Lp-PLA2 inhibition prevents Ang II-induced cardiac inflammation and fibrosis by blocking macrophage NLRP3 inflammasome activation

2021 ◽  
Author(s):  
Si-lin Lv ◽  
Zi-fan Zeng ◽  
Wen-qiang Gan ◽  
Wei-qi Wang ◽  
Tie-gang Li ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Inflammasome Activation ◽  
Ang Ii ◽  
Cardiac Inflammation ◽  
Nlrp3 Inflammasome Activation

scholarly journals NLRP3 inflammasome activation is involved in Ang II-induced kidney damage via mitochondrial dysfunction

Oncotarget ◽  
2016 ◽  
Vol 7 (34) ◽  
pp. 54290-54302 ◽  
Author(s):  
Yi Wen ◽  
Yiran Liu ◽  
Taotao Tang ◽  
Linli Lv ◽  
Hong Liu ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Nlrp3 Inflammasome ◽  
Kidney Damage ◽  
Inflammasome Activation ◽  
Ang Ii ◽  
Nlrp3 Inflammasome Activation

scholarly journals α1-AR overactivation induces cardiac inflammation through NLRP3 inflammasome activation

2019 ◽  
Vol 41 (3) ◽  
pp. 311-318 ◽  
Author(s):  
Jun-zhou Xin ◽  
Ji-min Wu ◽  
Guo-min Hu ◽  
Hui-jun Gu ◽  
Ye-nan Feng ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Inflammasome Activation ◽  
Cardiac Inflammation ◽  
Nlrp3 Inflammasome Activation

scholarly journals FNDC5 Attenuates Oxidative Stress and NLRP3 Inflammasome Activation in Vascular Smooth Muscle Cells via Activating the AMPK-SIRT1 Signal Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-15
Author(s):  
Bing Zhou ◽  
Yun Qiu ◽  
Nan Wu ◽  
Ai-Dong Chen ◽  
Hong Zhou ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Smooth Muscle ◽  
Nlrp3 Inflammasome ◽  
Inflammasome Activation ◽  
Ang Ii ◽  
Compound C ◽  
Ampk Phosphorylation ◽  
A7r5 Cells ◽  
Nlrp3 Inflammasome Activation ◽  
Vascular Oxidative Stress

Vascular oxidative stress and inflammation play a major role in vascular diseases. This study was aimed at determining the protective roles of fibronectin type III domain-containing 5 (FNDC5) in angiotensin II- (Ang II-) induced vascular oxidative stress and inflammation and underlying mechanisms. Wild-type (WT) and FNDC5-/- mice, primary mouse vascular smooth muscle cells (VSMCs), and the rat aortic smooth muscle cell line (A7R5) were used in the present study. Subcutaneous infusion of Ang II caused more serious hypertension, vascular remodeling, oxidative stress, NLRP3 inflammasome activation, AMPK phosphorylation inhibition, and SIRT1 downregulation in the aorta of FNDC5-/- mice than those of WT mice. Exogenous FNDC5 attenuated Ang II-induced superoxide generation, NADPH oxidase 2 (NOX2) and NLRP3 upregulation, mature caspase-1, and interleukin-1β (IL-1β) production in A7R5 cells. The protective roles of FNDC5 were prevented by SIRT-1 inhibitor EX527, AMPK inhibitor compound C, or integrin receptor inhibitor GLPG0187. FNDC5 attenuated the Ang II-induced inhibition in SIRT1 activity, SIRT1 protein expression, and AMPKα phosphorylation in A7R5 cells, which were prevented by compound C, EX527, and GLPG0187. FNDC5 deficiency deteriorated Ang II-induced oxidative stress, NLRP3 inflammasome activation, AMPK phosphorylation inhibition, and SIRT1 downregulation in primary aortic VSMCs of mice, which were prevented by exogenous FNDC5. These results indicate that FNDC5 deficiency aggravates while exogenous FNDC5 alleviates the Ang II-induced vascular oxidative stress and NLRP3 inflammasome activation via the AMPK-SIRT1 signal pathway in VSMCs.

scholarly journals Intermedin1-53 Inhibits NLRP3 Inflammasome Activation by Targeting IRE1α in Cardiac Fibrosis

2021 ◽  
Author(s):  
Lin-Shuang Zhang ◽  
Jin-Sheng Zhang ◽  
Yue-Long Hou ◽  
Wei-Wei Lu ◽  
Xian-Qiang Ni ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Cardiac Fibrosis ◽  
Underlying Mechanism ◽  
Inflammasome Activation ◽  
Rat Myocardium ◽  
Ang Ii ◽  
Receptor System ◽  
Nlrp3 Inflammasome Activation ◽  
Pka Pathway

