Search

Cardiac hypertrophy is a key pathophysiological process in the heart in response to stress cues. Although taking place in cardiomyocytes, the hypertrophic response is influenced by other cell types, both within the heart and derived from circulation. In the present study we investigated the myeloid-specific role of megakaryocytic leukemia 1 (MKL1) in cardiac hypertrophy. Following transverse aortic constriction (TAC), myeloid MKL1 conditional knockout (MFCKO) mice exhibit an attenuated phenotype of cardiac hypertrophy compared to the WT mice. In accordance, the MFCKO mice were protected from excessive cardiac inflammation and fibrosis as opposed to the WT mice. Conditioned media collected from macrophages enhanced the pro-hypertrophic response in cardiomyocytes exposed to endothelin in an MKL1-dependent manner. Of interest, expression levels of macrophage derived miR-155, known to promote cardiac hypertrophy, were down-regulated in the MFCKO mice compared to the WT mice. MKL1 depletion or inhibition repressed miR-155 expression in macrophages. Mechanistically, MKL1 interacted with NF-κB to activate miR-155 transcription in macrophages. In conclusion, our data suggest that MKL1 may contribute to pathological hypertrophy via regulating macrophage-derived miR-155 transcription.

Sex-determining region Y-related high mobility group-box 10 (SOX10), a member of the SOX family, has recently been highlighted as an essential transcriptional factor involved in developmental biology. Recently, the functionality of SOX 10 has been increasingly revealed by researchers worldwide. It has been reported that SOX10 significantly regulates the proliferation, migration, and apoptosis of tumors and is closely associated with the progression of cancer. In this review, we first introduce the basic background of the SOX family and SOX10 and then discuss the pathophysiological roles of SOX10 in cancer. Besides, we enumerate the application of SOX10 in the pathological diagnosis and therapeutic potential of cancer. Eventually, we summarize the potential directions and perspectives of SOX10 in neoplastic theranostics. The information compiled herein may assist in additional studies and increase the potential of SOX10 as a therapeutic target for cancer.

The matricellular protein SPON2 plays diverse roles in the development of cardiovascular diseases. SPON2 is expressed in endothelial cells, but its transcription regulation in the context of atherogenesis remains incompletely appreciated. Here we report that SPON2 expression was up-regulated by pro-atherogenic stimuli (oxLDL and TNF-α) in vascular endothelia cells. In addition, endothelial SPON2 was elevated in Apoe–/– mice fed on a Western diet compared to the control mice. Induction of SPON2 in endothelial cells by pro-atherogenic stimuli was mediated by BRG1, a chromatin remodeling protein, both in vitro and in vivo. Further analysis revealed that BRG1 interacted with the sequence-specific transcription factor Egr-1 to activate SPON2 transcription. BRG1 contributed to SPON2 trans-activation by modulating chromatin structure surrounding the SPON2 promoter. Functionally, activation of SPON2 transcription by the Egr-1/BRG1 complex provided chemoattractive cues for macrophage trafficking. SPON2 depletion abrogated the ability of BRG1 or Egr-1 to stimulate endothelial derived chemoattractive cue for macrophage migration. On the contrary, recombinant SPON2 rescued endothelial chemo-attractability in the absence of BRG1 or Egr-1. In conclusion, our data have identified a novel transcriptional cascade in endothelial cells that may potentially promote macrophage recruitment and vascular inflammation leading to atherogenesis.

Vascular endothelial cells contribute to the pathogenesis of cardiovascular diseases by producing and disseminating angiocrine factors. Nitric oxide (NO), catalyzed by endothelial NO synthase (eNOS), is one of the prototypical angiocrine factors. eNOS activity is modulated by site-specific phosphorylation. We have previously shown that endothelial-specific knockdown of BRG1 in Apoe–/– mice attenuates the development of atherosclerosis, in which eNOS-dependent NO catalysis plays an antagonizing role. Here we report that attenuation of atherogenesis in mice by BRG1 knockdown was accompanied by partial restoration of NO biosynthesis by 44% in the arteries and a simultaneous up-regulation of eNOS serine 1177 phosphorylation by 59%. Indeed, BRG1 depletion or inhibition ameliorated oxLDL-induced loss of NO bioavailability and eNOS phosphorylation in cultured endothelial cells. Further analysis revealed that BRG1 regulated eNOS phosphorylation and NO synthesis by activating the transcription of protein phosphatase 2A (PP2A) structural subunit a (encoded by PR65A). BRG1 interacted with ETS1, was recruited by ETS1 to the PR65A promoter, and cooperated with ETS1 to activate PR65A transcription. Finally, depletion of ETS1, similar to BRG1, repressed PR65A induction, normalized eNOS phosphorylation, and rescued NO biosynthesis in endothelial cells treated with oxLDL. In conclusion, our data characterize a novel transcriptional cascade that regulates NO bioavailability in vascular endothelial cells.

