Assistant Professor Texas Tech University Health Sciences Center Amarillo, Texas
The main pathophysiological effect associated with heart failure is the inability of the cardiomyocytes to regenerate. Meis1 and Hoxb13 transcription factors showed an evidence for their druggability to regulate postnatal cardiomyocyte cell cycle arrest, where concomitant deletion of both genes induced cardiomyocyte proliferation and regeneration following ischemic injury. Therefore, we performed an in-silico screen to identify FDA approved drugs to inhibit Meis1 and Hoxb13 transcriptional activity. Our screen concluded two drugs can induce neonatal rat ventricular myocytes proliferation in vitro, displayed dose-dependent inhibition of Meis1 and Hoxb13 activity, and disruption of DNA binding. X-ray crystal structure revealed that both drugs bind to Meis1 nearby Hoxb13 interaction. Dual administration of both drugs by i.p. injection in mice and IV in pigs induced cardiomyocyte proliferation, improved left ventricular (LV) systolic function, and decreased scar formation in ischemic injury models. Collectively, we repurposed FDA approved drugs for induction of heart regeneration in mammals.
Learning Objectives:
Identify the role of Meis1 and HoxB13 in the regulation of cardiac regeneration and
Understand the druggability potential of Meis1 and HOXB13 transcription factors in heart failure cases.
Identify structure-based drug repurposing strategy to inhbit Meis1 and HOXB13 transcription factors in heart failure cases.