5TNF-α and IL-1β Neutralization Ameliorates Angiotensin II-Induced Cardiac Damage in Male Mice

Inflammation is a key event in hypertensive organ damage, and TNF-α and IL-1β are elevated in hypertension. In this study, we evaluated the effects of TNF-α and IL-1β elevation on hypertensive cardiac damage by treatment with a bifunctional inflammatory inhibitor, TNF receptor 2-fragment crystalization-IL-1 receptor antagonist (TFI), which can neutralize these 2 cytokines simultaneously. A mouse hypertension model of angiotensin II (Ang II) infusion (1500 ng/kg·min for 7 d) was induced in wild-type mice. TNF-α and IL-1β were inhibited by TFI administration (5 mg/kg, every other day), the effects of inhibition on cardiac damage were examined, and its mechanism on inflammatory infiltration was further studied in vivo and in vitro. Ang II infusion induced cardiac injury, including increased macrophage infiltration, expression of inflammatory cytokines (IL-12, IL-6, etc), and cardiac fibrosis, such as elevated α-smooth muscle actin, collagen I, and TGF-β expression. Importantly, the Ang II-induced cardiac injury was suppressed by TFI treatment. Moreover, TFI reduced the expression of adhesion molecules (intercellular adhesion molecule-1 and vascular cell adhesion molecule-1) and monocyte chemotactic protein-1 expression in Ang II-treated hearts. Additionally, blockade of TNF-α and IL-1β by TFI reduced monocyte adherence to endothelia cell and macrophage migration. This study demonstrates that blocking TNF-α and IL-1β by TFI prevents cardiac damage in response to Ang II, and targeting these 2 cytokines simultaneously might be a novel tool to treat hypertensive heart injury.

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Angiotensin II is associated with activation of NF-κB-mediated genes and downregulation of PPARs

Physiological Genomics ◽

10.1152/physiolgenomics.00062.2002 ◽

2002 ◽

Vol 11 (1) ◽

pp. 21-30 ◽

Cited By ~ 197

Author(s):

Doris M. Tham ◽

Baby Martin-McNulty ◽

Yi-xin Wang ◽

Dennis W. Wilson ◽

Ronald Vergona ◽

...

Keyword(s):

Angiotensin Ii ◽

Adhesion Molecule ◽

Vascular Inflammation ◽

Aortic Aneurysms ◽

Intercellular Adhesion Molecule ◽

Ang Ii ◽

Inflammatory Genes ◽

Apoe Ko Mice ◽

Apoe Ko

Angiotensin II (ANG II) promotes vascular inflammation through nuclear factor-κB (NF-κB)-mediated induction of pro-inflammatory genes. The role of peroxisome proliferator-activated receptors (PPARs) in modulating vascular inflammation and atherosclerosis in vivo is unclear. The aim of the present study was to examine the effects of ANG II on PPARs and NF-κB-dependent pro-inflammatory genes in the vascular wall in an in vivo model of atherosclerosis and aneurysm formation. Six-month-old male apolipoprotein E-deficient (apoE-KO) mice were treated with ANG II (1.44 mg/kg per day for 30 days). ANG II enhanced vascular inflammation, accelerated atherosclerosis, and induced formation of abdominal aortic aneurysms. These effects of ANG II in the aorta were associated with downregulation of both PPAR-α and PPAR-γ mRNA and protein and an increase in transcription of monocyte chemotactic protein-1 (MCP-1), macrophage-colony stimulating factor (M-CSF), endothelial-selectin (E-selectin), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) throughout the entire aorta. ANG II also activated NF-κB with increases in both p52 and p65 NF-κB subunits. In summary, these in vivo results indicate that ANG II, through activation of NF-κB-mediated pro-inflammatory genes, promotes vascular inflammation, leading to acceleration of atherosclerosis and induction of aneurysm in apoE-KO mice. Downregulation of PPAR-α and -γ by ANG II may diminish the anti-inflammatory potential of PPARs, thus contributing to enhanced vascular inflammation.

