Abstract 1380: Antioxidants Decrease Neuronal Angiotensin II Type 1 Receptor in Heart Failure: Inhibition of Activator Protein 1 and Jun N-Terminal Kinase

In a previous study, we showed that Ang II type I receptor (AT1R) expression increased in the rostral ventrolateral medulla (RVLM) of chronic heart failure (CHF) rabbits and in normal rabbits infused with intracerebroventricular (ICV) Angiotensin II (AngII). The present study investigated if oxidative stress plays a role in Ang II induced AT1R upregulation and its relationship to the transcription factor activator protein 1 (AP1) in CHF rabbits and in the CATHa neuronal cell line. In neuronal cell cultures, Ang II significantly increased AT1R mRNA by 153 ± 22%, P <0.01; c-Jun mRNA by 90 ± 10%, P < 0.01; NADPH oxidase activity by 126 ± 43%, P < 0.01 versus untreated cells; Tempol, Apocynin and the AP 1 inhibitor Tanshinone II reversed the increased AT1R, c-Jun expression and NADPH oxidase activity induced by AngII. We examined the effect of ICV Tempol on expression of these proteins in the RVLM of CHF rabbits. Compared to untreated CHF rabbits Tempol significantly decreased AT1R protein expression (0.88±0.16 vs. 1.6±0.29, P <0.05), phosphorylated Jnk protein (0.10±0.02 vs. 0.31±0.10, P <0.05), and phosphorylated c-Jun (0.02±0.001 vs. 0.14±0.05, P <0.05). These data suggest that Ang II induces AT1R upregulation at the transcriptional level by activation of oxidative stress and AP1 in both cultured cells and in intact brain. Antioxidant agents may be beneficial in CHF by decreasing AT1R expression through the Jnk and AP1 pathway.

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Effect of renin inhibition and AT1R blockade on myocardial remodeling in the transgenic Ren2 rat

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00752.2007 ◽

2008 ◽

Vol 295 (1) ◽

pp. E103-E109 ◽

Cited By ~ 39

Author(s):

Adam Whaley-Connell ◽

Javad Habibi ◽

Shawna A. Cooper ◽

Vincent G. DeMarco ◽

Melvin R. Hayden ◽

...

Keyword(s):

Oxidative Stress ◽

Blood Pressure ◽

Nadph Oxidase ◽

Oxidase Activity ◽

Myocardial Remodeling ◽

Ang Ii ◽

Sprague Dawley ◽

Nadph Oxidase Activity ◽

Renin Inhibition

Angiotensin II (Ang II) stimulation of the Ang type 1 receptor (AT1R) facilitates myocardial remodeling through NADPH oxidase-mediated generation of oxidative stress. Components of the renin-angiotensin system constitute an autocrine/paracrine unit in the myocardium, including renin, which is the rate-limiting step in the generation of Ang II. This investigation sought to determine whether cardiac oxidative stress and cellular remodeling could be attenuated by in vivo renin inhibition and/or AT1R blockade in a rodent model of chronically elevated tissue Ang II levels, the transgenic (mRen2)27 rat (Ren2). The Ren2 overexpresses the mouse renin transgene with resultant hypertension, insulin resistance, and cardiovascular damage. Young (6- to 7-wk-old) heterozygous (+/−) male Ren2 and age-matched Sprague-Dawley rats were treated with the renin inhibitor aliskiren, which has high preferential affinity for human and mouse renin, an AT1R blocker, irbesartan, or placebo for 3 wk. Myocardial NADPH oxidase activity and immunostaining for NADPH oxidase subunits and 3-nitrotyrosine were evaluated and remodeling changes assessed by light and transmission electron microscopy. Blood pressure, myocardial NADPH oxidase activity and subunit immunostaining, 3-nitrotyrosine, perivascular fibrosis, mitochondrial content, and markers of activity were significantly increased in Ren2 compared with SD littermates. Both renin inhibition and blockade of the AT1R significantly attenuated cardiac functional and structural alterations, although irbesartan treatment resulted in greater reductions of both blood pressure and markers of oxidative stress. Collectively, these data suggest that both reduce changes driven, in part, by Ang II-mediated increases in NADPH oxidase and, in part, increases in blood pressure.

