ACTA PHARMACOLOGICA SINICA
·
2025
·
IF 8.4
Ye Hua,Wu Lin,Liu Yan-mei,Zhang Jun-xia,Hu Huan-tao,Dong Mao-long,Ren Jun
Septic cardiomyopathy (SCM), a severe complication in sepsis, significantly increases the mortality of septic patients. Ferroptosis, an iron-regulated cell death, has been implicated in the development of SCM. Wogonin, a flavonoid from the root of the skullcap, exhibits anti-inflammatory, anti-allergic, and anti-apoptotic activities. In this study, we investigated the effects of wogonin on SCM and associated cardiomyocyte ferroptosis. Cecal ligation and puncture (CLP) surgery was performed in mice to establish a SCM model. Wogonin (20, 40 and 60 mg·kg −1 , i.p.) was administered 2 h prior to CLP surgery. We showed that wogonin pretreatment dose-dependently mitigated CLP-induced cardiac dysfunction, myocardial damage, and deranged cardiomyocyte contractility. Furthermore, wogonin pretreatment ameliorated cardiac inflammation, oxidative stress, and mitochondrial dysfunction in CLP-challenged mice. We demonstrated that wogonin exerted the cardioprotective effects through suppressing cardiomyocyte ferroptosis both in vivo and in vitro. We revealed that wogonin directly bound to and inhibited ALOX15 (arachidonic acid 15-lipoxygenase), a lipoxygenase that governed the oxidation of polyunsaturated fatty acids to initiate ferroptosis. Pharmacological inhibition of ALOX15 using a specific inhibitor ML351 (10 mg·kg −1 ·d −1 , i.p. for 7 days prior to CLP surgery) markedly diminished cardiac abnormalities and cardiomyocyte ferroptosis in CLP-challenged mice. In LPS-challenged HL-1 cardiomyocytes, overexpression of ALOX15 or supplement of its downstream metabolite 15-HpETE (1 μM) diminished the anti-ferroptotic effects of wogonin. Our results demonstrate that wogonin protects against SCM through inhibition of ALOX15-meditated ferroptosis.
研究领域:
药理学
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病理学
·
心血管医学
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产品关联
DOI
PubMed
高影响因子
Journal of Materials Chemistry B
·
2022
·Vol. 10
·期 28
·5344-5351
·
IF 7.571
Qi Zhang,Lijuan Wang,Yong Yin,Jian Shen,Jun Xie,Jiang Yuan
Myocardial infarction is one of the leading causes of death worldwide. Thus, protection against myocardial ischemia-reperfusion injury is particularly important to improve the prognosis of myocardial infarction. Recently, hydrogen sulfide (H2S) has been reported to possess a protective effect against myocardial ischemia-reperfusion injury. However, an effective gas delivery system to release H2S controllably at an appropriate concentration needs to be further investigated. In this study, a new H2S-releasing hydrogel system was constructed and applied in an experimental I/R model of rats. The administration of the hydrogel significantly ameliorated microvascular obstruction, prevented myocardial fibrosis, and attenuated cardiac inflammation. This suggested that the novel H2S-releasing hydrogel represented a promising therapeutic strategy targeting myocardial ischemia-reperfusion injury.
研究领域:
心脏病学
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药剂学
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材料科学
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DOI
PubMed
高影响因子
BASIC RESEARCH IN CARDIOLOGY
·
2016
·Vol. 112
·期 1
·1-15
·
IF 6.038
Han Jibo,Zou Chunpeng,Mei Liqin,Zhang Yali,Qian Yuanyuan,You Shengban,Pan Yong,Xu Zheng,Bai Bin,Huang Weijian,Liang Guang
Angiotensin II (Ang II) induces cardiac inflammation and remodeling. Emerging evidence indicates that Ang II may utilize the Toll-like receptor 4 (TLR4) signaling pathway in mediating pro-inflammatory and pro-fibrotic activities. However, the precise mechanism is poorly understood. Myeloid differentiation 2 (MD2), a molecule that physically binds to TLR4, confers lipopolysaccharide responsiveness and may also be involved in mediating the actions of Ang II. We hypothesize that MD2 plays an essential role in cardiac inflammation and remodeling induced by local Ang II, and inhibition of MD2 can attenuate Ang II-induced cardiac dysfunction. Using a specific small molecule MD2 blocker L6H21 and the MD2 knockout mice, we show that MD2 deficiency significantly reduces cardiac inflammation and subsequent fibrosis, hypertrophy, and dysfunction in mice challenged with subcutaneous injection of Ang II. In rat cardiomyocyte-like H9c2 cells as well as rat primary cardiomyocytes, inhibition of MD2 by L6H21 or siRNA knockdown suppressed the Ang II-induced TLR4 signaling pathway activation including MyD88 recruitment, and reduced cardiomyocyte hypertrophy and matrix protein expression. These pro-inflammatory activities of Ang II were independent of the AT1 receptor. Finally, we demonstrated the direct interaction between Ang II and MD2 protein via hydrogen bonds on Arg-90, Glu-92, and Asp-100. Ang II produces an inflammatory response and cardiac remodeling by directly binding to MD2, activating MD2/TLR4 complex, and recruiting MyD88. MD2 may be a new therapeutic target for Ang II-mediated cardiac inflammation and remodeling.
