Notch-independent RBPJ controls angiogenesis in the adult heart

作者：Diaz Trelles Ramon^*; Scimia Maria Cecilia; Bushway Paul; Tran Danh; Monosov Anna; Monosov Edward; Peterson Kirk; Rentschler Stacey; Cabrales Pedro; Ruiz Lozano Pilar; Mercola Mark^*

来源：Nature Communications, 2016, 7(1): 12088.

DOI：10.1038/ncomms12088

Increasing angiogenesis has long been considered a therapeutic target for improving heart function after injury such as acute myocardial infarction. However, gene, protein and cell therapies to increase microvascularization have not been successful, most likely because the studies failed to achieve regulated and concerted expression of pro-angiogenic and angiostatic factors needed to produce functional microvasculature. Here, we report that the transcription factor RBPJ is a homoeostatic repressor of multiple pro-angiogenic and angiostatic factor genes in cardiomyocytes. RBPJ controls angiogenic factor gene expression independently of Notch by antagonizing the activity of hypoxia-inducible factors (HIFs). In contrast to previous strategies, the cardiomyocyte-specific deletion of Rbpj increased microvascularization of the heart without adversely affecting cardiac structure or function even into old age. Furthermore, the loss of RBPJ in cardiomyocytes increased hypoxia tolerance, improved heart function and decreased pathological remodelling after myocardial infarction, suggesting that inhibiting RBPJ might be therapeutic for ischaemic injury.

• 出版日期2016-6