scholarly journals Recruitment of macrophages from the spleen contributes to myocardial fibrosis and hypertension induced by angiotensin II

2017 ◽  
Vol 18 (2) ◽  
pp. 147032031770665 ◽  
Author(s):  
Ning-Ping Wang ◽  
James Erskine ◽  
Wei-Wei Zhang ◽  
Rong-Hua Zheng ◽  
Li-Hui Zhang ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
At1 Receptor ◽  
Sprague Dawley ◽  
Monocyte Chemoattractant Protein 1 ◽  
Sprague Dawley Rats ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Introduction: The purpose of this study was to determine whether macrophages migrated from the spleen are associated with angiotensin II-induced cardiac fibrosis and hypertension. Methods: Sprague-Dawley rats were subjected to angiotensin II infusion in vehicle (500 ng/kg/min) for up to four weeks. In splenectomy, the spleen was removed before angiotensin II infusion. In the angiotensin II AT1 receptor blockade, telmisartan was administered by gastric gavage (10 mg/kg/day) during angiotensin II infusion. The heart and aorta were isolated for Western blot analysis and immunohistochemistry. Results: Angiotensin II infusion caused a significant reduction in the number of monocytes in the spleen through the AT1 receptor-activated monocyte chemoattractant protein-1. Comparison of angiotensin II infusion, splenectomy and telmisartan comparatively reduced the recruitment of macrophages into the heart. Associated with this change, transforming growth factor β1 expression and myofibroblast proliferation were inhibited, and Smad2/3 and collagen I/III were downregulated. Furthermore, interstitial/perivascular fibrosis was attenuated. These modifications occurred in coincidence with reduced blood pressure. At week 4, invasion of macrophages and myofibroblasts in the thoracic aorta was attenuated and expression of endothelial nitric oxide synthase was upregulated, along with a reduction in aortic fibrosis. Conclusions: These results suggest that macrophages when recruited into the heart and aorta from the spleen potentially contribute to angiotensin II-induced cardiac fibrosis and hypertension.

scholarly journals Hypertensive female Sprague-Dawley rats require an intact nitric oxide synthase system for compensatory increases in renal regulatory T cells

2020 ◽  
Vol 319 (2) ◽  
pp. F192-F201
Author(s):  
Lindsey A. Ramirez ◽  
Ellen E. Gillis ◽  
Jacqueline B. Musall ◽  
Riyaz Mohamed ◽  
Elizabeth Snyder ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
T Cells ◽  
Angiotensin Ii ◽  
Nitric Oxide Synthase ◽  
Regulatory T Cells ◽  
Female Rats ◽  
Sprague Dawley ◽  
Albumin Excretion ◽  
Sprague Dawley Rats ◽  
Oxide Synthase

We have previously shown that hypertensive female rats have more regulatory T cells (Tregs), which contribute more to blood pressure (BP) control in female versus male rats. Based on known protective properties of Tregs, the goal of the present study was to investigate the mechanisms by which female rats maintain Tregs. The present study was designed to 1) compare the impact of three hypertension models on the percentage of renal Tregs and 2) test the hypothesis that nitric oxide synthase (NOS) inhibition prevents increases in renal Tregs and exacerbates renal damage in female Sprague-Dawley rats. Rats (11–14 wk old) were randomized to one of the following four groups: control, norepinephrine (NE) infusion, angiotensin II infusion, or the NOS inhibitor Nω-nitro-l-arginine methyl ester (l-NAME) in drinking water. BP was measured via tail cuff. After 2 wk of treatment, kidneys were isolated and processed to measure Tregs via flow cytometric analysis and renal injury via urinary albumin excretion, plasma creatinine, and histological analyses. Hypertensive treatments increased BP in all experimental animals. Increases in BP in norepinephrine-and angiotensin II-treated rats were associated with increases in renal Tregs versus control. In contrast, l-NAME treatment decreased Tregs compared with all groups. l-NAME treatment modestly increased albumin excretion. However, plasma creatinine was comparable among the groups, and there was no histological evidence of glomerular or tubular injury. This study provides insights into the mechanisms regulating renal Tregs and supports that an intact NOS system is crucial for female rats to have BP-related increases in renal Tregs.

