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Targeting Ca2+ cycling proteins and the action potential in heart failure by gene transfer
Roger Kaprielian1, Federica del Monte, Roger J Hajjar
1Cardiovascular Research Center, Massachusetts General Hospital, 149 13th Street, CNY-4, 4215, Charlestown, MA 02129, USA.
Insights
Gene transfer of SERCA2a restores contractile function in failing human hearts by improving calcium handling. This approach, along with targeting phospholamban and the Na/Ca exchanger, offers potential therapeutic strategies for heart failure.
Area of Science:
- Cardiology
- Molecular Biology
- Biochemistry
Background:
- Cardiomyocytes in failing human hearts exhibit contractile dysfunction and abnormal calcium (Ca2+) homeostasis.
- Key issues include reduced sarcoplasmic reticulum (SR) Ca2+ release, elevated diastolic Ca2+, and impaired Ca2+ removal.
- A decrease in SR Ca2+ ATPase (SERCA2a) function is linked to reduced SR Ca2+ load in heart failure.
Purpose of the Study:
- To investigate the therapeutic potential of enhancing SERCA2a function in failing human hearts.
- To explore strategies for improving Ca2+ handling and action potential duration in heart failure.
- To examine the long-term effects and energy cost of SERCA2a expression.
Main Methods:
- Adenoviral gene transfer to overexpress SERCA2a in cardiomyocytes.
- Utilizing a pressure-overload hypertrophy model in animals transitioning to failure.
- Employing Nuclear Magnetic Resonance (NMR) methods to assess energy cost.
- Investigating antisense strategies to decrease phospholamban expression.
- Targeting the Na/Ca exchanger for enhanced calcium removal.
- Using gene transfer of K+ channels to study action potential prolongation.
Main Results:
- Overexpression of SERCA2a via adenoviral gene transfer restored contractile function in cardiomyocytes from failing human hearts.
- Enhanced SERCA2a improved contractile function and reserve in a pressure-overload hypertrophy model.
- Research is ongoing to evaluate long-term SERCA2a expression and its energy cost.
- Strategies to decrease phospholamban and target the Na/Ca exchanger are being explored.
- Investigating the molecular and ionic basis of action potential prolongation and its impact on calcium handling.
Conclusions:
- Restoring SERCA2a function through gene transfer is a promising therapeutic approach for heart failure.
- Modulating Ca2+ homeostasis and action potential duration are key targets for improving cardiac function.
- Gene transfer holds potential as a novel therapeutic strategy for heart failure.
Abstract:
Cardiomyocytes isolated from failing human hearts are characterized by contractile dysfunction including prolonged relaxation, reduced systolic force and elevated diastolic force. These contractile abnormalities are paralleled by abnormal Ca2+ homeostasis such as reduced sarcoplasmic reticulum (SR) Ca2+ release, elevated diastolic Ca2+ and reduced rate of Ca2+ removal. In addition, failing human myocardium is characterized by a frequency-dependent decrease in systolic force and Ca2+ as opposed to normal myocardium where an increase in pacing rate results in potentiation of contractility and an increase in SR Ca2+ release. In the failing heart, the decrease in SR Ca2+ load has been linked to a decrease in SR Ca2+ ATPase (SERCA2a) function. We have recently shown that overexpression of SERCA2a by adenoviral gene transfer restores contractile function in cardiac myocytes from failing human hearts. In addition, we have shown that overexpression of SERCA2a in a model of pressure-overload hypertrophy in transition to failure improves contractile function and reserve in these animals. We are currently exploring the effect of long-term expression of SERCA2a in failing animals along with the energy cost of SERCA2a expression using NMR methods. We are also using a different strategy to improve SR Ca2+ ATPase activity which involves decreasing the expression of phospholamban by antisense strategies to enhance SR Ca2+ ATPase activity. The Na/Ca exchanger is also being targeted to enhance calcium removal in failing hearts. Action potential prolongation is attributed to reductions in transient outward current (Ito) density in human heart failure. This prolongation can alter contractility but can also cause afterdepolarization. Using gene transfer of various K channels responsible for Ito, we are investigating the molecular and the ionic basis of action potential prolongation in cardiac hypertrophy and failure and we are examining how intracellular calcium handling changes in response to alterations in action potential duration. Gene transfer, which serves initially as an experimental tool, may provide a novel therapeutic approach.