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Abstract 142: Angiotensin II Type 1 Receptor Autoantibody Inhibition Improves Blood Pressure and Markers of Neurological Damage and Oxidative Stress in Brains of Placental Ischemic Rats During Pregnancy

Hypertension ◽

10.1161/hyp.70.suppl_1.142 ◽

2017 ◽

Vol 70 (suppl_1) ◽

Author(s):

Mark W Cunningham ◽

Venkata Ramana Vaka ◽

Lorena Amaral ◽

Fan Fan ◽

Tarek Ibrahim ◽

...

Keyword(s):

Oxidative Stress ◽

Blood Pressure ◽

Angiotensin Ii ◽

Nadph Oxidase ◽

Oxidase Activity ◽

Neurological Complications ◽

Peptide Sequence ◽

Inhibitory Peptide ◽

Nadph Oxidase Activity

Preeclampsia (PE), hypertension in response to placental ischemia, is associated with angiotensin II type 1 receptor agonistic autoantibodies (AT1-AA), oxidative stress, and neurological complications, such as headaches, blurred vision, and seizures which could lead to stroke and death. We hypothesize that AT1AAs play a role in the cerebral pathology of PE. The objective of this study was to determine if administration of a specific peptide sequence to inhibit the AT1-AA from binding to the AT1 receptor, will improve blood pressure (MAP) and cerebral oxidative stress in the reduced uterine perfusion pressure (RUPP) rat model of PE. Pregnant Sprague Dawley rats were divided into 2 groups: RUPP (n=5) and RUPP+AT1-AA inhibitory peptide (7AA) (n=3). RUPP surgery was performed on gestational day (GD) 14 and the 7AA was administered (2ug/μl saline) via mini-osmotic pumps. On GD 19, MAP was determined and brains collected. Western blots were stained for Glial Fibrillary Acidic Protein (GFAP), endothelial NO synthase (eNOS), phosphorylated eNOS and NADPH oxidase activity was determined using chemilumenescence. MAP was decreased in RUPP+7AA vs. RUPP (95±2 vs. 130±6 mmHg). Brain/body weight ratio, which is indicative of edema, was reduced in RUPP+7AA (5.8±0.25 vs. 6.5±0.25 grams) vs. RUPP. NADPH oxidase activity was lower in RUPP+7AA (33275±3122 vs. 57408±10508 RLU/min/mg protein). Phosphorylated eNOS was 2 fold higher in the RUPP+7AA vs. RUPP (0.4±0.1 vs. 0.2±0.04 AU) and the phosphorylated eNOS/eNOS ratio was elevated (0.4±0.12 vs. 0.2±0.04 AU). GFAP a marker for activated astrocytes that increases during neurologic injury and serves as a compensatory mechanism for brain injury recovery was elevated in RUPP+7AA vs. RUPP (3.2±1.3 vs. 0.5±0.2 AU). Administration of AT1-AA inhibitory peptide to RUPP rats decreased blood pressure and improved markers of NO bioavailability, injury (GFAP), and cerebral swelling. In conclusion, our preliminary data suggests that AT1-AA inhibition could be a potential therapy to improve peripheral and neurological complications during PE. Research Supported by T32HL105324 (Cunningham), RO1HD067541-06 (LaMarca), DK-104184 (Roman), 050049 (Fan), P20-GM-104357 (cores B and C-Roman; Pilot-Fan) and AHA 16GRNT31200036 (Fan).

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Abstract 612: ACE2-Independent Sex Differences In Oxidative Stress

Hypertension ◽

10.1161/hyp.64.suppl_1.612 ◽

2014 ◽

Vol 64 (suppl_1) ◽

Author(s):

Jan Wysocki ◽

Karla Evora ◽

Moody Salem ◽

Christoph Maier ◽

Minghao Ye ◽

...