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Abstract 229: TNF Receptor 1 Signaling Is Critically Involved in Mediating Angiotensin II-Induced Cardiac Fibrosis and Dysfunction

Circulation Research ◽

10.1161/res.111.suppl_1.a229 ◽

2012 ◽

Vol 111 (suppl_1) ◽

Author(s):

Sandra B Haudek ◽

Jeff Crawford ◽

Erin Reineke ◽

Alberto A Allegre ◽

George E Taffet ◽

...

Keyword(s):

Angiotensin Ii ◽

Cardiac Fibrosis ◽

Smooth Muscle Actin ◽

Protein A ◽

Ang Ii ◽

Wild Type ◽

Monocyte Chemoattractant Protein 1 ◽

Reactive Fibrosis

Angiotensin-II (Ang-II) plays a key role in the development of cardiomyopathies, as it is associated with many conditions involving heart failure and pathologic hypertrophy. Using a murine model of Ang-II infusion, we found that Ang-II induced the synthesis of monocyte chemoattractant protein 1 (MCP-1) that mediated the uptake of CD34 + /CD45 + monocytic cells into the heart. These precursor cells differentiated into collagen-producing fibroblasts and were responsible for the Ang-II-induced development of reactive fibrosis. Preliminary in vitro data using our monocyte-to-fibroblast differentiation model, suggested that Ang-II required the presence of TNF to induce fibroblast maturation from monocytes. In vivo, they indicated that in mice deficient of both TNF receptors (TNFR1 and TNFR2), Ang-II-induced fibrosis was absent. We now assessed the hypothesis that specific TNFR1 signaling is necessary for Ang-II-mediated cardiac fibrosis. Mice deficient in either TNFR1 (TNFR1-KO) or TNFR2 (TNFR2-KO) were subjected to continuous infusion of Ang-II for 1 to 6 weeks (n=6-8/group). Compared to wild-type, we found that in TNFR1-KO, but not in TNFR2-KO mouse hearts, collagen deposition was attenuated, as was cardiac α-smooth muscle actin protein (a marker for activated fibroblasts). When we isolated viable cardiac fibroblasts and characterized them by flow cytometry, we found that Ang-II infusion in TNFR1-KO, but not in TNFR2-KO, resulted in a marked decrease of CD34 + /CD45 + cells. Quantitative RT-PCR demonstrated a striking reduction of type 1 and 3 collagen, as well of MCP-1 mRNA expression in TNFR1-KO mouse hearts. Further measurements of cardiovascular parameters indicated that TNFR1-KO animals developed lesser Ang-II-mediated LV remodeling, smaller changes in E-linear deceleration times/rates over time, and displayed a lower Tei index (a heart rate independent marker of cardiac function), indicating less stiffness in TNFR1-KO hearts compared to wild-type and TNFR2-KO hearts. The data suggest that Ang-II-dependent cardiac fibrosis requires TNF and its signaling through TNFR1 which enhances the induction of MCP-1 and uptake of monocytic fibroblast precursors that are associated with reactive fibrosis and cardiac remodeling and function.

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Adiponectin Suppresses Angiotensin II-Induced Inflammation and Cardiac Fibrosis through Activation of Macrophage Autophagy

Endocrinology ◽

10.1210/en.2013-2011 ◽

2014 ◽

Vol 155 (6) ◽

pp. 2254-2265 ◽

Cited By ~ 50

Author(s):

Guan-Ming Qi ◽

Li-Xin Jia ◽

Yu-Lin Li ◽

Hui-Hua Li ◽

Jie Du

Keyword(s):

