Clinical and angiographic outcomes up to three years after coronary-artery stenting were favorable, with a low rate of revascularization of the stented lesions. Late improvement in luminal diameter appears to occur between six months and three years.

The expression of endothelin-1 (ET-1) in cardiac myocytes is markedly induced during the development of heart failure in vivo and by stimulation with the ␣ 1 -adrenergic agonist phenylephrine in culture. Although recent studies have suggested a role for cardiac-specific zinc finger GATA factors in the transcriptional pathways that modulate cardiac hypertrophy, it is unknown whether these factors are also involved in cardiac ET-1 transcription and if so, how these factors are modulated during this process. Using transient transfection assays in primary cardiac myocytes from neonatal rats, we show here that the GATA element in the rat ET-1 promoter was required for phenylephrine-stimulated ET-1 transcription. Cardiac GATA-4 bound the ET-1 GATA element and activated the ET-1 promoter in a sequencespecific manner. Stimulation by phenylephrine caused serine phosphorylation of GATA-4 and increased its ability to bind the ET-1 GATA element. Inhibition of the extracellularly responsive kinase cascade with PD098059 blocked the phenylephrine-induced increase in the DNA binding ability and the phosphorylation of GATA-4. These findings demonstrate that serine phosphorylation of GATA-4 is involved in ␣ 1 -adrenergic agonist-responsive transcription of the ET-1 gene in cardiac myocytes and that extracellularly responsive kinase 1/2 activation plays a role upstream of GATA-4. Endothelin-1 (ET-1)1 was initially identified as a 21-amino acid vasoconstrictive peptide in porcine vascular endothelial cells (1). Later work showed that it acts not only as a vasoconstrictor but also as a potent growth-promoting peptide. For example, ET-1 can induce myocyte hypertrophy (2, 3) through coupling of ET receptors with G q protein. ET-1 signaling is also coupled with G i protein. Therefore, it is able to decrease intracellular cAMP levels (4). Although ET-1 is mainly produced by endothelial cells in the basal state, a number of cell types can synthesize ET-1 in response to various stimuli (5-8). ET-1 expression in cardiac myocytes is induced by myocardial stretch, angiotensin II, and norepinephrine (6 -8). Left ventricular levels of ET-1 increase markedly in close association with the deterioration of systolic function following myocardial infarction and pressure overload (9, 10). Immunohistochemical studies have demonstrated that ET-1 in the failing heart is localized in cardiac myocytes. ET receptor antagonists bosentan and BQ123 prevent the remodeling of the heart and have been shown to improve survival following myocardial infarction and pressure overload (9, 10). These findings demonstrate that up-regulated expression of ET-1 in cardiac myocytes plays a critical role in the development of heart failure in vivo. However, the molecular mechanisms leading to this up-regulation in the failing heart are unclear at present.The mechanisms regulating the transcription of the ET-1 gene have been studied in endothelial cells. The 204-bp sequences proximal to the transcription starting site is sufficient to drive high levels of expression in these...

To understand remodeling of human coronary arteries undergoing coronary angioplasty or atherectomy, serial intravascular ultrasonographic examinations were performed at preintervention and postintervention examinations and at 24 hours, 1 month, and 6 months. Complete serial data were obtained in 61 lesions (balloon angioplasty, 35 lesions; directional atherectomy, 26 lesions). Lumen area improved from 6.81+/-2.24 mm2 after intervention to 8.22+/-2.79 mm2 at 1 month (P=.0001) and decreased to 4.88+/-2.86 mm2 at 6 months (P=.0001). Vessel area enlarged from 17.32+/-5.35 mm2 after intervention to 19.39+/-5.33 mm2 at 1 month (P=.0001) and decreased to 16.33+/-5.54 mm2 at 6 months (P=.0001). Plaque+media area increased significantly from postintervention examination to 24 hours (10.51+/-4.38 versus 10.96+/-4.49 mm2, P=.0008) and from 24 hours to 6 months (10.96+/-4.49 versus 11.45+/-4.45 mm2, P=.03). Changes in lumen area in each study interval correlated more closely with changes in vessel area than with changes in plaque+media area. Restenotic lesions compared with nonrestenotic lesions had a greater decrease in the vessel area between 1 month and 6 months (-4.33+/-2.73 versus -2.49+/-2.15 mm2, P=.006) and greater increase in the plaque+media area both within 24 hours (0.84+/-1.22 versus 0.27+/-0.38 mm2, P=.04) and between 24 hours and 6 months (1.19+/-2.19 versus 0.18+/-1.46 mm2, P=.04). CONCLUSIONS; Remodeling after coronary angioplasty or atherectomy was characterized by early adaptive enlargement and late constriction of the vessel.

