Cell and gene based methods to improve cardiac function

摘要

Compositions and methods for improving cardiac function, myocardial contractility and relaxation in a mammal are provided. Cardiomyocytes transfected with one or more expression vectors comprising a ribonucleotide reductase subunit Rl -encoding nucleic acid sequence and a ribonucleotide reductase subunit R2-encoding nucleic acid sequence operably linked to a promoter are grafted to a mammalian myocardium. Alternatively, viral vector(s) having the Rl and R2-encoding construct(s) are administered to the mammal directly. Overexpression of Rl and R2 subunits leads to formation of the RR complex, which in turn generates dATP. Improvement of cardiac function can also be effected by administration of vectors comprising a nucleic acid sequence encoding a L48Q-substituted, I61Q-substituted, or L57Q-substituted cTnC variant. Also provided are compositions and methods for delivering dATP to a myocardium through grafting of donor cells overexpressing Rl and R2. dATP is thereby produced in situ and delivered through gap junctions established between donor cells and host cardiomyocytes.