Adenoviral-Mediated SERCA Gene Transfer Into Cardiac Myocytes

I n the last decade, a great deal of attention has been focused on adenoviral-mediated gene transfer into somatic cells as a possible therapeutic approach.Somatic gene transfer into postmitotic cells (such as cardiomyocytes) provides a very powerful means to deliver the protein of interest, which is either functionally defective or missing because of loss of gene expression.In recent years, gene therapy for heart failure has gained considerable interest, mainly because of improvements in vector technology, cardiac gene delivery, and a better understanding of the molecular basis of heart failure.1,2 Ca 2؉ Handling and Heart FailureHeart failure provides an attractive candidate for gene therapy, because several targets have been identified as either functionally impaired or defective.Studies using animal models and failing human hearts have identified several abnormalities that affect excitation-contraction coupling.In particular, changes at the level of sarcolemmal/sarcoplasmic reticulum Ca 2ϩ transport and contractile proteins are thought to contribute to depressed contractile function.Cardiomyocytes from failing animal and human hearts reveal abnormal Ca 2ϩ homeostasis, such as reduced sarcoplasmic reticulum (SR) Ca 2ϩ release, elevated diastolic Ca 2ϩ , and reduced rate of Ca 2ϩ removal.[3][4][5] There is strong evidence that reduced expression or activity of the SR Ca 2ϩ ATPase (SERCA) and increased expression of Na ϩ -Ca 2ϩ exchanger are key changes contributing to alterations in calcium homeostasis in the heart.6 -10 It is also believed that abnormalities in calcium cycling are responsible for blunting of the frequency potentiation of contractile force in the failing human heart.11 Thus, SR Ca 2ϩ ATPase plays a dominant role in removing cytosolic Ca 2ϩ and is the main mechanism for restoring SR Ca 2ϩ load.The Na ϩ -Ca 2ϩ exchanger, on the other hand, transports calcium outside the cell and is a competitor of SR Ca 2ϩ ATPase with respect to SR calcium accumulation and availability for Ca 2ϩ release.Therefore, stimulation of SR Ca 2ϩ ATPase activity either by increasing pump expression or inhibiting phospholamban interaction, a modulator of SR pump function, should increase SR Ca 2ϩ transport and SR Ca 2ϩ load.