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Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease. BAF60c, a unique subunit of the SWItch/ sucrose nonfermentable (SWI/SNF) chromatin remodeling complex, is critical for cardiac and skeletal myogenesis, yet little is known about its function in the vasculature and, specifically, in AAA pathogenesis. Here, we found that BAF60c was downregulated in human and mouse AAA tissues, with primary staining to vascular smooth muscle cells (VSMCs), confirmed by single-cell RNA-sequencing. In vivo studies revealed that VSMC-specific knockout of Baf60c significantly aggravated both angiotensin II- (Ang II-) and elastase-induced AAA formation in mice, with a significant increase in elastin degradation, inflammatory cell infiltration, VSMC phenotypic switch, and apoptosis. In vitro studies showed that BAF60c knockdown in VSMCs resulted in loss of contractile phenotype, increased VSMC inflammation, and apoptosis. Mechanistically, we demonstrated that BAF60c preserved VSMC contractile phenotype by strengthening serum response factor (SRF) association with its coactivator P300 and the SWI/SNF complex and suppressing VSMC inflammation by promoting a repressive chromatin state of NF-[kappa]B target genes as well as preventing VSMC apoptosis through transcriptional activation of KLF5-dependent B cell lymphoma 2 (BCL2) expression. Our identification of the essential role of BAF60c in preserving VSMC homeostasis expands its therapeutic potential in preventing and treating AAA., Introduction Abdominal aortic aneurysm (AAA) is one of the leading causes of death in developed countries, with an overall mortality rate of approximately 90% in case of rupture (1). AAA [...]

Recent genome-wide association studies have revealed that variations near the gene locus encoding the transcription factor Kruppel-like factor 14 (KLF14) are strongly associated with HDL cholesterol (HDL-C) levels, metabolic syndrome, and coronary heart disease. However, the precise mechanisms by which KLF14 regulates lipid metabolism and affects atherosclerosis remain largely unexplored. Here, we report that KLF14 is dysregulated in the liver of 2 dyslipidemia mouse models. We evaluated the effects of both KLF14 overexpression and genetic inactivation and determined that KLF14 regulates plasma HDL-C levels and cholesterol efflux capacity by modulating hepatic ApoA-I production. Hepatic-specific Klf14 deletion in mice resulted in decreased circulating HDL-C levels. In an attempt to pharmacologically target KLF14 as an experimental therapeutic approach, we identified perhexiline, an approved therapeutic small molecule presently in clinical use to treat angina and heart failure, as a KLF14 activator. Indeed, in WT mice, treatment with perhexiline increased HDL-C levels and cholesterol efflux capacity via KLF14-mediated upregulation of ApoA-I expression. Moreover, perhexiline administration reduced atherosclerotic lesion development in apolipoprotein E-deficient mice. Together, these results provide comprehensive insight into the KLF14-dependent regulation of HDL-C and subsequent atherosclerosis and indicate that interventions that target the KLF14 pathway should be further explored for the treatment of atherosclerosis., Introduction Atherosclerosis-related cardiovascular disease (CVD), including coronary heart disease (CHD), ischemic stroke, and peripheral arterial disease, is the most common cause of death and disability worldwide. Epidemiologic studies and experimental [...]

Nitroalkenes, the nitration products of unsaturated fatty acids formed via NO-dependent oxidative reactions, have been demonstrated to exert strong biological actions in endothelial cells and monocytes/macrophages; however, little is known about their effects on vascular smooth muscle cells ([VSM[C.sub.s]). The present study examined the role of nitro-linoleic acid ([LN[O.sub.2]) in the regulation of VSMC proliferation. We observed that [LN[O.sub.2] inhibited VSMC proliferation in a dose-dependent manner. In addition, [LN[O.sub.2] induced growth arrest of [VSM[C.sub.s] in the [G.sub.1]/S phase of the cell cycle with an upregulation of the cyclin-dependent kinase inhibitor [p27.sup.kip1]. Furthermore, [LN[O.sub.2] triggered nuclear factor-erythroid 2-related factor 2 (Nrf2) nuclear translocation and activation of the antioxidant-responsive element-driven transcriptional activity via impairing Kelch-like ECH-associating protein 1 (Keapl)-mediated negative control of Nrf2 activity in [VSM[C.sub.s]. [LN[O.sub.2] upregulated the expression of Nrf2 protein levels, but not mRNA levels, in [VSM[C.sub.s]. A forced activation of Nrf2 led to an upregulation of [p27.sup.kip1] and growth inhibition of [VSM[C.sub.s]. In contrast, knock down of Nrf2 using an Nrf2 siRNA approach reversed the [LN[O.sub.2]-induced upregulation of [p27.sup.kip1] and inhibition of cellular proliferation in [VSM[C.sub.s]. These studies provide the first evidence that nitroalkene [LN[O.sub.2] inhibits VSMC proliferation through activation of the Keapl/Nrf2 signaling pathway, suggesting an important role of nitroalkenes in vascular biology. nitroalkenes; nuclear factor-erythroid 2-related factor 2; Kelch-like ECH-associating protein 1 doi:10.1152/ajpregu.00261.2007