Glucose Degradation Products Result in Cardiovascular Toxicity in a Rat Model of Renal Failure

2010 ◽  
Vol 30 (1) ◽  
pp. 35-40 ◽  
Author(s):  
Sandra Müller–Krebs ◽  
Lars P. Kihm ◽  
Benjamin Zeier ◽  
Marie-Luise Gross ◽  
Anders Wieslander ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cardiovascular System ◽  
Degradation Products ◽  
Systemic Circulation ◽  
Sprague Dawley ◽  
Glucose Degradation Products ◽  
Cardiovascular Damage ◽  
Sprague Dawley Rats ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

BackgroundIt has been shown that glucose degradation products (GDP) generated during heat sterilization of peritoneal dialysis (PD) fluids impair the peritoneal membrane locally, then enter the systemic circulation and cause damage to the remnant kidney. Here we examined in subtotally nephrectomized (SNX) rats whether GDP also affect the cardiovascular system.Materials and MethodsStandard 5/6 nephrectomy was carried out in Sprague–Dawley rats; other rats were sham operated and left untreated for 3 weeks. Through an osmotic mini-pump, SNX+GDP group received GDP intravenously for 4 weeks; the SNX and the sham-operated groups remained without GDP. The experiment was terminated for all groups 7 weeks postoperatively. We analyzed cardiovascular damage by serum analyses and immunohistochemical investigation.ResultsIn SNX+GDP animals, expression of the advanced glycation end product (AGE) marker carboxymethyllysine and receptor of AGE (RAGE) were significantly higher in the myocardium and the aorta compared to the SNX rats. We also found significantly higher levels of apoptosis measured by caspase 3 staining in the cardiovascular system in the SNX+GDP group. Moreover, we observed a more pronounced expression of oxidative stress in the SNX+GDP rats compared to the SNX rats. In serum analyses, advanced oxidation protein products and reactive oxygen species were increased, as was immunohistochemical endothelial nitric oxide synthase.ConclusionsIn addition to local toxic effects, GDP cause systemic toxicity. Here we showed that, in SNX rats, administration of GDP increased cardiovascular damage. In particular, we found increased levels of AGE, RAGE, oxidative stress, and apoptosis. Whether these findings are of clinical relevance has to be further investigated.

Sex differences in nitrosative stress during renal ischemia

2010 ◽  
Vol 299 (5) ◽  
pp. R1387-R1395 ◽  
Author(s):  
Francisca Rodríguez ◽  
Susana Nieto-Cerón ◽  
Francisco J. Fenoy ◽  
Bernardo López ◽  
Isabel Hernández ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Sex Differences ◽  
Nitric Oxide Synthase ◽  
Nitrosative Stress ◽  
Differential Pulse ◽  
Sprague Dawley ◽  
Oxidative And Nitrosative Stress ◽  
Sprague Dawley Rats ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Females. suffer a less severe ischemic acute renal failure than males, apparently because of higher nitric oxide (NO) bioavailability and/or lower levels of oxidative stress. Because the renal ischemic injury is associated with outer medullary (OM) endothelial dysfunction, the present study evaluated sex differences in OM changes of NO and peroxynitrite levels (by differential pulse voltammetry and amperometry, respectively) during 45 min of ischemia and 60 min of reperfusion in anesthetized Sprague-Dawley rats. Endothelial nitric oxide synthase (eNOS) and neuronal nitric oxide synthase (nNOS) protein expression and their phosphorylated forms [peNOS(Ser1177) and pnNOS(Ser1417)], 3-nitrotyrosine, reduced sulfhydryl groups (-SH), and glomerular filtration rate (GFR) were also determined. No sex differences were observed in monomeric eNOS and nNOS expression, NO, or 3-nitrotyrosine levels in nonischemic kidneys, but renal -SH content was higher in females. Ischemia increased dimeric/monomeric eNOS and nNOS ratio more in females, but the dimeric phosphorylated peNOS(Ser1177) and pnNOS(Ser1417) forms rose similarly in both sexes, indicating no sex differences in nitric oxide synthase activation. However, NO levels increased more in females than in males (6,406.0 ± 742.5 and 4,058.2 ± 272.35 nmol/l respectively, P < 0.05), together with a lower increase in peroxynitrite current (5.5 ± 0.7 vs. 12.7 ± 1.5 nA, P < 0.05) and 3-nitrotyrosine concentration, (28.7 ± 3.7 vs. 48.7 ± 3.7 nmol/mg protein, P < 0.05) in females than in males and a better preserved GFR after ischemia in females than in males (689.7 ± 135.0 and 221.4 ± 52.5 μl·min−1·g kidney wt−1, P < 0.01). Pretreatment with the antioxidants N-acetyl-l-cysteine or ebselen abolished sex differences in peroxynitrite, nitrotyrosine, and GFR, suggesting that a greater oxidative and nitrosative stress worsens renal damage in males.

