Excessive activation of the NLRP3 inflammasome is implicated in cardiovascular diseases. Statins exert an anti-inflammatory effect independent of their cholesterol-lowering effect. This study investigated the potential role of statins in the activation of the NLRP3 inflammasome in endothelial cells (ECs). Western blotting and quantitative reverse-transcription polymerase chain reaction showed that oxidized low-density lipoprotein (ox-LDL) or tumor necrosis factor α (TNF) activated the NLRP3 inflammasome in ECs. Simvastatin or mevastatin significantly suppressed the effects of ox-LDL or TNF Promoter reporter assays and small interfering RNA knockdown revealed that statins inhibit ox-LDL-mediated NLRP3 inflammasome activation via the pregnane X receptor (PXR). In addition, PXR agonists (rifampicin and SR12813) or overexpression of a constitutively active PXR markedly suppressed the NLRP3 inflammasome activation. Conversely, PXR knockdown abrogated the suppressive effect of rifampicin on NLRP3 inflammasome activation. Knockdown of lectin-like ox-LDL receptor or overexpression of IB-attenuated ox-LDL- or TNF-triggered activation of the NLRP3 inflammasome. Chromatin immunoprecipitation assays indicated that mevastatin inhibited nuclear factor-κB binding to the promoter regions of the human NLRP3 gene. Collectively, these results demonstrate that the statin activation of PXR inhibits the activation of NLRP3 inflammasome in response to atherogenic stimuli such as ox-LDL and TNF in ECs, providing a new mechanism for the cardiovascular benefit of statins.
Procyanidins, a subclass of flavonoids found in commonly consumed foods, possess potential anti-inflammatory activity. Manipulation of M1/M2 macrophage homeostasis is an effective strategy for the treatment of metabolic inflammatory diseases. The objective of this study was to determine the effect of procyanidins on macrophage polarization. Procyanidin B2 (PCB2), the most widely distributed natural procyanidins, enhanced the expressions of M2 macrophage markers (Arg1, Ym1, and Fizz1). PCB2 activated peroxisome proliferator-activated receptor γ (PPARγ) activity and increased the expressions of PPARγ target genes (CD36 and ABCG1) in macrophages. Inhibition of PPARγ using siRNA or antagonist GW9662 attenuated the PCB2-induced expressions of M2 macrophage markers. In addition, we identified cognate PPAR-responsive elements (PPREs) within the 5'-flanking regions of the mouse Arg1, Ym1, and Fizz1 genes. Furthermore, macrophages isolated from db/db diabetic mice showed lower expressions of M2 markers. PCB2 effectively restored the Arg1, Ym1, and Fizz1 expressions in a PPARγ-dependent manner. These findings support the notion that PCB2 regulated macrophage M2 polarization via the activation of PPARγ. Our results provide a new mechanism by which procyanidins exert their beneficial anti-inflammatory effects.
BackgroundHyperhomocysteinemia (HHcy) is an independent risk factor for cardiovascular diseases (CVDs). Stachydrine (STA) is an active component in Chinese motherwort Leonurus heterophyllus sweet, which has been widely used for gynecological and cardiovascular disorders. This study is aimed to examine the effects of STA on homocysteine (Hcy)-induced endothelial dysfunction.MethodsThe effects of STA on vascular relaxation in rat thoracic aortas (TA), mesenteric arteries (MA) and renal arteries (RA) were measured by using Multi Myograph System. The levels of nitric oxide (NO), tetrahydrobiopterin (BH4) and guanosine 3′, 5′ cyclic monophosphate (cGMP) were determined. Endothelial nitric oxide synthase (eNOS) dimers and monomers were assayed by using Western blotting. GTP cyclohydrolase 1 (GTPCH1) and dihydrofolate reductase (DHFR) expressions were measured by using quantitative reverse transcriptase-PCR (qRT-PCR) and Western blotting.ResultsSTA effectively blocked Hcy-induced impairment of endothelium-dependent vasorelaxation in rat TA, MA and RA. STA-elicited arterial relaxations were reduced by NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME) or the NO-sensitive guanylyl cyclase inhibitor 1H- [1, 2, 4] Oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), but not by inducible iNOS inhibitor 1400 W nor the nonselective COX inhibitor indomethacin. Hcy caused eNOS uncoupling and decreases in NO, cGMP and BH4, which were attenuated by STA. Moreover, STA prevented decreases of GTPCH1 and DHFR levels in Hcy-treated BAECs.ConclusionWe demonstrated that STA effectively reversed the Hcy-induced endothelial dysfunction and prevented eNOS uncoupling by increasing the expression of GTPCH1 and DHFR. These results revealed a novel mechanism by which STA exerts its beneficial vascular effects.Electronic supplementary materialThe online version of this article (10.1186/s10020-018-0010-0) contains supplementary material, which is available to authorized users.