The accelerated myocardial synthesis of ET-1 contributes directly to LV contractile dysfunction during the transition from LVH to CHF. Unelevated levels of LV ET-1 at the established LVH stage and lack of effects on LV mass by chronic bosentan treatment suggest that myocardial growth is mediated through alternative pathways. These studies indicate that chronic ET antagonism may provide an additional strategy for heart failure therapy in humans.

A cellular target of adenovirus E1A oncoprotein, p300 is a transcriptional coactivator and a negative regulator of cellular proliferation. A previous study suggests that the p300 family is also involved in cell type-specific transcription in cardiac myocytes. However, nothing is known about which cardiac transcription factor(s) interact with and transactivate through these proteins. The transcription factors GATA-4/5/6 have been implicated as key regulators of cardiogenesis, and they participate in the transcription of many cardiac-specific genes. Here we show that E1A represses the GATA-5-dependent transactivation of a promoter derived from the cardiac-restricted atrial natriuretic factor gene. This repression is correlated with the interaction of E1A with p300, indicating that p300 participates in GATA-5-dependent transactivation. E1A markedly down-regulates endogenous atrial natriuretic factor expression, as well as disrupts the interaction between p300 and GATA-5. A small fragment of p300 containing the carboxyl-terminal cysteine/histidine-rich domain, sufficient to interact with GATA-5, prevents transcriptional activation by GATA-5 as a dominant-negative mutant. Consistent with its role as a coactivator, p300 markedly potentiates GATA-5-activated transcription. These results implicate p300 as an important component of myocardial cell differentiation and provide an insight into the relationship between mechanisms that mediate cell type-specific transcription and cell cycle regulation during cardiogenesis.

Increases in the expression of endothelin-1 (ET-1) in cardiac myocytes play a critical role in the development of heart failure in vivo. Whereas norepinephrine (NE) is a potent inducer of ET-1 expression in cardiac myocytes, the signaling pathways that link NE to inducible cardiac ET-1 expression are unknown. Adrenergic stimulation results in an increase in intracellular calcium levels, which in turn activates calcineurin. Here, we have shown that stimulation with NE markedly increased the expression of the ET-1 gene in primary cardiac myocytes from neonatal rats. This increase was severely attenuated by a ␤-adrenergic antagonist, metoprolol, but not by an ␣-adrenergic antagonist, prazosin. Consistent with these data, the ␤-adrenergic agonist isoproterenol (ISO) activated the rat ET-1 promoter activity to an extent that was similar to NE. The ISO-stimulated increase in promoter activity was significantly inhibited by a Ca 2؉ -antagonist, nifedipine, and an immunosuppressant, cyclosporin A, which blocks calcineurin. Mutation analysis indicated that the GATA4 binding site is required for ISO-responsive ET-1 transcription. Stimulation with ISO enhanced the interaction between NFATc and GATA4 in cardiac myocytes. Consistent with this interaction, overexpression of GATA4 and NFATc synergistically activated the ET-1 promoter. These findings demonstrate that NE-stimulated ET-1 expression in cardiac myocytes is mediated predominantly via a ␤-adrenergic pathway, and that calcium-activated calcineurin-GATA4 plays a role in this process. Endothelin-1 (ET-1)1 was initially identified as a 21 amino acid vasoconstrictive peptide in porcine vascular endothelial cells (1). Later work showed that ET-1 acts not only as a vasoconstrictor but also as a potent growth-promoting peptide. For example, ET-1 can induce myocyte hypertrophy (2, 3) through coupling of ET receptors with the G q protein. Whereas ET-1 is mainly produced by endothelial cells in the basal state, a number of cell types can synthesize ET-1 in response to various stimuli (4 -7). ET-1 expression in cardiac myocytes is induced by myocardial stretch, angiotensin II, and norepinephrine (5-7). Left ventricular levels of ET-1 increase markedly in close association with the deterioration of systolic function following myocardial infarction and pressure overload (8 -10). Immunohistochemical studies have demonstrated that ET-1 in the failing heart is localized in cardiac myocytes. ET receptor antagonists bosentan or BQ123 prevent the remodeling of the heart and have been shown to improve survival following myocardial infarction and pressure overload (9, 10). These findings demonstrate that upregulated expression of ET-1 in cardiac myocytes plays a critical role in the development of heart failure in vivo. However, the precise mechanisms leading to this upregulation in the failing heart are unclear at present.Because a number of neurohormonal factors are activated in congestive heart failure (11, 12), they may possibly play positive and negative roles in regulating ET-1 expr...