Keyword(s):

Oxidative Stress ◽

Sex Differences ◽

Nadph Oxidase ◽

Total Protein ◽

Oxidase Activity ◽

Kidney Injury ◽

Ang Ii ◽

Male Mice ◽

Nadph Oxidase Activity ◽

Female Mice

Many of the pathophysiological effects of angiotensin II (Ang II) are attributed to its stimulation of NADPH oxidases and the consequent production of reactive oxygen species. Female sex has generally lower cardiovascular morbidity and is also less susceptible to kidney injury than males. The basis of these phenomena is not well understood but it is possible that sex-differential regulation of oxidative stress through activation of the RAS and its key effector, Ang II, plays an important contributor role. Here we hypothesized that Ang II levels are higher in male mice and that this is associated with sex-differences in kidney levels of ACE2, an Ang II-degrading enzyme abundantly expressed in the kidney. Parameters of oxidative stress such as, NADPH oxidase activity and malondialdehyde levels (MDA) were measured in kidneys from female and age-matched male C57BL6 mice. At 40 weeks of age, NADPH oxidase activity (p<0.01) and MDA levels (p<0.05) were significantly lower in female than in male mice. Female mice had lower kidney levels of the pro-oxidant peptide, Ang II (0.94±0.19 vs. 1.66±0.17 fmol/mg total protein, p<0.05, respectively). The difference in kidney Ang II levels between females and males was also observed in the face of complete ACE2 genetic deficiency (1.08±0.16 vs 1.97±0.25 fmol/mg total protein, p<0.05, respectively). Consistent with kidney Ang II levels, urinary Ang II levels measured in urines from female WT mice were also significantly lower than in male WT mice (23.6±2.2 vs. 47.9±8.8 pg/mg creatinine, p<0.05) despite significantly higher levels of urinary ACE2 activity in male mice as compared to female mice (7.0±0.5 vs. 3.6±0.3, p<0.01, respectively). Female mice have lower basal levels of kidney oxidative stress than males and exhibit lower levels of kidney and urinary Ang II. The mechanism involved in sex differences in the levels of kidney and urine Ang II does not appear to depend on ACE2.

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AT1 receptor-mediated augmentation of angiotensinogen, oxidative stress, and inflammation in ANG II-salt hypertension

AJP Renal Physiology ◽

10.1152/ajprenal.00351.2011 ◽

2012 ◽

Vol 302 (1) ◽

pp. F85-F94 ◽

Cited By ~ 51

Author(s):

Lucienne S. Lara ◽

Michael McCormack ◽

Laura C. Semprum-Prieto ◽

Sylvia Shenouda ◽

Dewan S. A. Majid ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Proliferation ◽

Nadph Oxidase ◽

Oxidase Activity ◽

Tissue Injury ◽

Collagen Deposition ◽

Ang Ii ◽

Mesangial Expansion ◽

Nadph Oxidase Activity ◽

Salt Hypertension

Augmentation of intrarenal angiotensinogen (AGT) synthesis, secretion, and excretion is associated with the development of hypertension, renal oxidative stress, and tissue injury during ANG II-dependent hypertension. High salt (HS) exacerbates hypertension and kidney injury, but the mechanisms remain unclear. In this study, we determined the consequences of HS intake alone compared with chronic ANG II infusion and combined HS plus ANG II on the stimulation of urinary AGT (uAGT), renal oxidative stress, and renal injury markers. Sprague-Dawley rats were subjected to 1) a normal-salt diet [NS, n = 5]; 2) HS diet [8% NaCl, n = 5]; 3) ANG II infusion in NS rats [ANG II 80 ng/min, n = 5]; 4) ANG II infusion in HS rats [ANG II+HS, n = 5]; and 5) ANG II infusion in HS rats treated with ANG II type 1 receptor blocker (ARB) [ANG II+HS+ARB, n = 5] for 14 days. Rats fed a HS diet alone did not show changes in systolic blood pressure (SBP), proteinuria, cell proliferation, or uAGT excretion although they did exhibit mesangial expansion, collagen deposition, and had increased NADPH oxidase activity accompanied by increased peroxynitrite formation in the kidneys. Compared with ANG II rats, the combination of ANG II infusion and a HS diet led to exacerbation in SBP (175 ± 10 vs. 221 ± 8 mmHg; P < 0.05), proteinuria (46 ± 7 vs. 127 ± 7 mg/day; P < 0.05), and uAGT (1,109 ± 70 vs.. 7,200 ± 614 ng/day; P < 0.05) associated with greater collagen deposition, mesangial expansion, interstitial cell proliferation, and macrophage infiltration. In both ANG II groups, the O2− levels were increased due to increased NADPH oxidase activity without concomitant increases in peroxynitrite formation. The responses in ANG II rats were prevented or ameliorated by ARB treatment. The results indicate that HS independently stimulates ROS formation, which may synergize with the effect of ANG II to limit peroxynitrite formation, leading to exacerbation of uAGT and greater injury during ANG II salt hypertension.

