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.

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 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 Protection of Sacubitril/Valsartan against Pathological Cardiac Remodeling by Inhibiting the NLRP3 Inflammasome after Relief of Pressure Overload in Mice

2020 ◽  
Vol 34 (5) ◽  
pp. 629-640
Author(s):  
Xueling Li ◽  
Qin Zhu ◽  
Qingcheng Wang ◽  
Qinggang Zhang ◽  
Yaru Zheng ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Cardiac Remodeling ◽  
Cardiac Fibrosis ◽  
Pressure Overload ◽  
Myocardial Cell ◽  
Heart Weight ◽  
Inflammasome Activation ◽  
Clinical Prognosis ◽  
Nlrp3 Inflammasome Activation ◽  
Neprilysin Inhibitor

Abstract Background/aims The persistent existence of pathological cardiac remodeling, resulting from aortic stenosis, is related to poor clinical prognosis after successful transcatheter aortic valve replacement (TAVR). Sacubitril/valsartan (Sac/Val), comprising an angiotensin receptor blocker and a neprilysin inhibitor, has been demonstrated to have a beneficial effect against pathological cardiac remodeling, including cardiac fibrosis and inflammation in heart failure. The aim of this study was to determine whether Sac/Val exerts a cardioprotective effect after pressure unloading in mice. Methods and results Male C57BL/6 J mice were subjected to debanding (DB) surgery after 8 weeks (wk) of aortic banding (AB). Cardiac function was assessed by echocardiography, which indicated a protective effect of Sac/Val after DB. After treatment with Sac/Val post DB, decreased heart weight and myocardial cell size were observed in mouse hearts. In addition, histological analysis, immunofluorescence, and western blot results showed that Sac/Val attenuated cardiac fibrosis and inflammation after DB. Finally, our data indicated that Sac/Val treatment could significantly suppress NF-κB signaling and NLRP3 inflammasome activation in mice after relief of pressure overload. Conclusion Sac/Val exerted its beneficial effects to prevent maladaptive cardiac fibrosis and dysfunction in mice following pressure unloading, which was at least partly due to the inhibition of NLRP3 inflammasome activation.

Abstract 215: Angiotensin-II-induced Cardiac Remodeling is Reduced in TNFR1-deficient Mice Despite Increased Blood Pressure

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Clemens Duerrschmid ◽  
Fernando Aguirre-Amezquite ◽  
George E Taffet ◽  
Mark L Entman ◽  
Sandra B Haudek
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Cardiac Function ◽  
Cardiac Fibrosis ◽  
Weight Ratio ◽  
Heart Weight ◽  
Ang Ii ◽  
Long Term Effects ◽  
2D Echocardiography ◽  
Collagen Iii

Background: Infusion of angiotensin-II (Ang-II) to wild-type (WT) mice results in hypertension, development of interstitial cardiac fibrosis and hypertrophy, and deterioration of myocardial function. We previously showed that after 1 week of Ang-II infusion, these effects were absent in mice deficient in tumor necrosis factor receptor 1 (TNFR1). We now investigated long-term effects of Ang-II infusion. Methods: WT and TNFR1-KO mice were infused with Ang-II for 6 weeks. Systolic blood pressure (SBP) was measured by tail-cuff plethysmography; cardiac function by 2D-echocardiography and Doppler ultrasound. Hearts were analyzed for collagen deposition (histology) and expression of fibrosis- and hypertrophy- related genes (quantitative PCR). Results: In WT mice, SBP increased within 7 days and remained elevated at 6 weeks (152±4 mmHg); cardiac fibrosis developed after 1 week and persisted at 6 weeks (6.2±1.1% collagen area). By contrast, in TNFR1-KO mice, SBP at 7 days was low, but increased by 6 weeks (144±4 mmHg), whereas cardiac fibrosis was absent at 1 week and did not significantly increase by 6 weeks (2.5±0.5%). In support of these data, collagen I and collagen III mRNA expression at 6 weeks were upregulated in WT (2.9±0.6 and 4.1±0.8 -fold over sham), but not in TNFR1-KO hearts (1.3±0.1 and 1.8±0.2). In both mouse groups, cardiac hypertrophy and cardiac dysfunction developed over time, however, these changes were less prominent in TNFR1-KO mice: at 6 weeks, the heart-weight to body-weight ratio in WT was 6.7±0.4, in TNFR1-KO mice 5.5±0.2; the changes in anterior and posterior wall thicknesses in WT were 44±12% and 32±15%, in TNFR1-KO mice 19±8% and 17±10%; the change in ejection fraction in WT was -67±12%, in TNFR1-KO mice -39±5%; and the change in Tei-index (myocardial performance) in WT was 18±9%, in TNFR1-KO -1±7%. Also, hypertrophy-related atrial natriuretic peptide (ANP) and beta-myosin heavy chain (b-MHC) mRNA were upregulated in WT (4.3±0.9 and 4.3±0.6 -fold over sham), but less in TNFR1-KO hearts (2.6±0.5 and 2.4±0.5). Conclusion: Despite a significant increase in blood pressure over 6 weeks of Ang-II infusion, TNFR1-KO mice developed less cardiac fibrosis and hypertrophy and had better cardiac function compared to WT mice.