Nitroalkene derivatives of linoleic acid (nitrolinoleic acid, LN[O.sub.2]) are formed via nitric oxide-dependent oxidative inflammatory reactions and are found at concentrations of [approximately equal to] 500 nM in the blood of healthy individuals. We report that LNO2 is a potent endogenous ligand for peroxisome proliferator-activated receptor [gamma] (PPA[R.sub.[gamma]]; [K.sub.i] [approximately equal to] 133 nM) that acts within physiological concentration ranges. This nuclear hormone receptor (PPA[R.sub.[gamma]],) regulates glucose homeostasis, lipid metabolism, and inflammation. PPA[R.sub.[gamma]] ligand activity is specific for LN[O.sub.2] and not mediated by LN[O.sub.2] decay products, NO donors, linoleic acid (LA), or oxidized LA. LN[O.sub.2] is a significantly more robust PPA[R.sub.[gamma]] ligand than other reported endogenous PPA[R.sub.[gamma]] ligands, including lysophosphatidic acid (16:0 and 18:1), 15-deoxy-[[DELTA].sup.-12,14]-PG[J.sub.2], conjugated LA and azelaoyl-phosphocholine. LN[O.sub.2] activation of PPA[R.sub.[gamma]], via CV-1 cell luciferase reporter gene expression analysis revealed a ligand activity that rivals or exceeds synthetic PPA[R.sub.[gamma]], agonists such as rosiglitazone and ciglitazone, is coactivated by 9 cis-retinoic acid and is inhibited by the PPA[R.sub.[gamma]] antagonist GW9662. LN[O.sub.2] induces PPA[R.sub.[gamma]],-dependent macrophage CD-36 expression, adipocyte differentiation, and glucose uptake also at a potency rivaling thiazolidinediones. These observations reveal that NO-mediated cell signaling reactions can be transduced by fatty acid nitration products and PPAR-dependent gene expression. fatty acid | nitric oxide | free radical | adipocyte differentiation | redox

Aims Atherosclerosis is the dominant pathologic basis of many cardiovascular diseases. Large genome-wide association studies have identified that single-nucleotide polymorphisms proximal to Krüppel-like factor 14 (KLF14), a member of the zinc finger family of transcription factors, are associated with higher cardiovascular risks. Macrophage dysfunction contributes to atherosclerosis development and has been recognized as a potential therapeutic target for treating many cardiovascular diseases. Herein, we address the biologic function of KLF14 in macrophages and its role during the development of atherosclerosis. Methods and results KLF14 expression was markedly decreased in cholesterol loaded foam cells, and overexpression of KLF14 significantly increased cholesterol efflux and inhibited the inflammatory response in macrophages. We generated myeloid cell-selective Klf14 knockout (Klf14 LysM) mice in the ApoE-/- background for the atherosclerosis study. Klf14 LysM ApoE -/- and litter-mate control mice (Klf14 fl/fl ApoE -/-) were placed on the Western Diet for 12 weeks to induce atherosclerosis. Macrophage Klf14 deficiency resulted in increased atherosclerosis development without affecting the plasma lipid profiles. Klf14 -deficient peritoneal macrophages showed significantly reduced cholesterol efflux resulting in increased lipid accumulation and exacerbated inflammatory response. Mechanistically, KLF14 upregulates the expression of a key cholesterol efflux transporter, ABCA1 (ATP-binding cassette transporter A1), while it suppresses the expression of several critical components of the inflammatory cascade. In macrophages, activation of KLF14 by its activator, perhexiline, a drug clinically used to treat angina, significantly inhibited the inflammatory response and increased cholesterol efflux in a KLF14-dependent manner in macrophages without triggering hepatic lipogenesis. Conclusions This study provides insights into the anti-atherosclerotic effects of myeloid KLF14 through promoting cholesterol efflux and suppressing the inflammatory response. Activation of KLF14 may represent a potential new therapeutic approach to prevent or treat atherosclerosis. [ABSTRACT FROM AUTHOR]

The HIV envelope protein gp120 can cause cell death in the endothelium, including umbilical vein endothelium. The endothelium is the lining inside blood vessels. gp120 appears to interact with the CXCR4 and CCR5 cell receptors.