Endothelin-1–Dependent Nuclear Factor of Activated T Lymphocyte Signaling Associates With Transcriptional Coactivator p300 in the Activation of the B Cell Leukemia-2 Promoter in Cardiac Myocytes

Abstract

Abstract-Endothelin-1 (ET-1) is a potent survival factor that protects cardiac myocytes from apoptosis. ET-1 induces cardiac gene transcription and protein expression of antiapoptotic B cell leukemia-2 (bcl-2) in a calcineurin-dependent manner. A cellular target of adenovirus early region 1A (E1A) oncoprotein, p300 also activates bcl-2 transcription in cardiac myocytes and is required for their survival. p300 acts as a calcineurin-regulated nuclear factors of activated T lymphocytes (NFATc), downstream targets of calcineurin. In addition, the bcl-2 promoter contains multiple NFAT consensus sequences. These findings prompted us to investigate the role of NFATc in ET-1-dependent and p300-dependent bcl-2 transcription in cardiac myocytes. In primary cardiac myocytes prepared from neonatal rats, mutation of 2 NFAT sites within the bcl-2 promoter completely abolished the ET-1-and p300-induced increases in the activity of this promoter. We show here that p300 markedly potentiates the binding of NFATc1 to the bcl-2 NFAT element by interacting with NFATc1 in an E1A-dependent manner. On the other hand, stimulation of cardiac myocytes with ET-1 causes nuclear translocation of NFATc1, which interacts with p300 and increases DNA binding. Expression of E1A did not change the cardiac nuclear localization of NFATc1 but blocked its interaction with p300, DNA binding, and bcl-2 promoter activation. These findings suggest that ET-1-dependent NFATc signaling associates with p300 in the transactivation of bcl-2 gene in cardiac myocytes.

Histone Acetyltransferase Activity of p300 Is Required for the Promotion of Left Ventricular Remodeling After Myocardial Infarction in Adult Mice In Vivo

“…However, these data do not rule out the possible redundant and compensative roles of GATA-6 during LV remodeling after MI. In addition, p300 is able to interact not only with GATA-4 15,20 but also with other hypertrophy-responsive transcription factors such as myocyte enhancing factor-2, 27 nuclear factor of activated T-lymphocyte, 28 and AP-1. 29 Our findings might be applicable to these factors as well.…”

Multiple ryanodine receptor subtypes and heterogeneous ryanodine receptor-gated Ca2+stores in pulmonary arterial smooth muscle cells

“…The role of Ca 2ϩ sparks on the regulation of transcription factors in PASMCs has not been examined. However, since ET-1 is a potent mitogenic agonist involved in pulmonary vascular remodeling in pulmonary hypertension (7,22) and is known to activate NFAT and other Ca 2ϩ -sensitive transcription factors (28,47) that mediate vascular cell proliferation, it is possible that Ca 2ϩ sparks originating in the perinuclear regions may be involved in the regulation of gene expressions in PASMCs, perhaps in pulmonary hypertension.…”

The role of nuclear factor of activated T cells in pulmonary arterial hypertension

“…15,16,60 In clinic, efficacy and safety of endothelin-receptor antagonist has been confirmed in PAH patients. [61][62][63][64] Because ET-1 (upregulated in PAH) activates NFATc1, which in turn increases bcl ¡ 2 expression, contributing to the prosurvival and antiapoptotic effects of ET-1, 65 endothelin-receptor antagonist might also inhibit NFAT activation. At present, most of studies found that interventions targeting NFAT pathway may be effective for PAH therapy.…”