首页 | 本学科首页   官方微博 | 高级检索  
     


Targeting Ca 2+ cycling proteins and the action potential in heart failure by gene transfer
Authors:Roger Kaprielian   Federica del Monte  Roger J. Hajjar
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 Ca 2+ homeostasis such as reduced sarcoplasmic reticulum (SR) Ca 2+ release, elevated diastolic Ca 2+ and reduced rate of Ca 2+ removal. In addition, failing human myocardium is characterized by a frequency-dependent decrease in systolic force and Ca 2+ as opposed to normal myocardium where an increase in pacing rate results in potentiation of contractility and an increase in SR Ca 2+ release. In the failing heart, the decrease in SR Ca 2+ load has been linked to a decrease in SR Ca 2+ 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 Ca 2+ ATPase activity which involves decreasing the expression of phospholamban by antisense strategies to enhance SR Ca 2+ 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.
Keywords:
本文献已被 SpringerLink 等数据库收录!
设为首页 | 免责声明 | 关于勤云 | 加入收藏

Copyright©北京勤云科技发展有限公司  京ICP备09084417号