Curcumin and Saikosaponin A Inhibit Chemical-Induced Liver Inflammation and Fibrosis in Rats

2010 ◽  
Vol 38 (01) ◽  
pp. 99-111 ◽  
Author(s):  
Shu-Ju Wu ◽  
Ka-Wai Tam ◽  
Ya-Hui Tsai ◽  
Chun-Chao Chang ◽  
Jane C.-J. Chao
Keyword(s):  
Transforming Growth Factor ◽  
Interleukin 10 ◽  
Transforming Growth Factor Β1 ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Anti Inflammatory ◽  
Factor Α ◽  
Histopathological Results ◽  
Necrosis Factor ◽  
Saikosaponin A

Curcumin and saikosaponin A as antioxidants improve antioxidant status. This study investigated the anti-inflammatory and antifibrotic actions of curcumin and saikosaponin A on CCl4 -induced liver damage. Sprague-Dawley rats were randomly divided into control, CCl4 , CCl4+ curcumin (0.005%; CU), CCl4 + saikosaponin A (0.004%; SS), and CCl4 + curcumin + saikosaponin A (0.005% + 0.004%; CU + SS) groups. Carbon tetrachloride (40% in olive oil) at a dose of 0.75 ml/kg was injected intraperitoneally once a week. Curcumin and saikosaponin A were supplemented alone or in combination with diet 1 week before CCl4 injection for 8 weeks. After 8-week supplementation, histopathological results showed hepatic collagen deposition was significantly reduced in the CU and SS groups, and activated nuclear factor-κ B expression induced by CCl4 in the liver was significantly inhibited by curcumin and/or saikosaponin A. Hepatic proinflammatory cytokines tumor necrosis factor-α, interleukin-1β, and interleukin-6 were significantly inhibited, and anti-inflammatory cytokine interleukin-10 was significantly increased by supplementation with curcumin and/or saikosaponin A. Additionally, curcumin and/or saikosaponin A significantly reduced the increased levels of hepatic transforming growth factor-β1 and hydroxyproline after CCl4 treatment. Therefore, supplementation with curcumin and/or saikosaponin A suppress inflammation and fibrogenesis in rats with CCl4 -induced liver injury. However, the combination has no additive effects on anti-inflammation and antifibrosis.

scholarly journals The Effect of Ophiocephalus striatus sp. Extract on Nitric Oxide in Ischemic Stroke Model

2021 ◽  
Vol 9 (T3) ◽  
pp. 68-74
Author(s):  
Iskandar Nasution ◽  
Hasan Sjahrir ◽  
Syafruddin Ilyas ◽  
Muhammad Ichwan
Keyword(s):  
Nitric Oxide ◽  
Ischemic Stroke ◽  
Experimental Studies ◽  
Stroke Therapy ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Stroke Models ◽  
Angiogenesis Process ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

BACKGROUND: One of alternative medicine in stroke therapy is Ophiocephalus striatus sp. extract. The nutrients contained in the O. striatus sp. extract, namely amino acids, fatty acids, cuprum, and zinc, are useful for the process of angiogenesis in poststroke patients through increased endothelial nitric oxide synthase. AIM: We hypothesized that there was an effect of giving O. striatus sp. extract to cerebral angiogenesis process of Sprague Dawley rats ischemic stroke models through the level of NO. METHODS: This was evidenced by conducting experimental studies on rats ischemic stroke models which were divided into five groups, (a) K (−) group (no ligation, no treatment), (b) K (+) group (ligation, no treatment), (c) P1 group (ligation, 200 mg extract), (d) P2 group (ligation, 400 mg extract), and (e) P3 group (ligation, 800 mg extract). Then blood sample was taken on day 3 to assess levels of NO. RESULTS: There was increased level of NO in P1 (p = 0.001), P2 (p < 0.001), and P3 (p < 0.001) groups compared to K (+) group. The level of NO increases along with the increasing dose of O. striatus sp. extract. Histological examination revealed that there was formation of new blood vessel in the P1, P2, and P3 groups compared to K (+) group. CONCLUSION: Our study showed that O. striatus sp. extract improves cerebral angiogenesis in rat models of ischemic stroke.

A traditional formula, Chunggan extract, attenuates thioacetamide-induced hepatofibrosis via GSH system in rats

2010 ◽  
Vol 30 (9) ◽  
pp. 1322-1332 ◽  
Author(s):  
Kyeong-Gue Kwak ◽  
Jing-Hua Wang ◽  
Jang-Woo Shin ◽  
Dong-Soo Lee ◽  
Chang-Gue Son
Keyword(s):  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Sprague Dawley ◽  
Necrosis Factor Alpha ◽  
Antifibrotic Effect ◽  
Sprague Dawley Rats ◽  
Tnf Α ◽  
Factor Alpha ◽  
Per Oral ◽  
Oxide Synthase

Chunggan extract (CGX) is a hepatotherapeutic herbal formula which has been traditionally used for patients suffering from various hepatic disorders. This study aimed to elucidate antifibrotic effect and mechanisms of CGX in thioacetamide (TAA) model. Hepatic fibrosis was induced in 45 Sprague-Dawley rats by TAA (200 mg kg–1, intraperitoneally [ip]) on twice per week for 12 weeks. CGX (100 or 200 mg kg–1, per oral [po]) was administrated once a day throughout the experiment. CGX treatment ameliorated serum biomarkers. CGX administration significantly attenuated distortion of histopathologic finding, and accumulation of hydroxyproline and malondialdehyde (MDA). CGX treatment significantly decreased transforming growth factor-beta (TGF-β) concentrations and inactivated hepatic stellate cells (HSCs). CGX treatment drastically restored glutathione (GSH) system, while inducible nitric oxide synthase (iNOS) and tumor necrosis factor-alpha (TNF-α) significantly down-regulated in liver tissue. CGX showed antifibrotic effect in thioacetamide-induced chronic liver injury model. Its corresponding mechanisms may be mediated via anti-oxidative stress property sustaining GSH system and inhibition of ROS production.

scholarly journals Endothelial Forkhead Box Transcription Factor P1 Regulates Pathological Cardiac Remodeling Through Transforming Growth Factor-β1–Endothelin-1 Signal Pathway

Circulation ◽  
2019 ◽  
Vol 140 (8) ◽  
pp. 665-680 ◽  
Author(s):  
Jie Liu ◽  
Tao Zhuang ◽  
Jingjiang Pi ◽  
Xiaoli Chen ◽  
Qi Zhang ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Remodeling ◽  
Cardiac Dysfunction ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Target Delivery ◽  
Endothelin 1 ◽  
Forkhead Box ◽  
Tgf Β1

Background: Pathological cardiac fibrosis and hypertrophy, the common features of left ventricular remodeling, often progress to heart failure. Forkhead box transcription factor P1 (Foxp1) in endothelial cells (ECs) has been shown to play an important role in heart development. However, the effect of EC-Foxp1 on pathological cardiac remodeling has not been well clarified. This study aims to determine the role of EC-Foxp1 in pathological cardiac remodeling and the underlying mechanisms. Methods: Foxp1 EC-specific loss-of-function and gain-of-function mice were generated, and an angiotensin II infusion or a transverse aortic constriction operation mouse model was used to study the cardiac remodeling mechanisms. Foxp1 downstream target gene transforming growth factor-β1 (TGF-β1) was confirmed by chromatin immunoprecipitation and luciferase assays. Finally, the effects of TGF-β1 blockade on EC-Foxp1 deletion–mediated profibrotic and prohypertrophic phenotypic changes were further confirmed by pharmacological inhibition, more specifically by RGD-peptide magnetic nanoparticle target delivery of TGF-β1–siRNA to ECs. Results: Foxp1 expression is significantly downregulated in cardiac ECs during angiotensin II–induced cardiac remodeling. EC-Foxp1 deletion results in severe cardiac remodeling, including more cardiac fibrosis with myofibroblast formation and extracellular matrix protein production, as well as decompensated cardiac hypertrophy and further exacerbation of cardiac dysfunction on angiotensin II infusion or transverse aortic constriction operation. In contrast, EC-Foxp1 gain of function protects against pathological cardiac remodeling and improves cardiac dysfunction. TGF-β1 signals are identified as Foxp1 direct target genes, and EC-Foxp1 deletion upregulates TGF-β1 signals to promote myofibroblast formation through fibroblast proliferation and transformation, resulting in severe cardiac fibrosis. Moreover, EC-Foxp1 deletion enhances TGF-β1–promoted endothelin-1 expression, which significantly increases cardiomyocyte size and reactivates cardiac fetal genes, leading to pathological cardiac hypertrophy. Correspondingly, these EC-Foxp1 deletion–mediated profibrotic and prohypertrophic phenotypic changes and cardiac dysfunction are normalized by the blockade of TGF-β1 signals through pharmacological inhibition and RGD-peptide magnetic nanoparticle target delivery of TGF-β1–siRNA to ECs. Conclusions: EC-Foxp1 regulates the TGF-β1–endothelin-1 pathway to control pathological cardiac fibrosis and hypertrophy, resulting in cardiac dysfunction. Therefore, targeting the EC–Foxp1–TGF-β1–endothelin-1 pathway might provide a future novel therapy for heart failure.

Renal endothelial dysfunction and impaired autoregulation after ischemia-reperfusion injury result from excess nitric oxide

2006 ◽  
Vol 291 (3) ◽  
pp. F619-F628 ◽  
Author(s):  
Zhengrong Guan ◽  
Glenda Gobé ◽  
Desley Willgoss ◽  
Zoltán H. Endre
Keyword(s):  
Nitric Oxide ◽  
Renal Failure ◽  
Angiotensin Ii ◽  
Endothelial Dysfunction ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Artery Occlusion ◽  
Tubuloglomerular Feedback ◽  
Sprague Dawley ◽  
Endothelial Nitric Oxide

Endothelial dysfunction in ischemic acute renal failure (IARF) has been attributed to both direct endothelial injury and to altered endothelial nitric oxide synthase (eNOS) activity, with either maximal upregulation of eNOS or inhibition of eNOS by excess nitric oxide (NO) derived from iNOS. We investigated renal endothelial dysfunction in kidneys from Sprague-Dawley rats by assessing autoregulation and endothelium-dependent vasorelaxation 24 h after unilateral (U) or bilateral (B) renal artery occlusion for 30 (U30, B30) or 60 min (U60, B60) and in sham-operated controls. Although renal failure was induced in all degrees of ischemia, neither endothelial dysfunction nor altered facilitation of autoregulation by 75 pM angiotensin II was detected in U30, U60, or B30 kidneys. Baseline and angiotensin II-facilitated autoregulation were impaired, methacholine EC50 was increased, and endothelium-derived hyperpolarizing factor (EDHF) activity was preserved in B60 kidneys. Increasing angiotensin II concentration restored autoregulation and increased renal vascular resistance (RVR) in B60 kidneys; this facilitated autoregulation, and the increase in RVR was abolished by 100 μM furosemide. Autoregulation was enhanced by Nω-nitro-l-arginine methyl ester. Peri-ischemic inhibition of inducible NOS ameliorated renal failure but did not prevent endothelial dysfunction or impaired autoregulation. There was no significant structural injury to the afferent arterioles with ischemia. These results suggest that tubuloglomerular feedback is preserved in IARF but that excess NO and probably EDHF produce endothelial dysfunction and antagonize autoregulation. The threshold for injury-producing, detectable endothelial dysfunction was higher than for the loss of glomerular filtration rate. Arteriolar endothelial dysfunction after prolonged IARF is predominantly functional rather than structural.

scholarly journals Inflammatory Monocytes Determine Endothelial Nitric-oxide Synthase Uncoupling and Nitro-oxidative Stress Induced by Angiotensin II

2014 ◽  
Vol 289 (40) ◽  
pp. 27540-27550 ◽  
Author(s):  
Sabine Kossmann ◽  
Hanhan Hu ◽  
Sebastian Steven ◽  
Tanja Schönfelder ◽  
Daniela Fraccarollo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Angiotensin Ii ◽  
Nitric Oxide Synthase ◽  
Endothelial Nitric Oxide Synthase ◽  
Inflammatory Monocytes ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Aucubin Protects against TGFβ1-Induced Cardiac Fibroblasts Activation by Mediating the AMPKα/mTOR Signaling Pathway

Planta Medica ◽  
2017 ◽  
Vol 84 (02) ◽  
pp. 91-99 ◽  
Author(s):  
Yang Xiao ◽  
Wei Chang ◽  
Qing-Qing Wu ◽  
Xiao-Han Jiang ◽  
Ming-Xia Duan ◽  
...  
Keyword(s):  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Cardiac Fibroblasts ◽  
Smooth Muscle Actin ◽  
Mammalian Target Of Rapamycin ◽  
Transforming Growth Factor Β1 ◽  
Neonatal Rat ◽  
Cell Counting ◽  
Compound C ◽  
Underlying Mechanisms

AbstractFibrosis is a key feature of various cardiovascular diseases and compromises cardiac systolic and diastolic performance. The lack of effective anti-fibrosis drugs is a major contributor to the increasing prevalence of heart failure. The present study was performed to investigate whether the iridoid aucubin alleviates cardiac fibroblast activation and its underlying mechanisms. Neonatal rat cardiac fibroblasts were incubated with aucubin (1, 10, 20, 50 µM) followed by transforming growth factor β1 (TGFβ1, 10 ng/mL) stimulation for 24 h. Fibrosis proliferation was measured by cell counting kit-8 assay. The differentiation of fibroblasts into myofibroblasts was determined by measuring the expression of α-smooth muscle actin. Then, the expressions levels of cardiac fibrosis-related proteins in myofibroblasts were analyzed by western blot and real-time PCR to confirm the anti-fibrosis effect of aucubin. As a result, aucubin suppressed TGFβ1-induced proliferation in fibroblasts and inhibited the TGFβ1-induced activation of fibroblasts to myofibroblasts. In addition, aucubin further attenuated fibrosis-related protein expression in myofibroblasts. Furthermore, this protective effect was related to increased adenosine 5′-monophosphate-activated protein kinase (AMPK) phosphorylation and decreased mammalian target of rapamycin (mTOR) phosphorylation, which was confirmed by an mTOR inhibitor (rapamycin), an AMPK agonist (AICAR) and an AMPKα inhibitor compound C. Collectively, our findings suggest that aucubin protects against TGFβ1-induced fibroblast proliferation, activation and function by regulating the AMPKα/mTOR signal axis.

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