Angiotensin Ii ◽

Protein Kinase ◽

Cardiac Fibrosis ◽

Inflammatory Responses ◽

Smooth Muscle Actin ◽

Underlying Mechanism ◽

Nuclear Factor Κb ◽

Ang Ii ◽

Compound C

Previous studies have indicated that adiponectin (APN) protects against cardiac remodeling, but the underlying mechanism remains unclear. The present study aimed to elucidate how APN regulates inflammatory responses and cardiac fibrosis in response to angiotensin II (Ang II). Male APN knockout (APN KO) mice and wild-type (WT) C57BL/6 littermates were sc infused with Ang II at 750 ng/kg per minute. Seven days after Ang II infusion, both APN KO and WT mice developed equally high blood pressure levels. However, APN KO mice developed more severe cardiac fibrosis and inflammation compared with WT mice. This finding was demonstrated by the up-regulation of collagen I, α-smooth muscle actin, IL-1β, and TNF-α and increased macrophage infiltration in APN KO mice. Moreover, there were substantially fewer microtubule-associated protein 1 light chain 3-positive autophagosomes in macrophages in the hearts of Ang II-infused APN KO mice. Additional in vitro studies also revealed that globular APN treatment induced autophagy, inhibited Ang II-induced nuclear factor-κB activity, and enhanced the expression of antiinflammatory cytokines, including IL-10, macrophage galactose N-acetyl-galactosamine specific lectin 2, found in inflammatory zone 1, and type-1 arginase in macrophages. In contrast, APN-induced autophagy and antiinflammatory cytokine expression was diminished in Atg5-knockdown macrophages or by Compound C, an inhibitor of adenosine 5′-monophosphate-activated protein kinase. Our study indicates that APN activates macrophage autophagy through the adenosine 5′-monophosphate-activated protein kinase pathway and suppresses Ang II-induced inflammatory responses, thereby reducing the extent of cardiac fibrosis.

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Estrogen prevents intestinal inflammation after trauma-hemorrhage via downregulation of angiotensin II and angiotensin II subtype I receptor

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.90443.2008 ◽

2008 ◽

Vol 295 (5) ◽

pp. G1131-G1137 ◽

Cited By ~ 16

Author(s):

Jianguo Chen ◽

Shaolong Yang ◽

Shunhua Hu ◽

Mashkoor A. Choudhry ◽

Kirby I. Bland ◽

...

Keyword(s):

Angiotensin Ii ◽

Intestinal Inflammation ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Intercellular Adhesion Molecule ◽

Ang Ii ◽

Sprague Dawley ◽

Total Blood ◽

Tnf Α ◽

Salutary Effect

Although angiotensin II (Ang II) plays a key role in development of organ ischemia-reperfusion injury, it remains unclear whether it is involved in development of intestinal injury following trauma-hemorrhage (T-H). Studies have shown that 17β-estradiol (E2) administration following T-H improves small intestinal blood flow; however, it is unclear whether Ang II plays a role in this E2-mediated salutary effect. Male Sprague-Dawley rats underwent laparotomy and hemorrhagic shock (removal of 60% total blood volume, fluid resuscitation after 90 min). At onset of resuscitation, rats were treated with vehicle, E2, or E2 and estrogen receptor antagonist ICI 182,780 (ICI). A separate group of rats was treated with Ang II subtype I receptor (AT1R) antagonist losartan. At 24 h after T-H, plasma Ang II, IL-6, TNF-α, intercellular adhesion molecule (ICAM)-1, cytokine-induced neutrophil chemoattractant (CINC)-1 and CINC-3 levels, myeloperoxidase (MPO) activity, and AT1R expression were determined. T-H significantly increased plasma and intestinal Ang II, IL-6, TNF-α levels, intestinal ICAM-1, CINC-1, CINC-3 levels, MPO activity, and AT1R protein compared with shams. E2 treatment following T-H attenuated increased intestinal MPO activity, Ang II level, and AT1R protein expression. ICI administration abolished the salutary effects of E2. In contrast, losartan administration attenuated increased MPO activity without affecting Ang II and AT1R levels. Thus Ang II plays a role in producing small intestine inflammation following T-H, and the salutary effects of E2 on intestinal inflammation are mediated in part by Ang II and AT1R downregulation.

