Targeting calcium cycling proteins in heart failure through gene transfer

Abstract

Our understanding of cardiac excitation-contraction coupling has improved significantly over the last 10 years. Furthermore, defects in the various steps of excitation-contraction coupling that characterize cardiac dysfunction have been identified in human and experimental models of heart failure. The various abnormalities in ionic channels, transporters, kinases and various signalling pathways collectively contribute to the 'failing phenotype.' However, deciphering the causative changes continues to be a challenge. An important tool in dissecting the importance of the various changes in heart failure has been the use of cardiac gene transfer. To achieve effective cardiac gene transfer a number of obstacles remain, including appropriate vectors for gene delivery, appropriate delivery systems, and a better understanding of the biology of the disease. In this review, we will examine our current understanding of these various factors. Gene transfer provides not only a potential therapeutic modality but also an approach to identifying and validating molecular targets.

Figure 1. Gene transfer method in rat models involving the cross-clamping of the aorta and pulmonary artery while the viral solution is injected in the aortic root

Modified from Hajjar et al. (2000a).

Figure 2. Changes in calcium handling proteins in heart failure superimposed on an excitation-contraction coupling scheme

Modified from Hajjar et al. (2000a).

Figure 3. Left ventricular pressure vs. left ventricular volume detected by piezoelectric crystals in a sham + Ad.GFP heart, a failing + Ad.GFP heart and a failing + Ad.SERCA2a heart

Ad.GFP and Ad.SERCA2a depict modified adenoviruses carrying either the reporter gene green fluorescent protein (GFP) or SERCA2a. The end-systolic pressure volume relationship is restored to normal and the diastolic ventricular volume is decreased in the failing heart with gene targeted SERCA2a overexpression. Modified from del Monte et al. (2001).

Figure 4. Survival curves in failing rats compared with failing rats who have had SERCA2a gene transfer

Modified from del Monte et al. (2001).

Figure 5. In rats with heart failure, the PCr-to-ATP ratio and the PCr and ATP contents are lower than in the sham hearts

Overexpression of SERCA2a restores the PCr-to-ATP ratio back to normal. Modified from del Monte et al. (2001b).