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Influence of N-Acetylcysteine on Oxidative Stress in Slow-Twitch Soleus Muscle of Heart Failure Rats

Cellular Physiology and Biochemistry ◽

10.1159/000369683 ◽

2015 ◽

Vol 35 (1) ◽

pp. 148-159 ◽

Cited By ~ 17

Author(s):

Paula F. Martinez ◽

Camila Bonomo ◽

Daniele M. Guizoni ◽

Silvio A. Oliveira Junior ◽

Ricardo L. Damatto ◽

...

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Skeletal Muscle ◽

Nadph Oxidase ◽

Soleus Muscle ◽

Oxidase Activity ◽

Left Ventricular ◽

Exercise Intolerance ◽

Contributing Factors ◽

Nadph Oxidase Activity

Background: Chronic heart failure is characterized by decreased exercise capacity with early exacerbation of fatigue and dyspnea. Intrinsic skeletal muscle abnormalities can play a role in exercise intolerance. Causal or contributing factors responsible for muscle alterations have not been completely defined. This study evaluated skeletal muscle oxidative stress and NADPH oxidase activity in rats with myocardial infarction (MI) induced heart failure. Methods and Results: Four months after MI, rats were assigned to Sham, MI-C (without treatment), and MI-NAC (treated with N-acetylcysteine) groups. Two months later, echocardiogram showed left ventricular dysfunction in MI-C; NAC attenuated diastolic dysfunction. In soleus muscle, glutathione peroxidase and superoxide dismutase activity was decreased in MI-C and unchanged by NAC. 3-nitrotyrosine was similar in MI-C and Sham, and lower in MI-NAC than MI-C. Total reactive oxygen species (ROS) production was assessed by HPLC analysis of dihydroethidium (DHE) oxidation fluorescent products. The 2-hydroxyethidium (EOH)/DHE ratio did not differ between Sham and MI-C and was higher in MI-NAC. The ethidium/DHE ratio was higher in MI-C than Sham and unchanged by NAC. NADPH oxidase activity was similar in Sham and MI-C and lower in MI-NAC. Gene expression of p47phox was lower in MI-C than Sham. NAC decreased NOX4 and p22phox expression. Conclusions: We corroborate the case that oxidative stress is increased in skeletal muscle of heart failure rats and show for the first time that oxidative stress is not related to increased NADPH oxidase activity.

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Apelin-13 alleviated cardiac fibrosis via inhibiting the PI3K/Akt pathway to attenuate oxidative stress in rats with myocardial infarction-induced heart failure

Bioscience Reports ◽

10.1042/bsr20200040 ◽

2020 ◽

Vol 40 (4) ◽

Cited By ~ 1

Author(s):

Shan Zhong ◽

Hongli Guo ◽

Hui Wang ◽

Dan Xing ◽

Tingting Lu ◽

...

Keyword(s):

