Identifying panaxynol, a natural activator of nuclear factor erythroid-2 related factor 2 (Nrf2) from American ginseng as a suppressor of inflamed macrophage-induced cardiomyocyte hypertrophy. (20th June 2015)

• Record Type: Journal Article
• Authors: Qu, Chen; Li, Bin; Lai, Yimu; Li, Hechu; Windust, Anthony; Hofseth, Lorne J.; Nagarkatti, Mitzi; Nagarkatti, Prakash; Wang, Xing Li; Tang, Dongqi; Janicki, Joseph S.; Tian, Xingsong; Cui, Taixing
• Is Part Of: Journal of ethnopharmacology. Volume 168(2015)
• Page Start: 326
• Page End: 336
• Publication Date: 2015-06-20
• Subjects: Nrf2 nuclear factor erythroid-2 related factor 2 -- Am. G American ginseng -- iNOS inducible nitric oxide synthase -- LPS lipopolysaccharide -- MCP-1 monocyte chemotactic protein-1 -- MIP-1β macrophage inflammatory protein-1 beta -- IL-1β interleukin-1 beta -- IL-6 interleukin-6 -- TNFα tumor necrosis factor alpha -- ARE antioxidant response element -- Atg7 autophagy related gene 7 -- CSF colony-stimulating factor -- FACS fluorescence activated cell sorting -- LDH lactate dehydrogenase -- NQO-1 NAD(P)H dehydrogenase, quinone 1 -- WT wild type -- LC–UV DAD Liquid chromatography with UV diode array detection -- LC–MS Liquid chromatography mass spectrometry; American ginseng -- Panaxynol -- Nrf2 -- Inflammation -- Macrophages -- Cardiomyocytes; Ethnopharmacology -- Periodicals; Pharmacognosy -- Periodicals; Herbs -- Periodicals; Herbs -- Periodicals; Pharmacognosy -- Periodicals; Pharmacognosie -- Périodiques; Herbes -- Périodiques; 615.1
• DOI: 10.1016/j.jep.2015.04.004
• Languages: English
• ISSNs: 0378-8741

Abstract

Abstract: Ethnopharmacological relevance: American ginseng is capable of ameliorating cardiac dysfunction and activating Nrf2, a master regulator of antioxidant defense, in the heart. This study was designed to isolate compounds from American ginseng and to determine those responsible for the Nrf2-mediated resolution of inflamed macrophage-induced cardiomyocyte hypertrophy. Materials and methods: A standardized crude extract of American ginseng was supplied by the National Research Council of Canada, Institute for National Measurement Standards. A bioassay-based fractionization of American ginseng was performed to identify the putative substances which could activate Nrf2-mediated suppression of pro-inflammatory cytokine expression in macrophages and macrophage-mediated pro-hypertrophic growth in cardiomyocytes. Results: A hexane fraction of an anti-inflammatory crude extract of American ginseng was found to be most effective in suppressing the inflammatory responses in macrophages. Preparative, reverse-phase HPLC and a comparative analysis by analytical scale LC–UV/MS revealed the hexane fraction contains predominantly C17 polyacetylenes and linolenic acid. Panaxynol, one of the major polyacetylenes, was found to be a potent Nrf2 activator. Panaxynol posttranscriptionally activated Nrf2 by inhibiting Kelch-like ECH-associated protein (Keap) 1-mediated degradation without affecting the binding of Keap1 and Nrf2. Moreover, panaxynol suppressed a selected set of cytokine expression via the activation of Nrf2 while minimally regulating nuclear factor-kappa B (NF-κB)-mediated cytokine expression in macrophages. It also dramatically inhibited the inflamed macrophage-mediated cardiomyocyte death and hypertrophy by activating Nrf2 in macrophages. Conclusions: These results demonstrate that American ginseng-derived panaxynol is a specific Nrf2 activator and panaxynol-activated Nrf2 signaling is at least partly responsible for American ginseng-induced health benefit in the heart. Graphical abstract: Emerging evidence has suggested that regular use of ginseng is helpful for the treatment of cardiovascular diseases; however, the underlying mechanisms are not fully understood. Our results reveal for the first time that panaxynol isolated from American ginseng activates Nrf2-operated anti-inflammatory signaling in inflamed macrophages, thereby suppressing inflamed macrophage-mediated cardiomyocyte death and hypertrophy.