UC San Diego

Heart disease and the resultant heart failure is one of the leading causes of death in the world. Although advances in treating heart failure have improved patient outcomes, the morbidity and mortality of the disease still remains high. Based on the finding that up-regulation of brain natriuretic peptide (BNP) is a biomarker of heart failure, which can be a result of abnormal stretch of cardiomyocytes, in this thesis, we attempted to make adenoviral reporter constructs using BNP promoter that is activated upon mechanical stretch to establish a basis for gene transfer therapy for heart failure. Using a mechanical device to mimic abnormal stretch of cardiomyocytes, we investigated the stretch-induced expression of several reporter constructs, which contained different combinations of regulatory sequences (GATA4, M- CAT and Nkx2-5) known to be involved in stretch-induced BNP expression. Our study concluded that among those reporter constructs we prepared, only GATA4-containing construct showed significant level of expression with up- regulation of 1.57 fold upon stretch. Although such result from this has much to be improved, the identification of stretch-inducible artificial gene construct will serve as an important framework to let us focus on increasing the degree of up-regulation for clinical applications