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NF-E2-related factor 2 (Nrf2) has been shown to be protective in atherosclerosis. The loss of Nrf2 in macrophages enhances foam cell formation and promotes early atherogenesis. Tanshindiol C (Tan C) is isolated from the root of Salvia miltiorrhiza Bge., a traditional Chinese medicine that has been used for the treatment of several cardiovascular diseases for many years. This study was aimed to test the potential role of Tan C against macrophage foam cell formation and to explore the underlying mechanism. Firstly, we observed that Tan C markedly suppressed oxidized low-density lipoprotein (oxLDL) induced macrophage foam cell formation. Then, we found that Tan C was an activator of both Nrf2 and Sirtuin 1 (Sirt1) in macrophages. Nrf2 and Sirt1 synergistically activated the transcription of anti-oxidant peroxiredoxin 1 (Prdx1) after Tan C treatment. More important, we demonstrated that silencing of Prdx1 promoted oxLDL-induced macrophage foam cell formation. Prdx1 upregulated adenosine triphosphate-binding cassette (ABC) transporter A1 (ABCA1) expression and decreased intracellular lipid accumulation. Furthermore, Tan C ameliorated oxLDL induced macrophage foam cell formation in a Prdx1-dependent manner. These observations suggest that Tan C protects macrophages from oxLDL induced foam cell formation via activation of Prdx1/ABCA1 signaling and that Prdx1 may be a novel target for therapeutic intervention of atherosclerosis. [ABSTRACT FROM AUTHOR]

Aging provokes both morphological and functional changes in cells, which are accompanied by a fundamental shift in gene expression patterns. One of the characteristic alterations associated with senescence in fibroblast cells is the down-regulation of collagen type I genes. In the present study, we investigated the contribution of myocardin-related transcription factor A, or MRTF-A, in this process. In mouse embryonic fibroblast (MEF) cells and human foreskin fibroblast (HFF) cells, senescence, induced by either progressive passage or treatment with hydrogen peroxide (H 2 O 2), led to augmented lysine acetylation of MRTF-A paralleling down-regulation of collagen type I and SIRT1, a lysine deacetylase. SIRT1 interacted with MRTF-A to promote MRTF-A deacetylation. SIRT1 over-expression or activation by selective agonists enhanced trans-activation of the collagen promoters by MRTF-A. On the contrary, SIRT1 depletion or inhibition by specific antagonists suppressed trans-activation of the collagen promoters by MRTF-A. Likewise, mutation of four lysine residues within MRTF-A rendered it more potent in terms of activating the collagen promoters but unresponsive to SIRT1. Importantly, SIRT1 activation in senescent fibroblasts mitigated repression of collagen type I expression whereas SIRT1 inhibition promoted the loss of collagen type I expression prematurely in young fibroblasts. Mechanistically, SIRT1 enhanced the affinity of MRTF-A for the collagen type I promoters. In conclusion, our data unveil a novel mechanism that underscores aging-associated loss of collagen type I in fibroblasts via SIRT1-mediated post-translational modification of MRTF-A. • Senescence-induced repression of collagen type I accompanies augmented MRTF-A acetylation. • SIRT1 interacts with and deacetylates MRTF-A. • SIRT1 enhances the ability of MRTF-A to activate collagen type I transcription. • SIRT1 promotes MRTF-A recruitment to the collagen promoters defying collagen repression. [ABSTRACT FROM AUTHOR]

Endothelial-derived factors regulate a wide range of pathophysiological events. It has been reported previously that IL-33 promotes acute kidney injury (AKI) in mice although the underlying epigenetic mechanism is unclear. In the present study we investigated the role of BRG1, a chromatin remodeling protein, in AKI with a focus on its regulation of IL-33 expression in endothelial cells. Smarca4 -flox mice were crossbred with Cdh5 -Cre mice to achieve endothelial-specific deletion of BRG1. AKI was induced by unilateral renal ischemia followed by reperfusion. Compared to wild type (WT) littermates, endothelial conditional BRG1 knockout (CKO) mice were protected from ischemia-reperfusion induced AKI as evidenced by decreased plasma creatinine levels, attenuated caste and tubular necrosis, and diminished immune infiltrates. CKO mice also developed less severe renal fibrosis as indicated by expression levels of extracellular matrix proteins, picrosirius red staining of collagenous tissues, and quantification of renal hydroxylproline levels. Of interest, renal expression of IL-33 was down-regulated as result of endothelial BRG1 deficiency. In cultured endothelial cells, BRG1 directly bound to the IL-33 promoter to activate transcription. Endothelial cell-derived conditioned media promoted the synthesis of pro-fibrogenic proteins in renal tubular epithelial cells. Knockdown of either BRG1 or IL-33 in endothelial cells blunted the pro-fibrogenic response in renal tubular epithelial cells. In conclusion, we propose that BRG1 may contribute to ischemia-reperfusion induced renal injury and fibrosis by promoting IL-33 transcription in endothelial cells. • Endothelial BRG1 deletion attenuates renal IR injury in mice. • Endothelial BRG1 deletion attenuates renal fibrosis in mice. • BRG1 activates IL-33 transcription in endothelial cells. • BRG1 regulates renal tubular epithelial cell injury by activating IL-33. [ABSTRACT FROM AUTHOR]