A New Dual-Promoter System for Cardiomyocyte-Specific Conditional Induction of Apoptosis

Abstract

Apoptosis is a key determinant of major pathological processes, including chronic cardiac failure. We developed and testedin vitroa novel system to induce cardiomyocyte-specific apoptosis by virus-mediated delivery of a conditional transgene. The entire system was packaged in a lentiviral vector. We used the cardiomyocyte-specific Na+-Ca2+exchange promoter to control the transcription of the reverse tetracycline transactivator, while the transgene expression was driven by the tetracycline-responsive element. The proapoptotic transgene of choice was the short isoform of the apoptosis-inducing factor, known to quickly induce the caspase-independent apoptosis when overexpressed in cells. Transduction of cardiomyocyte cells with this vector caused a tetracycline-regulated induction of apoptosis, which was not observed in noncardiac cells. Therefore, our system proved a valuable molecular tool for inducing controlled apoptosis in selected cells. Furthermore, the vector we developed is suitable for “lentivirus transgenesis,” an interesting strategy recently proposed for the genetic manipulation of animals other than mice, including large mammals.