Rationale: Hypoplastic left heart syndrome (HLHS) remains a lethal congenital cardiac defect. Recent studies have suggested that intracoronary administration of autologous cardiosphere-derived cells (CDCs) may improve ventricular function. Objective: The aim of this study was to test whether intracoronary delivery of CDCs is feasible and safe in patients with hypoplastic left heart syndrome. Methods and Results: Between January 5, 2011, and January 16, 2012, 14 patients (1.8±1.5 years) were prospectively assigned to receive intracoronary infusion of autologous CDCs 33.4±8.1 days after staged procedures (n=7), followed by 7 controls with standard palliation alone. The primary end point was to assess the safety, and the secondary end point included the preliminary efficacy to verify the right ventricular ejection fraction improvements between baseline and 3 months. Manufacturing and intracoronary delivery of CDCs were feasible, and no serious adverse events were reported within the 18-month follow-up. Patients treated with CDCs showed right ventricular ejection fraction improvement from baseline to 3-month follow-up (46.9%±4.6% to 52.1%±2.4%; P =0.008). Compared with controls at 18 months, cardiac MRI analysis of CDC-treated patients showed a higher right ventricular ejection fraction (31.5%±6.8% versus 40.4%±7.6%; P =0.049), improved somatic growth ( P =0.0005), reduced heart failure status ( P =0.003), and lower incidence of coil occlusion for collaterals ( P =0.007). Conclusions: Intracoronary infusion of autologous CDCs seems to be feasible and safe in children with hypoplastic left heart syndrome after staged surgery. Large phase 2 trials are warranted to examine the potential effects of cardiac function improvements and the long-term benefits of clinical outcomes. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01273857.
ERG (Ets Related Gene) is an ETS transcription factor that has recently been shown to regulate a number of endothelial cell (EC) restricted genes including VE-cadherin, von Willebrand Factor (vWF), endoglin, and intercellular adhesion molecule-2 (ICAM-2). Our preliminary data demonstrate that unlike other ETS factors, ERG exhibits a highly EC-restricted pattern of expression in cultured primary cells and several adult mouse tissues including the heart, lung, and brain. In response to inflammatory stimuli, such as TNF-α, we observed a marked reduction of ERG expression in EC. To further define the role of ERG in the regulation of normal EC function we used RNA interference to knockdown ERG. Microarray analysis of RNA derived from ERG siRNA- or TNF-α–treated HUVEC revealed significant overlap (P value <0.01) in the genes that are up- or downregulated. Of particular interest to us was a significant change in expression of interleukin-8 (IL-8) at both protein and RNA levels. Exposure of EC to TNF-α is known to be associated with increased neutrophil attachment. We observed that knockdown of ERG in HUVEC is similarly associated with increased neutrophil attachment compared to control siRNA-treated cells. This enhanced adhesion could be blocked with IL-8 neutralizing or IL-8 receptor blocking antibodies. ERG can inhibit the activity of the IL-8 promoter in a dose dependent manner. Direct binding of ERG to the IL-8 promoter in EC was confirmed by chromatin immunoprecipitation. In summary, our findings support a role for ERG in promoting anti-inflammatory effects in EC through repression of inflammatory genes such as IL-8.
Objective MicroRNA (miRNA) play important roles in vascular biology, but the regulation of endothelial specific miRNA is not well characterized. MiR-126 is highly expressed in endothelial cells, and it regulates angiogenesis and vascular inflammation. Here we show that the transcription factors Ets-1 and Ets-2 regulate miR-126 expression. Methods and Results A genomic region between −71 and −100 bp upstream of the miR-126 transcriptional start site is critical for transactivation of the gene containing miR-126. This genomic region contains a potential Ets binding site. Mutations within the Ets binding site block transactivation, and Ets-1 and Ets-2 interact with this critical genomic region. Knockdown of endogenous Ets-1 and Ets-2 decreases miR-126 expression. Finally, knockdown of miR-126 alters regulation of an Ets-1 target gene. Conclusions Taken together, these data show that the transcription factors Ets-1 and Ets-2 play a key role in controlling the expression of miR-126, and suggest that miR-126 may mediate some of their vascular effects.
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