Oxidative Stress ◽

Myocardial Infarction ◽

Heart Failure ◽

Oxidase Activity ◽

Cardiac Fibrosis ◽

Akt Pathway ◽

Ang Ii ◽

Superoxide Anions ◽

Nadph Oxidase Activity ◽

Collagen Iii

Abstract The present study aimed to determine whether apelin-13 could attenuate cardiac fibrosis via inhibiting the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway to inhibit reactive oxygen species in heart failure (HF) rats. HF models were established by inducing ischemia myocardial infarction (MI) through ligation of the left anterior descending artery in Sprague–Dawley (SD) rats. MI-induced changes in hemodynamics and cardiac function were reversed by apelin-13 administration. The increases in the levels of collagen I, collagen III, α-smooth muscle actin (SMA), and transforming growth factor-β (TGF-β) in the heart of MI rats and cardiac fibroblasts (CFs) treated with angiotensin (Ang) II were inhibited by apelin-13. The levels of PI3K and p-Akt increased in Ang II-treated CFs, and these increases were blocked by apelin-13. The PI3K overexpression reversed the effects of apelin-13 on Ang II-induced increases in collagen I, collagen III, α-SMA, and TGF-β, NADPH oxidase activity and superoxide anions in CFs. Apelin-13 reduced the increases in the levels of NADPH oxidase activity and superoxide anions in the heart of MI rats and CFs with Ang II treatment. The results demonstrated that apelin-13 improved cardiac dysfunction, impaired cardiac hemodynamics, and attenuated fibrosis of CFs induced by Ang II via inhibiting the PI3K/Akt signaling pathway to inhibit oxidative stress.

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Neuroprotective Benefits of Exercise and MitoQ on Memory Function, Mitochondrial Dynamics, Oxidative Stress, and Neuroinflammation in D-Galactose-Induced Aging Rats

Brain Sciences ◽

10.3390/brainsci11020164 ◽

2021 ◽

Vol 11 (2) ◽

pp. 164

Author(s):

Jae-Hoon Jeong ◽

Jung-Hoon Koo ◽

Jang Soo Yook ◽

Joon-Yong Cho ◽

Eun-Bum Kang

Keyword(s):

Oxidative Stress ◽

Antioxidant Activity ◽

Cognitive Impairment ◽

Nadph Oxidase ◽

Learning And Memory ◽

Oxidase Activity ◽

Mitochondrial Dynamics ◽

Nadph Oxidase Activity ◽

Aging Rats ◽

Positive Effects

Exercise and antioxidants have health benefits that improve cognitive impairment and may act synergistically. In this study, we examined the effects of treadmill exercise (TE) and mitochondria-targeted antioxidant mitoquinone (MitoQ), individually or combined, on learning and memory, mitochondrial dynamics, NADPH oxidase activity, and neuroinflammation and antioxidant activity in the hippocampus of D-galactose-induced aging rats. TE alone and TE combined with MitoQ in aging rats reduced mitochondrial fission factors (Drp1, Fis1) and increased mitochondrial fusion factors (Mfn1, Mfn2, Opa1). These groups also exhibited improved NADPH oxidase activity and antioxidant activity (SOD-2, catalase). TE or MitoQ alone decreased neuroinflammatory response (COX-2, TNF-α), but the suppression was greater with their combination. In addition, aging-increased neuroinflammation in the dentate gyrus was decreased in TE but not MitoQ treatment. Learning and memory tests showed that, contrarily, MitoQ alone demonstrated some similar effects to TE but not a definitive improvement. In conclusion, this study demonstrated that MitoQ exerted some positive effects on aging when used as an isolated treatment, but TE had a more effective role on cognitive impairment, oxidative stress, inflammation, and mitochondria dysfunction. Our findings suggest that the combination of TE and MitoQ exerted no synergistic effects and indicated regular exercise should be the first priority in neuroprotection of age-related cognitive decline.

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Attenuation of renal excretory responses to ANG II during inhibition of superoxide dismutase in anesthetized rats

AJP Renal Physiology ◽

10.1152/ajprenal.00511.2009 ◽

2010 ◽

Vol 298 (2) ◽

pp. F401-F407 ◽

Cited By ~ 2

Author(s):

Md. Abdul Hye Khan ◽

Mohammed Toriqul Islam ◽

Alexander Castillo ◽

Dewan Syed Abdul Majid

Keyword(s):