研究领域:
心脏病学
·
免疫学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
iMeta
·
2024
·
IF 23.7
Hao Zhang,Jiawan Wang,Jianghua Shen,Siqi Chen,Hailong Yuan,Xuan Zhang,Xu Liu,Ying Yu,Xinran Li,Zeyu Gao,Yaohui Wang,Jun Wang,Moshi Song
Emerging evidence has demonstrated the profound impact of the gut microbiome on cardiovascular diseases through the production of diverse metabolites. Using an animal model of myocardial ischemia–reperfusion (I/R) injury, we found that the prophylactic administration of a well-known probiotic, Bifidobacterium infantis ( B. infantis ), exhibited cardioprotective effects in terms of preserving cardiac contractile function and preventing adverse cardiac remodeling following I/R and that these cardioprotective effects were recapitulated by its metabolite inosine. Transcriptomic analysis further revealed that inosine mitigated I/R-induced cardiac inflammation and cell death. Mechanistic investigations elucidated that inosine suppressed the production of pro-inflammatory cytokines and reduced the numbers of dendritic cells and natural killer cells, achieved through the activation of the adenosine A2A receptor (A2AR) that when inhibited abrogated the cardioprotective effects of inosine. Additionally, in vitro studies using C2C12 myoblasts revealed that inosine attenuated cell death by serving as an alternative carbon source for adenosine triphosphate (ATP) generation through the purine salvage pathway when subjected to oxygen-glucose deprivation/reoxygenation that simulated myocardial I/R injury. Likewise, inosine reversed the I/R-induced decrease in ATP levels in mouse hearts. Taken together, our findings indicate that B. infantis or its metabolite inosine exerts cardioprotective effects against I/R by suppressing cardiac inflammation and attenuating cardiac cell death, suggesting prophylactic therapeutic options for acute ischemic cardiac injury. Graphical In this study, we found that the prophylactic administration of a well-known probiotic, Bifidobacterium infantis ( B. infantis ), exhibited cardioprotective effects against myocardial ischemia–reperfusion (I/R) injury, which was recapitulated by its metabolite inosine. Specifically, inosine suppressed cardiac inflammation by reducing the production of pro-inflammatory cytokines and decreasing the numbers of dendritic cells and natural killer cells after I/R. Additionally, inosine attenuated cell death by serving as an alternative carbon source for adenosine triphosphate generation through the purine salvage pathway in stressed myocytes and in I/R-injured mouse hearts. Collectively, our findings indicate that B. infantis or its metabolite inosine exerts pleiotropic cardioprotective effects against I/R, suggesting prophylactic therapeutic options for acute ischemic cardiac injury. Highlights Bifidobacterium infantis , a well-known probiotic, exhibits prophylactic cardioprotective effects against myocardial I/R injury. The cardioprotective effects of Bifidobacterium infantis are recapitulated by its metabolite inosine. Inosine treatment suppresses cardiac inflammation by reducing the production of pro-inflammatory cytokines and decreasing the numbers of dendritic cells and natural killer cells after I/R. Inosine treatment attenuates cell death by serving as an alternative carbon source for adenosine triphosphate generation through the purine salvage pathway in stressed myocytes and in I/R-injured mouse hearts.
研究领域:
心血管疾病
·
微生物组
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免疫学
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代谢组学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
Oxidative Medicine and Cellular Longevity
·
2022
·
IF 7.31
Yawen Deng,Zhitong Li,Xiangbo An,Rui Fan,Yao Wang,Jiatian Li,Xiaolei Yang,Jiawei Liao,Yunlong Xia
Hyperhomocysteinemia (HHcy) is positively linked with several cardiovascular diseases; however, its role and underlying mechanisms in pathological cardiac hypertrophy are still unclear. Here, we focused on the effects and underlying mechanisms of HHcy in hypertensive cardiac hypertrophy, one of the most common and typical types of pathological cardiac hypertrophy. By a retrospective analysis of the association between HHcy and cardiac hypertrophy in a hypertensive cohort, we found that the prevalence of HHcy was higher in patients with hypertrophy and significantly associated with the presence of cardiac hypertrophy after adjusting for other conventional risk factors. In mice, HHcy induced by a methionine (2% wt/wt) diet feeding significantly promoted cardiac hypertrophy as well as cardiac inflammation and fibrosis induced by 3-week angiotensin ІІ (AngІІ) infusion (1000 ng/kg/min), while folic acid (0.006% wt/wt) supplement corrected HHcy and attenuated AngII-stimulated cardiac phenotypes. Mechanistic studies further showed that homocysteine (Hcy) exacerbated AngII-stimulated expression of Calcineurin and nuclear factor of activated T cells (NFAT), which could be attenuated by folic acid both in mice and in neonatal rat cardiomyocytes. Moreover, treatment with cyclosporin A, an inhibitor of Calcineurin, blocked Hcy-stimulated Calcineurin-NFAT signaling and hypertrophy in neonatal rat cardiomyocytes. In conclusion, our study indicates that HHcy promotes cardiac hypertrophy in hypertension, and Calcineurin-NFAT pathway might be involved in the pro-hypertrophic effect of Hcy.
研究领域:
心血管疾病
·
分子生物学
·
病理生理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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