Hyperglycemia-induced endothelial endoplasmic reticulum (ER) stress is implicated in the pathophysiology of diabetes and its vascular complications. Procyanidins are enriched in many plant foods and have been demonstrated to exert several beneficial effects on diabetes, cardiovascular and other metabolic diseases. In the present study, we investigated the effect of procyanidin B2 (PCB2), the most widely distributed natural procyanidin, on ER stress evoked by high glucose in endothelial cells (ECs) and the underlying mechanisms. We showed that PCB2 mitigated the high glucose-activated ER stress pathways (PERK, IRE1α and ATF6) in human vascular ECs. In addition, we found that PCB2 attenuated endothelial ER stress via the activation of peroxisome proliferator-activated receptor δ (PPARδ). We demonstrated that PCB2 directly bound to and activated PPARδ. Conversely, GSK0660, a selective PPARδ antagonist, attenuated the suppressive effect of PCB2 on the ER stress signal pathway. Functionally, PCB2 ameliorated the high glucose-impaired endothelium-dependent relaxation in mouse aortas. The protective effect of PCB2 on vasodilation was abolished in the aortas pretreated with GSK0660 or those from the EC-specific PPARδ knockout mice. Moreover, the protective effects of PCB2 on ER stress and endothelial dysfunction required the inter-dependent actions of PPARδ and AMPK. Collectively, we demonstrated that PCB2 mitigated ER stress and ameliorated vasodilation via a PPARδ-mediated mechanism beyond its classic action as a scavenger of free radicals. These findings further highlighted the novel roles of procyanidins in intervening the ER stress and metabolic disorders related to endothelial dysfunction.
At the end of 2019, the COVID-19 virus spread worldwide, infecting millions of people. Infectious diseases induced by pathogenic microorganisms such as influenza virus, hepatitis virus, and Mycobacterium tuberculosis are...
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Background and Purpose Impaired endothelium‐dependent relaxation (EDR) is a hallmark of endothelial dysfunction. A deficiency of tetrahydrobiopterin (BH4) causes endothelial NOS to produce ROS rather than NO. PPARδ is an emerging target for pharmacological intervention of endothelial dysfunction. Thus, the present study examined the role of PPARδ in the regulation of dihydrofolate reductase (DHFR), a key enzyme in the BH4 salvage pathway. Experimental Approach Gene expression was measured by using qRT‐PCR and western blotting. Biopterins and ROS were determined by using HPLC. NO was measured with fluorescent dye and electron paramagnetic resonance spectroscopy. Vasorelaxation was measured by Multi Myograph System. Key Results The PPARδ agonist GW501516 increased DHFR and BH4 levels in endothelial cells (ECs). The effect was blocked by PPARδ antagonist GSK0660. Chromatin immunoprecipitation identified PPAR‐responsive elements within the 5′‐flanking region of the human DHFR gene. The promoter activity was examined with luciferase assays using deletion reporters. Importantly, DHFR expression was suppressed by palmitic acid (PA, a saturated fatty acid) but increased by docosahexaenoic acid (DHA, a polyunsaturated fatty acid). GSK0660 prevented DHA‐induced increased DHFR expression. Conversely, the suppressive effect of PA was mitigated by GW501516. In mouse aortae, GW501516 ameliorated the PA‐impaired EDR. However, this vasoprotective effect was attenuated by DHFR siRNA or methotrexate. In EC‐specific Ppard knockout mice, GW501516 failed to improve vasorelaxation. Conclusion and Implications PPARδ prevented endothelial dysfunction by increasing DHFR and activating the BH4 salvage pathway. These results provide a novel mechanism for the protective roles of PPARδ against vascular diseases.
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