Superoxide Dismutase ◽

Nadph Oxidase ◽

Oxidase Activity ◽

Ang Ii ◽

Sod Activity ◽

Doppler Flowmetry ◽

Nadph Oxidase Activity ◽

Blood Flows ◽

Renal Responses

To examine the functional interaction between superoxide dismutase (SOD) and NADPH oxidase activity, we assessed renal responses to acute intra-arterial infusion of ANG II (0.5 ng·kg−1·min−1) before and during administration of a SOD inhibitor, diethyldithiocarbamate (DETC, 0.5 mg·kg−1·min−1), in enalaprilat-pretreated (33 μg·kg−1·min−1) rats ( n = 11). Total (RBF) and regional (cortical, CBF; medullary; MBF) renal blood flows were determined by Transonic and laser-Doppler flowmetry, respectively. Renal cortical and medullary tissue NADPH oxidase activity in vitro was determined using the lucigenin-chemiluminescence method. DETC treatment alone resulted in decreases in RBF, CBF, MBF, glomerular filtration rate (GFR), urine flow (V), and sodium excretion (UNaV) as reported previously. Before DETC, ANG II infusion decreased RBF (−18 ± 3%), CBF (−16 ± 3%), MBF [−5 ± 6%; P = not significant (NS)], GFR (−31 ± 4%), V (−34 ± 2%), and UNaV (−53 ± 3%). During DETC infusion, ANG II also caused similar reductions in RBF (−20 ± 4%), CBF (−19 ± 3%), MBF (−2 ± 2; P = NS), and in GFR (−22 ± 7%), whereas renal excretory responses (V; −12 ± 2%; UNaV; −24 ± 4%) were significantly attenuated compared with those before DETC. In in vitro experiments, ANG II (100 μM) enhanced NADPH oxidase activity both in cortical [13,194 ± 1,651 vs. 20,914 ± 2,769 relative light units (RLU)/mg protein] and in medullary (21,296 ± 2,244 vs. 30,597 ± 4,250 RLU/mg protein) tissue. Application of DETC (1 mM) reduced the basal levels and prevented ANG II-induced increases in NADPH oxidase activity in both tissues. These results demonstrate that renal excretory responses to acute ANG II administration are attenuated during SOD inhibition, which seems related to a downregulation of NADPH oxidase in the deficient condition of SOD activity.

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Protective Role of Endogenous Kallistatin in Vascular Injury and Senescence by Inhibiting Oxidative Stress and Inflammation

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/4138560 ◽

2018 ◽

Vol 2018 ◽

pp. 1-8 ◽

Cited By ~ 10

Author(s):

Julie Chao ◽

Youming Guo ◽

Lee Chao

Keyword(s):

Oxidative Stress ◽

Endothelial Cells ◽

Nadph Oxidase ◽

Vascular Injury ◽

Oxidase Activity ◽

Sirtuin 1 ◽

Mouse Lung ◽

Heparin Binding ◽

Diabetic Mice ◽

Nadph Oxidase Activity

Kallistatin was identified in human plasma as a tissue kallikrein-binding protein and a serine proteinase inhibitor. Kallistatin exerts pleiotropic effects on angiogenesis, oxidative stress, inflammation, apoptosis, fibrosis, and tumor growth. Kallistatin levels are markedly reduced in patients with coronary artery disease, sepsis, diabetic retinopathy, inflammatory bowel disease, pneumonia, and cancer. Moreover, plasma kallistatin levels are positively associated with leukocyte telomere length in young African Americans, indicating the involvement of kallistatin in aging. In addition, kallistatin treatment promotes vascular repair by increasing the migration and function of endothelial progenitor cells (EPCs). Kallistatin via its heparin-binding site antagonizes TNF-α-induced senescence and superoxide formation, while kallistatin’s active site is essential for inhibiting miR-34a synthesis, thus elevating sirtuin 1 (SIRT1)/eNOS synthesis in EPCs. Kallistatin inhibits oxidative stress-induced cellular senescence by upregulating Let-7g synthesis, leading to modulate Let-7g-mediated miR-34a-SIRT1-eNOS signaling pathway in human endothelial cells. Exogenous kallistatin administration attenuates vascular injury and senescence in association with increased SIRT1 and eNOS levels and reduced miR-34a synthesis and NADPH oxidase activity, as well as TNF-α and ICAM-1 expression in the aortas of streptozotocin- (STZ-) induced diabetic mice. Conversely, endothelial-specific depletion of kallistatin aggravates vascular senescence, oxidative stress, and inflammation, with further reduction of Let-7g, SIRT1, and eNOS and elevation of miR-34a in mouse lung endothelial cells. Furthermore, systemic depletion of kallistatin exacerbates aortic injury, senescence, NADPH oxidase activity, and inflammatory gene expression in STZ-induced diabetic mice. These findings indicate that endogenous kallistatin displays a novel role in protection against vascular injury and senescence by inhibiting oxidative stress and inflammation.

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