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Abstract 139: Loss of Thymosin b4 Exacerbates Renal and Cardiac Damage in Angiotensin-II Hypertension

Hypertension ◽

10.1161/hyp.70.suppl_1.139 ◽

2017 ◽

Vol 70 (suppl_1) ◽

Author(s):

Nitin Kumar ◽

Tang-Dong Liao ◽

Cesar Romero ◽

Mani Maheshwari ◽

Ed Peterson ◽

...

Keyword(s):

Angiotensin Ii ◽

Tissue Damage ◽

Cardiac Fibrosis ◽

Organ Damage ◽

Protective Role ◽

High Expression ◽

Ang Ii ◽

Cardiac Damage ◽

Filtration Barrier

Angiotensin-II (Ang-II)-induced hypertension is associated with tissue damage and fibrosis in the kidney and heart. Thymosin β4 (Tβ4) regulates cell morphology, inflammation and fibrosis in several organs and administration of exogenous Tβ4 is protective in diabetic nephropathy and unilateral ureteral obstruction model. However, role of endogenous Tβ4 in hypertension-induced organ damage is unknown. We hypothesize that, loss of Tβ4 accelerates renal and cardiac fibrosis and damage in Ang-II hypertension. To test our hypothesis, Tβ4 knockout (Tβ4 -/- ) and wild-type (Tβ4 +/+ ) C57BL/6 mice (n=6-10) were infused continuously for six-weeks with either Ang-II (980 ng/kg/min) or vehicle via osmotic minipumps. All the results are presented in table 1. In Ang-II infusion, systolic blood-pressure were not different between both strains (Table 1). Interestingly, urinary albuminuria was significantly higher in Tβ4 -/- mice compared to Tβ4 +/+ mice by Ang-II. High expression of Tβ4 is found in the glomeruli along with high expression of Nephrin, an important protein in the filtration barrier of the kidney. In Ang-II infusion, nephrin protein expression was greatly reduced in mice deficient of Tβ4, suggesting that loss of nephrin is one of the mechanism for elevated urinary albumin in Tβ4 -/- mice. Additionally, renal fibrosis was higher in Tβ4 -/- mice. We also studied cardiac damage and observed that in Ang-II infusion, cardiac hypertrophy and cardiac fibrosis were much higher in Tβ4 -/- mice. These data indicate that loss of endogenous Tβ4 caused significant tissue damage in the kidney and heart in Ang-II hypertension, suggesting renal and cardiac protective role of this peptide.

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Etanercept Ameliorates Cardiac Fibrosis in Rats with Diet-Induced Obesity

Pharmaceuticals ◽

10.3390/ph14040320 ◽

2021 ◽

Vol 14 (4) ◽

pp. 320

Author(s):

Chia-Chen Hsu ◽

Yingxiao Li ◽

Chao-Tien Hsu ◽

Juei-Tang Cheng ◽

Mang Hung Lin ◽

...

Keyword(s):

High Fat Diet ◽

Cardiac Fibrosis ◽

Cardiac Injury ◽

Vehicle Group ◽

Necrosis Factor Alpha ◽

Etanercept Treatment ◽

Diet Induced Obesity ◽

Tnf Α ◽

Factor Alpha ◽

Necrosis Factor

Diet-induced obesity (DIO) is considered the main risk factor for cardiovascular diseases. Increases in the plasma levels of tumor necrosis factor alpha (TNF-α) is associated with DIO. Etanercept, a TNF-α inhibitor, has been shown to alleviate cardiac hypertrophy. To investigate the effect of etanercept on cardiac fibrosis in DIO model, rats on high fat diet (HFD) were subdivided into two groups: the etanercept group and vehicle group. Cardiac injury was identified by classic methods, while fibrosis was characterized by histological analysis of the hearts. Etanercept treatment at 0.8 mg/kg/week twice weekly by subcutaneous injection effectively alleviates the cardiac fibrosis in HFD-fed rats. STAT3 activation seems to be induced in parallel with fibrosis-related gene expression in the hearts of HFD-fed rats. Decreased STAT3 activation plays a role in the etanercept-treated animals. Moreover, fibrosis-related genes are activated by palmitate in parallel with STAT3 activation in H9c2 cells. Etanercept may inhibit the effects of palmitate, but it is less effective than a direct inhibitor of STAT3. Direct inhibition of STAT3 activation by etanercept seems unlikely. Etanercept has the ability to ameliorate cardiac fibrosis through reduction of STAT3 activation after the inhibition of TNF-α and/or its receptor.