Abstract Intermedin (IMD), a paracrine/autocrine peptide, protects against cardiac fibrosis. However, the underlying mechanism remains poorly understood. Previous study reports that activation of Nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome contributed to cardiac fibrosis. In this study, we aimed to investigate whether IMD mitigates cardiac fibrosis by inhibiting NLRP3. Cardiac fibrosis was induced by angiotensin II (Ang II) infusion for 2 weeks in rats. Western blot, real-time PCR, histological staining, immunofluorescence assay, RNA sequencing, echocardiography and hemodynamics were used to detect the role and the mechanism of IMD in cardiac fibrosis. Ang II infusion resulted in rat cardiac fibrosis, shown as over-deposition of myocardial interstitial collagen and cardiac dysfunction. Importantly, NLRP3 activation and endoplasmic reticulum stress (ERS) was found in Ang II treated rat myocardium. Ang II infusion decreased the expression of IMD and increased the expression of the receptor system of IMD in the fibrotic rat myocardium. IMD treatment attenuated the cardiac fibrosis and improved cardiac function. In addition, IMD inhibited the upregulation of NLRP3 markers and ERS markers induced by Ang II. In vitro, IMD knockdown by small interfering RNA significantly promoted the Ang II-induced cardiac fibroblast and NLRP3 activation. Moreover, silencing of inositol requiring enzyme 1 α (IRE1α) blocked the effects of IMD inhibiting fibroblast and NLRP3 activation. Pre-incubation with PKA pathway inhibitor H89 blocked the effects of IMD on the anti-ERS, anti-NLRP3 and anti-fibrotic response. In conclusion, IMD alleviates cardiac fibrosis by inhibiting NLRP3 inflammasome activation via suppressing IRE1α and cAMP/PKA pathway.

scholarly journals Nlrp3 Deficiency Alleviates Angiotensin II-Induced Cardiomyopathy by Inhibiting Mitochondrial Dysfunction

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Yu Chen ◽  
Meiying Zeng ◽  
Yang Zhang ◽  
Hui Guo ◽  
Wei Ding ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Function ◽  
Mitochondrial Dysfunction ◽  
Nlrp3 Inflammasome ◽  
Gene Deletion ◽  
Cardiac Fibrosis ◽  
Inflammasome Activation ◽  
Ang Ii ◽  
Nlrp3 Gene ◽  
Nlrp3 Inflammasome Activation

Inflammation has been considered a key component in the pathogenesis and progression of angiotensin II- (Ang II-) induced cardiac hypertrophy and related cardiomyopathy. As a vital mediator of inflammation, the role of the Nlrp3 inflammasome in Ang II-induced cardiomyopathy remains unclear. This study was aimed to determine whether Nlrp3 inflammasome activation and its downstream pathway were involved in Ang II-induced cardiomyopathy. We established an Ang II infusion model in both wild-type and Nlrp3-/- mice to determine the contribution of Nlrp3 to cardiac function. Cardiac fibrosis was determined by Masson’s trichrome staining, real-time PCR, and TUNEL assay; cardiac function was assessed by echocardiography. Nlrp3 inflammasome activation and related downstream cytokines were measured by Western blotting and enzyme-linked immunosorbent assays; mitochondrial dysfunction was examined by transmission electron microscopy and real-time PCR. We found that Ang II-infused mice showed impaired cardiac function, as evidenced by increased cardiac fibrosis, apoptosis, inflammation, and left ventricular dysfunction. However, these alterations were significantly alleviated in the mice with Nlrp3 gene deletion. Moreover, Ang II-infused mice showed increased Nlrp3 inflammasome activity relative to that of the cytokines IL-1β and IL-18, increased reactive oxygen species, mitochondrial abnormalities, and decreased mtDNA copy number and ATP synthase activity. These molecular and pathological alterations were also attenuated in Nlrp3 deficient mice. In conclusion, Nlrp3 inflammasome-induced mitochondrial dysfunction is involved in Ang II-induced cardiomyopathy. Nlrp3 gene deletion attenuated mitochondrial abnormalities, cardiac inflammation, oxidative stress, and fibrosis and thus alleviated heart dysfunction and hypertrophy. Targeting the Nlrp3 inflammasome and/or mitochondria may be a therapeutic approach for Ang II-induced cardiac diseases.

scholarly journals NLRP3 Gene Deletion Attenuates Angiotensin II-Induced Phenotypic Transformation of Vascular Smooth Muscle Cells and Vascular Remodeling

2017 ◽  
Vol 44 (6) ◽  
pp. 2269-2280 ◽  
Author(s):  
Xing-Sheng Ren ◽  
Ying Tong ◽  
Li Ling ◽  
Dan Chen ◽  
Hai-Jian Sun ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle Cells ◽  
Nlrp3 Inflammasome ◽  
Vascular Remodeling ◽  
Gene Deletion ◽  
Inflammasome Activation ◽  
Ang Ii ◽  
Nlrp3 Gene ◽  
Nlrp3 Inflammasome Activation ◽  
Phenotypic Transformation

Background/Aims: Angiotensin (Ang) II plays vital roles in vascular inflammation and remodeling in hypertension. Phenotypic transformation of vascular smooth muscle cells (VSMCs) is a major initiating factor for vascular remodeling. The present study was designed to determine the roles of NLRP3 inflammasome activation in Ang II-induced VSMC phenotypic transformation and vascular remodeling in hypertension. Methods: Primary VSMCs from the aorta of NLRP3 knockout (NLRP3-/-) mice and wild-type (WT) mice were treated with Ang II for 24 h. Subcutaneous infusion of Ang II via osmotic minipump for 2 weeks was used to induce vascular remodeling and hypertension in WT and NLRP3-/- mice. Results: NLRP3 gene deletion attenuates Ang II-induced NLRP3 inflammasome activation, phenotypic transformation from a contractile phenotype to a synthetic phenotype and proliferation in primary mice VSMCs. Ang II-induced hypertension and vascular remodeling in WT mice were attenuated in NLRP3-/- mice. Furthermore, Ang II-induced NLRP3 inflammasome activation, phenotypic transformation and proliferating cell nuclear antigen (PCNA) upregulation were inhibited in the media of aorta of NLRP3-/- mice. Conclusions: NLRP3 inflammasome activation contributes to Ang II-induced VSMC phenotypic transformation and proliferation as well as vascular remodeling and hypertension.

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