Endothelial cell derived angiocrine factors contribute to the disruption of homeostasis and the pathogenesis of cardiovascular diseases in response to stress stimuli. In the present study we investigated the role of BRG1, a key component of the chromatin remodeling complex, in the regulation of angiocrine signaling. We report that angiotensin II (Ang II) induced pathological cardiac hypertrophy was attenuated in mice with endothelial-specific ablation of BRG1 (ecKO) compared to the control mice (WT). Mitigation of cardiac hypertrophy as a result of BRG1 deficiency was accompanied by decreased macrophage homing to the hearts. This could be explained by the observation that the ecKO mice exhibited down-regulation of myeloid-related protein 8 (MRP8), a well-established chemokine for macrophages, in vascular endothelial cells compared to the WT mice. Further analysis revealed that BRG1 mediated the activation of MRP8 expression by Ang II treatment in endothelial cells to promote macrophage migration. BRG1 was recruited to the MRP8 promoter by interacting with hypoxia-inducible factor 1 (HIF-1α). Reciprocally, BRG1 facilitated the binding of HIF-1α to the MRP8 promoter by sequentially recruiting histone acetyltransferase p300 and histone demethylase KDM3A. Depletion of either p300 or KDM3A repressed the induction of MRP8 expression by Ang II and ameliorated macrophage migration. In conclusion, our data delineate a novel epigenetic pathway whereby Ang II stimulates MRP8 production and macrophage homing to promote cardiac hypertrophy.

Cardiac ischemia-reperfusion injury (IRI) represents a major pathophysiological event associated with permanent loss of heart function. Several inter-dependent processes contribute to cardiac IRI that include accumulation of reactive oxygen species (ROS), aberrant inflammatory response, and depletion of energy supply. Inducible nitric oxide synthase (iNOS) is a pro-inflammatory mediator and a major catalyst of ROS generation. In the present study we investigated the epigenetic mechanism whereby iNOS transcription is up-regulated in macrophages in the context of cardiac IRI. We report that germline deletion or systemic inhibition of myocardin-related transcription factor A (MRTF-A) in mice attenuated up-regulation of iNOS following cardiac IRI in the heart. In cultured macrophages, depletion or inhibition of MRTF-A suppressed iNOS induction by hypoxia-reoxygenation (HR). In contrast, MRTF-A over-expression potentiated activation of the iNOS promoter by HR. MRTF-A directly binds to the iNOS promoter in response to HR stimulation. MRTF-A binding to the iNOS promoter was synonymous with active histone modifications including trimethylated H3K4, acetylated H3K9, H3K27, and H4K16. Further analysis revealed that MRTF-A interacted with H4K16 acetyltransferase TIP60 to synergistically activate iNOS transcription. TIP60 depletion or inhibition achieved equivalent effects as MRTF-A depletion/inhibition in terms of iNOS repression. Of interest, TIP60 appeared to form a crosstalk with the H3K4 trimethyltransferase complex to promote iNOS trans-activation. In conclusion, we data suggest that the MRTF-A-TIP60 axis may play a critical role in iNOS transcription in macrophages and as such be considered as a potential target for the intervention of cardiac IRI.

Trans-differentiation of endothelial cells to myofibroblast contributes to liver fibrosis. Reactive oxygen species (ROS) plays a key role in endothelial-mesenchymal transition (EndMT) although the underlying epigenetic mechanism is unclear. Here we report that endothelial conditional knockout of Brg1, a chromatin remodeling protein, attenuated liver fibrosis in mice. Brg1 deficiency in endothelial cells was paralleled by a decrease in ROS production and blockade of EndMT both in vivo and in vitro. The ability of BRG1 to regulate ROS production and EndMT was abolished by NOX4 depletion or inhibition. Further analysis revealed that BRG1 interacted with SMAD3 and AP-1 to mediate TGF-β induced NOX4 transcription in endothelial cells. Mechanistically, BRG1 recruited various histone modifying enzymes to alter the chromatin structure surrounding the NOX4 locus thereby activating its transcription. In conclusion, our data uncover a novel epigenetic mechanism that links NOX4-dependent ROS production to EndMT and liver fibrosis. Targeting the BRG1-NOX4 axis may yield novel therapeutics against liver fibrosis.