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Direct Activation of Human Endothelial Cells by Plasmodium falciparum-Infected Erythrocytes

Infection and Immunity ◽

10.1128/iai.73.6.3271-3277.2005 ◽

2005 ◽

Vol 73 (6) ◽

pp. 3271-3277 ◽

Cited By ~ 37

Author(s):

Nicola K. Viebig ◽

Ulrich Wulbrand ◽

Reinhold Förster ◽

Katherine T. Andrews ◽

Michael Lanzer ◽

...

Keyword(s):

Endothelial Cells ◽

Plasmodium Falciparum ◽

Endothelial Cell ◽

Adhesion Molecule ◽

Cell Activation ◽

Physical Contact ◽

Intercellular Adhesion Molecule ◽

Immune Reactivity ◽

Human Endothelial Cells ◽

Tnf Α

ABSTRACT Cytoadherence of Plasmodium falciparum-infected erythrocytes (PRBC) to endothelial cells causes severe clinical disease, presumably as a of result perfusion failure and tissue hypoxia. Cytoadherence to endothelial cells is increased by endothelial cell activation, which is believed to occur in a paracrine fashion by mediators such as tumor necrosis factor alpha (TNF-α) released from macrophages that initially recognize PRBC. Here we provide evidence that PRBC directly stimulate human endothelial cells in the absence of macrophages, leading to increased expression of adhesion-promoting molecules, such as intercellular adhesion molecule 1. Endothelial cell stimulation by PRBC required direct physical contact for a short time (30 to 60 min) and was correlated with parasitemia. Gene expression profiling of endothelial cells stimulated by PRBC revealed increased expression levels of chemokine and adhesion molecule genes. PRBC-stimulated endothelial cells especially showed increased expression of molecules involved in parasite adhesion but failed to express molecules promoting leukocyte adhesion, such as E-selectin and vascular cell adhesion molecule 1, even after challenge with TNF-α. Collectively, our data suggest that stimulation of endothelial cells by PRBC may have two effects: prevention of parasite clearance through increased cytoadherence and attenuation of leukocyte binding to endothelial cells, thereby preventing deleterious immune reactivity.

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Suppressive Effects of the Gynura bicolor Ether Extract on Endothelial Permeability and Leukocyte Transmigration in Human Endothelial Cells Induced by TNF-α

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2020/9413724 ◽

2020 ◽

Vol 2020 ◽

pp. 1-13

Author(s):

Shu-Ling Hsieh ◽

Jyh-Jye Wang ◽

Kuan-Hua Su ◽

Ying-Lan Kuo ◽

Shuchen Hsieh ◽

...

Keyword(s):

