A critical role for HEXIM1 in heart development

The transcription factor Hexamethylene‐bis‐acetamide‐inducible protein 1 ( HEXIM1) is a tumor suppressor and a cyclin‐dependent kinase inhibitor. We and others found that these functions are mainly dependent on the C‐terminal region. We created mice with an insertional mutation in the HEXIM1 gene that disrupts this C‐terminal region. HEXIM1 is expressed in heart tissues from embryonic day 10.5 with the most intense staining in the myocardium and epicardium. HEXIM1−/ − mice died perinatally and had growth retardation, abnormal coronary patterning, thin ventricular walls, and increased ventricular chamber size. The thin myocardium may be partly attributed to increased myocardial apoptosis in HEXIM −/ − mice. PECAM‐1 immunostaining of HEXIM mutant heart sections indicated markedly decreased vascularization of the myocardium despite the presence of coronary vessels in the epicardium. Angioblast invasion is mediated by VEGF and FGF pathways and members of these pathways VEGFR2, VEGF‐A and FGF9 were decreased in expression in HEXIM1−/ − compared to HEXIM+/+ littermates. Thus mutation of HEXIM1 affected the VEGF and FGF pathway, contributing to dysregulation of coronary vessel development, and influencing ventricular compaction. Since epicardial FGF9 signaling is essential for myocardial proliferation, effects of HEXIM1 in the myocardium may also be mediated through this pathway. Our results suggest that HEXIM1 signaling regulates critical pathways in coronary vessel patterning, myocardial vascularization, and ventricular compaction in the developing heart.