NF2 signaling pathway plays a pro-apoptotic role in ?-adrenergic receptor stimulated cardiac myocyte apoptosis.

ABSTRACT: Treatment of adult rat ventricular myocytes (ARVMs) with ?-AR agonist (isoproterenol) for 15 min increased phosphorylation (serine-518) and sumoylation of NF2. Co-immunoprecipitation assay confirmed ?-AR-stimulated sumoylation of NF2. ?-AR stimulation enhanced nuclear translocation of phosphorylated and sumoylated NF2. Specific inhibition of ?1-AR and protein kinase A (PKA) decreased ?-AR-stimulated increase in NF2 post-translational modifications, while inhibition of ?2-AR had no effect. Activation of adenylyl cyclase using forskolin (FSK) mimicked the effects of ?-AR stimulation. ?-AR stimulation and expression of wild-type (WT)-NF2 using adenoviruses increased phosphorylation of mammalian sterile like kinase-1/2 (MST1/2) and yes activated protein (YAP), downstream targets of NF2. Knockdown of NF2 using siRNA in H9C2 cardiomyocytes decreased ?-AR-stimulated increase in NF2 and YAP phosphorylation. siRNA-mediated knockdown of NF2 decreased ?-AR-stimulated increase in apoptosis, while expression of WT-NF2 induced apoptosis in ARVMs. Expression of WT-NF2 stimulated the mitochondrial death pathway as evidenced by activation of c-Jun N-terminal Kinases (JNKs), and increase in cytosolic cytochrome c levels and Bax expression.?-AR stimulation affects post-translational modifications of NF2 via the involvement ?1-AR/PKA/cAMP pathway, and NF2 plays a pro-apoptotic role in ?-AR-stimulated myocyte apoptosis via the phosphorylation (inactivation) of YAP and involvement of mitochondrial death pathway.

SUBMITTER: Dalal S 

PROVIDER: S-EPMC5927447 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature