Viral vector-mediated gene transfer in fundamental and applied cardiovascular research

Abstract

To treat various cardiac diseases, modification of gene expression for the purpose of increased or decreased expression of a particular gene, is regarded as a potential therapy. As a vehicle to introduce the gene of choice into the heart cell, virus vectors have given the most promising results. This thesis describes studies that are undertaken to investigate how virus vectors may be used to efficiently target cardiac cells and what the effects of certain genetic interventions are on the (patho)physiology of heart cells. We used lentivirus vectors to study the effects of integrin stimulation in neonatal rat cardiomyocytes on the uptake of macromolecules by these cells and through which pathway integrin stimulation leads to cardiac hypertrophy. Furthermore, the role of gap junctional coupling in the development of arrhythmias and in the cardiac differentiation of mesenchymal stem cells was investigated by modulating the expression of connexin 43 using lentivirus vectors. As adeno-associated virus vectors in particular have shown great potential as vector system to target the heart, we aimed to develop AAV vectors that may be used to specifically target either the cardiomyocytes or fibroblasts in the heart.