Proinflammatory Stimuli Engage Brahma Related Gene 1 and Brahma in Endothelial Injury

Abstract

Rationale Endothelial dysfunction inflicted by inflammation is found in a host of cardiovascular pathologies. One hallmark event in this process is the aggregation and adhesion of leukocyte to the vessel wall mediated by the up-regulation of adhesion molecules (CAM) in endothelial cells at the transcriptional level. The epigenetic modulator(s) of CAM transactivation and its underlying pathophysiological relevance remain poorly defined. Objective Our goal was to determine the involvement of Brg1 and Brm in CAM transactivation and its relevance in the pathogenesis of atherosclerosis. Methods and Results In the present study, we report that pro-inflammatory stimuli augmented the expression of Brg1 and Brm in vitro in cultured endothelial cells and in vivo in arteries isolated from rodents. Over-expression of Brg1 and Brm promoted whereas knockdown of Brg1 and Brm abrogated transactivation of adhesion molecules and leukocyte adhesion induced by inflammatory signals. Brg1 and Brm interacted with and were recruited to the CAM promoters by NF-κB/p65. Conversely, depletion of Brg1 and Brm disrupted the kinetics of p65 binding on CAM promoters and crippled CAM activation. Silencing of Brg1 and Brm also altered key epigenetic changes associated with CAM transactivation. Of intrigue, 17β-estradiol antagonized both the expression and activity of Brg1/Brm. Most importantly, endothelial-targeted elimination of Brg1/Brm conferred atheroprotective effects to Apoe−/− mice on a Western diet. Conclusion Therefore, our data suggest that Brg1 and Brm integrate various pro-inflammatory cues into CAM transactivation and endothelial malfunction and as such may serve as potential therapeutic targets in treating inflammation related cardiovascular diseases.

Histone Methyltransferase SET1 Mediates Angiotensin II–Induced Endothelin-1 Transcription and Cardiac Hypertrophy in Mice

“…22 Evidence is mounting that in stressed vascular endothelium, the epigenetic machinery can actively regulate transcription to modify endothelial function tailoring to the inputs by various pathological cues. [12][13][14]23,24 By means of paracrine and endocrine, these stress signals can be relayed from the endothelium to other parts of the cardiovascular system (eg, the heart) to trigger detrimental changes. In this report, we detail an epigenetically regulated pathway wherein the histone H3K4 methyltransferase SET1 activates endothelin-1 transcription in endothelial cells and contributes to the pathogenesis of cardiac hypertrophy in response to chronic Ang II treatment ( Figure 7M).…”

“…In the meantime, SET1 was silenced by lentiviral delivery of an endothelial-specific vector carrying interfering RNA targeting SET1 as have been shown for other proteins previously. 13,14,21 Immunofluorescence staining suggested that SET1 expression was specifically suppressed in the vascular endothelium ( Figure Figure 6A) and protein ( Figure 6B) levels in Ang II-infused mice. Consequently, there was a decrease of H3K4Me3 levels on the endothelin-1 promoter in the lungs ( Figure 6C).…”

Myocardin-Related Transcription Factor A Epigenetically Regulates Renal Fibrosis in Diabetic Nephropathy

“…ChIP and re-ChIP assays were performed essentially as described before 48 with anti-MRTF-A, anti-p300 (Santa Cruz Biotechnology), anti-acetyl H3K9, anti-acetyl H3K18, anti-acetyl H3K27, anti-trimethyl H3K4 (EMD Millipore), or anti-WDR5 (Bethyl Laboratories). Precipitated genomic DNA was amplified by real-time PCR with the primers listed in Table 1.…”

Endothelial MRTF-A mediates angiotensin II induced cardiac hypertrophy

“…To further verify this cell model in vivo, we injected C57/BL6 mice with lentivirus carrying MRTF-A-targeting shRNA (Endo-shMRTF-A) under the influence of Tie2 gene promoter to specifically knockdown MRTF-A in the endothelium [22]. The Hannon laboratory was among the first to demonstrate that synthesis of shRNA can be driven by RNA polymerase II [23,24].…”