2+)(i) 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 TNF alpha stimulation.
Conclusions:
Enhancement of intrinsic cardiomyocyte Ca(2+)(i) cycling and contractile function may not be sufficient to overcome several parallel pathophysiologic processes present in the failing heart.