Endothelial Cells ◽

Adhesion Molecule ◽

Far East ◽

Endothelial Permeability ◽

Intercellular Adhesion Molecule ◽

Ether Extract ◽

Human Endothelial Cells ◽

Tnf Α ◽

Ea.Hy926 Cells ◽

Gynura Bicolor

Gynura bicolor (Roxb. and Willd.) DC (G. bicolor) is generally used as a dietary vegetable and traditional herb in Taiwan and the Far East. G. bicolor exerts antioxidant and anti-inflammatory effects and regulates blood lipids and cholesterol. However, the effects of G. bicolor on endothelial transmigration and atherosclerosis are not clear. The present study investigated the effects of G. bicolor on endothelial permeability and transmigration in human endothelial cells. We prepared G. bicolor ether extract (GBEE) for use as the experimental material. Under TNF-α stimulation, HL-60 cell adherence to EA.hy926 cells, the shape of EA.hy926 cells, and the expression of adhesion molecules and transmigration-related regulatory molecules were analysed after pretreatment with GBEE for 24 h. GBEE inhibited leukocyte adhesion to endothelial cells, reduced intercellular adhesion molecule-1 (ICAM-1) and platelet endothelial cell adhesion molecule-1 (PECAM-1) expressions, and decreased endothelial monolayer permeability. GBEE also reduced paracellular transmigration by reducing the levels of reactive oxygen species (ROS), Src phosphorylation, and vascular endothelial-cadherin (VE-cadherin) phosphorylation. GBEE reduced transcellular migration via inhibition of Ras homolog family member A (RhoA) and Rho-associated protein kinase (ROCK) expression and phosphorylation of the ezrin-radixin-moesin (ERM) protein. Incubation of EA.hy926 cells with GBEE for 8 h and stimulation with TNF-α for 3 h reduced the phosphorylation of the inhibitor of kappa B (IĸB) and DNA-binding activity of nuclear factor-ĸB (NF-ĸB). These results suggest that GBEE has a protective effect against endothelial dysfunction via suppression of leukocyte-endothelium adhesion and transmigration.

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Renovascular hypertension induces myocardial mitochondrial damage, contributing to cardiac injury and dysfunction in pigs with metabolic syndrome

American Journal of Hypertension ◽

10.1093/ajh/hpaa202 ◽

2020 ◽

Author(s):

Arash Aghajani Nargesi ◽

Mohamed C Farah ◽

Xiang-Yang Zhu ◽

Lei Zhang ◽

Hui Tang ◽

...

Keyword(s):

Metabolic Syndrome ◽

Renovascular Hypertension ◽

Cardiac Fibrosis ◽

Cardiac Injury ◽

Left Ventricular ◽

Mitochondrial Damage ◽

Mitochondrial Morphology ◽

H2o2 Production ◽

Cardiac Damage ◽

Cardiovascular Morbidity And Mortality

Abstract Background Subjects with renovascular hypertension (RVH) often manifest with metabolic syndrome (MetS) as well. Coexisting MetS and hypertension increases cardiovascular morbidity and mortality, but the mechanisms underlying cardiac injury remain unknown. We hypothesized that superimposition of MetS induces myocardial mitochondrial damage, leading to cardiac injury and dysfunction in swine RVH. Methods Pigs were studied after 16 weeks of diet-induced MetS with or without RVH (unilateral renal artery stenosis), and Lean controls (n=6 each). Systolic and diastolic cardiac function were assessed by multi-detector CT, and cardiac mitochondrial morphology (transmission electron microscopy) and myocardial function in tissue and isolated mitochondria. Results Body weight was similarly higher in MetS groups vs. Lean. RVH groups achieved significant stenosis and developed hypertension. Mitochondrial matrix density and ATP production were lower and H2O2 production higher in RVH groups versus Lean and MetS. Lean+RVH (but not MetS+RVH) activated mitophagy, which was associated with decreased myocardial expression of mitophagy-related microRNAs. MetS groups exhibited higher numbers of inter-mitochondrial junctions (IMJs), which could have prevented membrane depolarization/activation of mitophagy in MetS+RVH. Cardiac fibrosis, hypertrophy (increased left ventricular muscle mass), and diastolic function (decreased E/A ratio) were greater in MetS+RVH versus Lean+RVH. Conclusions Superimposition of MetS on swine RVH induces myocardial mitochondrial damage and dysfunction. MetS+RVH failed to activate mitophagy, resulting in greater cardiac remodeling, fibrosis, and diastolic dysfunction. Mitochondrial injury and impaired mitophagy may constitute important mechanisms and potential therapeutic targets to ameliorate cardiac damage and dysfunction in patients with coexisting MetS and RVH.

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