Abstract P141: Immunosuppressant Treatment Attenuates Augmentation Of Intrarenal NLRP-3 Inflammasome In Angiotensin II-dependent Hypertension

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Ryousuke Satou ◽  
Martha G Franco ◽  
Akemi Katsurada ◽  
Courtney M Dugas ◽  
L G NAVAR
Keyword(s):  
Angiotensin Ii ◽  
Nlrp3 Inflammasome ◽  
Bacterial Infections ◽  
Kidney Injury ◽  
Control Group ◽  
Inflammasome Activation ◽  
Mrna Levels ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Normotensive Control

Activated inflammasomes enhance maturation of pro-inflammatory cytokines, which facilitates the development of kidney injury. NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3), one of major subunits in the inflammasome complex, plays a crucial role in innate immunity and inflammation. Although NLRP3 inflammasome is activated by ATP-P2Y7 axis and reactive oxygen species, the expression of pro-NLRP3 is promoted by NF-κB activated by cytokines or PAMPs/DAMPs. Thus, we hypothesized that mycophenolate mofetil (MMF), an immunosuppressant, attenuates augmentation of intrarenal NLRP3 and consequent progression of kidney injury in angiotensin II (Ang II)-dependent hypertension. Ang II (80 ng/min) was infused with/without daily MMF administration (50 ng/kg) to Sprague-Dawley rats for 2 weeks. mRNA levels of intrarenal NLRP3 and AIM2, which forms another type of inflammasome complex by viral or bacterial infections, were measured by droplet digital PCR. Furthermore, kidney injury was evaluated. MMF treatment mitigated Ang II-induced macrophage infiltration into kidneys, suggesting immunosuppression by the drug. Ang II infusion significantly increased intrarenal NLRP3 mRNA levels (normotensive control group: 4.12±1.1 copies/ng RNA vs. Ang II-infused group: 9.96±1.8 copies, N=5). The elevated NLRP3 expression in kidneys of Ang II-infused rats was attenuated by MMF treatment (6.24±1.4 copies). In contrast, intrarenal AIM2 levels were lower than NLRP3 in the control group and the levels were not altered by Ang II infusion or MMF treatment (normotensive control group: 0.42±0.1 copies, Ang II-infused group: 0.35±0.06 copies and Ang II+MMF group: 0.35±0.08 copies). Urinary protein and angiotensinogen levels were elevated in Ang II-infused rats and MMF treatment suppressed the augmentations. Histological analyses also showed the development of kidney injury including mesangial expansion and tubulointerstitial fibrosis observed in the hypertensive rats, but these injury markers were mitigated by MMF. These results demonstrate activation of the NLRP3 inflammasome in Ang II dependent hypertension and indicate that immunosuppression by MMF mitigates the inflammasome activation, which contributes to attenuation of the kidney injury.

Abstract P075: Angiotensin II Induces Endothelial Dysfunction And Vascular Remodeling Dependent Of Nlrp3 Inflammasome

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Stefany B Cau ◽  
Marcondes da Silva ◽  
Nathanne d Ferreira ◽  
Rita C Tostes ◽  
Thiago Bruder-Nascimento
Keyword(s):  
Angiotensin Ii ◽  
Endothelial Dysfunction ◽  
Nlrp3 Inflammasome ◽  
Vascular Remodeling ◽  
Vascular Diseases ◽  
Vascular Damage ◽  
Mesenteric Arteries ◽  
Cell Counting ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation

The NLRP3 inflammasome is a multimeric protein complex constituted by NLRP3, Asc and Capase-1 (Casp1). It triggers an inflammatory response by releasing the pro-inflammatory cytokines IL-1β and IL-18. NLRP3 inflammasome is expressed in different cells and its activation has been associated with several diseases including atherosclerosis and hypertension. Herein we tested the hypothesis that angiotensin II (AngII) induces vascular damage by activating the NLPR3 inflammasome in the vasculature. C57BL/6J male mice (Ctrl) and Casp-1 deficient mice (Casp1-/-) were treated with AngII (490 ng/min/kg/14 days by osmotic mini pump). In Ctrl mice, AngII treatment impaired the vascular relaxation to acetylcholine in mesenteric arteries, increased aorta media thickness [Ctrl: 49.4 ± 2.5 vs AngII: 62.3 ± 2.3* (μm), *P<0.05] and cross-sectional area [Ctrl: 0.11 ± 0.1 vs AngII: 0.15 ± 0.2* (mm), *P<0.05] and triggered NLRP3 inflammasome activation in aorta and mesenteric arteries, analyzed by caspase-1 cleavage and IL-1B maturation via western blot and casp1 activity - FAM-FLICA assay. Fascinatingly, Casp1-/- mice were protected from AngII-induced endothelial dysfunction and vascular remodeling. Furthermore, AngII (0.1uM) incubation, combined or not with lipopolysaccharide (500 ng.ml –1 ultrapure) or Nigericin (20 μM), elevated Casp1 cleavage and IL-1B maturation in Rat Aortic Smooth Muscle Cells (RASMC). Moreover, AngII elevated PCNA (~2.5-fold) and CyclinD1 (~2.1-fold) protein expression and induced vascular migration and proliferation measured by scratch assay and cell counting kit-8 (CCK-8) assay respectively. Interestingly NLRP3 antagonist incubation (MCC950, 1uM) abolished PCNA expression and attenuated the vascular migration and proliferation produced by AngII incubation. Our data suggest that AngII induces vascular damage by activating NLPR3 inflammasome directly in the vasculature. We place this innate immune receptor as a master regulator of the vascular phenotype and as a target for therapeutic strategies for vascular diseases. Future studies will be helpful providing a better understanding into the molecular mechanism of NLRP3 inflammasome activation and regulation in the control of vascular diseases.

scholarly journals Effects of the TLR4/Myd88/NF-κB Signaling Pathway on NLRP3 Inflammasome in Coronary Microembolization-Induced Myocardial Injury

2018 ◽  
Vol 47 (4) ◽  
pp. 1497-1508 ◽  
Author(s):  
Qiang Su ◽  
Lang Li ◽  
Yuhan Sun ◽  
Huafeng Yang ◽  
Ziliang Ye ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Cardiac Function ◽  
Nlrp3 Inflammasome ◽  
Myocardial Injury ◽  
Neonatal Rat ◽  
Myocardial Inflammation ◽  
Inflammasome Activation ◽  
Coronary Microembolization ◽  
Coronary Syndrome ◽  
Nlrp3 Inflammasome Activation

Background/Aims: Coronary microembolization (CME) is a common complication of acute coronary syndrome (ACS) and percutaneous coronary intervention (PCI); Myocardial inflammation, caused by CME, is the main cause of cardiac injury. TLR4/MyD88/NF-κB signaling plays an important role in the development of myocardial inflammation, but its effects on CME remain unclear. To assess the cardiac protective effects of TAK-242 (TLR4 specific inhibitor) on CME-induced myocardial injury, and explore the underlying mechanism. Methods: Cardiac function, serum c-troponin I level, microinfarct were examined by cardiac ultrasound, myocardial enzyme assessment, HBFP staining. The levels of TLR4/MyD88/NF-κB signaling and NLRP3 inflammasome pathway were detected by ELISA, qRT-PCR and western blot. Results: The results showed inflammatory responses in the myocardium after CME, with increased expression levels of pro-inflammatory factors TNF-α, IL-1β and IL-18. Meanwhile, TLR4/MyD88/NF-κB signaling and the NLRP3 inflammasome were involved in the inflammatory process. TAK-242 administration before CME effectively inhibited the inflammatory response in the rat myocardium after CME and reduced myocardial injury, mainly by inhibiting TLR4/ MyD88/NF-κB signaling and reducing NLRP3 inflammasome activation. In addition, in vitro assays with neonatal rat cardiomyocytes further confirmed that TLR4/MyD88/NF-κB signaling was significantly activated in the inflammatory response of LPS-induced cardiomyocytes, via activation of the NLRP3 inflammasome. Inhibition of TLR4/MyD88/NF-κB signaling resulted in increased survival of cardiomyocytes mainly by reducing the release of inflammatory cytokines and decreasing NLRP3 inflammasome activation. Conclusions: TLR4/MyD88/NF-κB signaling participates in the inflammatory response of the myocardium after CME, activating the NLRP3 inflammasome, promoting the inflammatory cascade, and aggravating myocardial injury. Blocking TLR4/MyD88/NF-κB signaling may help reduce myocardial injury and improve cardiac function after CME.

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