on behalf of the CREDO-Kyoto PCI/ CABG Registry Cohort-2 Investigators Background-Optimal duration of dual antiplatelet therapy (DAPT) after drug-eluting stent (DES) implantation has not been yet fully elucidated. Methods and Results-We assessed the influence of prolonged thienopyridine therapy on clinical outcomes with landmark analysis at 4 and 13 months after DES implantation. Among 6802 patients with at least 1 DES implantation in the CREDO-Kyoto Registry Cohort-2, 6309 patients (on thienopyridine, 5438 patients; off thienopyridine, 871 patients) and 5901 patients (on thienopyridine, 4098 patients; off thienopyridine, 1803 patients) were eligible for the 4-and 13-month landmark analyses, respectively. The majority of patients had stable coronary artery disease (73%) and received sirolimus-eluting stents (93%), and approximately 90% of thienopyridine was ticlopidine. Patients taking thienopyridine had more complex comorbidities and more complex lesion and procedural characteristics as compared with patients not taking thienopyridine. After adjusting for confounders, thienopyridine use was not associated with decreased risk for death/myocardial infarction/stroke (hazard ratio [HR], 1.13; 95% confidence interval [CI], 0.89 -1.43, Pϭ0.32 in the 4-month landmark analysis; HR, 1.14; 95% CI, 0.90 -1.45, Pϭ0.29 in the 13-month landmark analysis, respectively), whereas the risk for GUSTO moderate/severe bleeding tended to be higher in patients taking thienopyridine (HR, 1.51; 95% CI, 1.00 -2.23, Pϭ0.049 in the 4-month landmark analysis; HR, 1.44; 95% CI, 0.99 -2.09, Pϭ0.057 in the 13-month landmark analysis, respectively). Conclusions-Prolonged thienopyridine therapy beyond 4 and 13 months appeared not to be associated with reduction in ischemic events but to be associated with a trend toward increased bleeding. Optimal duration of DAPT after DES implantation might be shorter than the currently recommended 1-year interval. (Circ Cardiovasc Interv. 2012;5:381-391.)

Leukemia inhibitory factor is a member of a family of structurally related cytokines sharing the receptor component gp130. Activation of gp130 by leukemia inhibitory factor is sufficient to induce myocardial cell hypertrophy accompanied by specific changes in the pattern of gene expression. However, the molecular mechanisms that link gp130 activation to these changes have not been clarified. The present study investigated the transcriptional pathways by which leukemia inhibitory factor activates ␤-myosin heavy chain expression during myocardial cell hypertrophy. Mutation of the GATA motif in the ␤-myosin heavy chain promoter totally abolished leukemia inhibitory factor-responsive transcription without changing basal transcriptional activity. In contrast, endothelin-1 responsiveness was unaffected by the GATA mutation. Among members of the cardiac GATA transcription factor subfamily (GATA-4, -5, and -6), GATA-5 was the sole and potent transactivator for the ␤-myosin heavy chain promoter. This transactivation was dependent on sequence-specific binding of GATA-5 to the ␤-myosin heavy chain GATA element. Cardiac nuclear factors that bind to to the ␤-myosin heavy chain GATA element were induced by leukemia inhibitory factor stimulation. Last, leukemia inhibitory factor stimulation markedly increased transcripts of cardiac GATA-5, the expression of which is normally restricted to the early embryo. Thus, GATA-5 may be involved in gp130 signaling in cardiac myocytes.