Abstract 211: Inhibition of Heme Oxygenase-1 (HO-1) Induces Mild Hypertension in Pregnant Rats

In the preeclamptic patient, inadequate remodeling of the maternal vasculature exacerbates this effect, causing dramatically increased oxidative stress in the placenta, which has been shown to be an important component of the maternal hypertension. There is also increasing awareness that HO-1 may act as an important regulator of placental function during normal pregnancy and decreases in HO-1 activity have been implicated in the pathogenesis of preeclampsia. While previous work in pregnant mice demonstrated that pharmacological inhibition of HO-1 leads to elevations in blood pressure, the mechanisms involved in the hypertension are unclear. The purpose of this study was to test the hypothesis that HO inhibition in late gestation leads to increases in maternal blood pressure by altering angiogenic balance and increasing placental oxidative stress in pregnant rats. HO activity was inhibited with tin mesoporphyrin (SnMP) was administered on gestational day 14, and blood pressure was measured on gestational day 19 by indwelling carotid catheter before sacrifice. In response to SnMP treatment, maternal MAP was significantly increased (99±1 vs 113±2 mmHg, p<0.05, n=15 per group). Placental sFlt-1 (631±47 vs 648±26 pg/mg, p=0.76) levels in the placenta were not affected by HO inhibition. Additionally, there was no significant difference in free VEGF in the maternal circulation (287±22 vs 329±14 pg/ml, p=0.11). There was, however, a significant increase in placental NADPH oxidase activity in SnMP treated rats (2021±238 vs 3005±301 RLU/min/mg, p<0.05) as determined by NADPH dependent lucigenin luminescence. This is likely due to decreased production of bilirubin, which is known to inhibit NADPH oxidase activity, and suggests an important role for HO-1 as an antioxidant in the developing placenta.

Download Full-text

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.

Download Full-text

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).

Download Full-text

Abstract 077: Renal Denervation Attenuates Salt-Sensitive Hypertension and Oxidative Stress in Rats with Unilateral Hydronephrosis

Hypertension ◽

10.1161/hyp.64.suppl_1.077 ◽

2014 ◽

Vol 64 (suppl_1) ◽

Author(s):

Maria Peleli ◽

Ammar Al-Mashhadi ◽

Ting Yang ◽

Erik G Persson ◽

Mattias Carlstrom

Keyword(s):

Oxidative Stress ◽

Blood Pressure ◽

Nadph Oxidase ◽

Mrna Expression ◽

Oxidase Activity ◽

Renal Denervation ◽

Urine Osmolality ◽

Nadph Oxidase Activity ◽

Urine Production ◽

Salt Sensitive Hypertension

Hydronephrotic rats and mice have impaired renal function and develop salt-sensitive hypertension, which are associated with oxidative stress. Increased sympathetic nerve activity and oxidative stress in the kidney may play important roles in renovascular hypertension. This study aimed to investigate the contribution of renal sympathetic nerve activity in the development of hypertension in hydronephrosis. A partial unilateral ureteral obstruction (PUUO) was created in 3-weeks old rats to induce hydronephrosis. Surgical denervation, or sham operation, of the PUUO kidney was performed at the time of ureteral obstruction and again 4-weeks later during implantation of a telemetric blood pressure device. Hydronephrotic animals had higher blood pressure (115±3 mmHg) compared with controls (87±1 mmHg), and the blood pressure elevation to a high salt diet was more pronounced (15±2 vs 5±1 mmHg) (p<0.05). Hydronephrosis was also associated with increased urine production (40±4 μl/24h/gBW) and lower urine osmolality (1242±109 mOsm/kg H2O) compared with controls (28±3 μl/24h/gBW and 1751±83 mOsm) (p<0.05). Renal denervation in rats with PUUO attenuated hypertension (97±3 mmHg) and normalized salt-sensitivity (5±1 mmHg), urine production (32±2 μl/24h/gBW) and urine osmolality (1586±127 mOsm/kg H2O) (p<0.05). NADPH oxidase activity in renal cortex from PUUO rats was increased compared with controls (4608±396 vs 3373±217 CLU/min/mg protein) (p<0.05). This was associated with increased cortical mRNA expression of Nox2 (2.3±0.43), p22phox (2.65±0.67) and p47phox (1.39±0.23) compared with controls (p<0.05). Remarkably, denervation in PUUO rats normalized both NADPH oxidase activity (3363±258 CLU/min/mg protein) and mRNA expression of Nox2, p22phox and p47phox (p<0.05). Interestingly, also myocardial tissue from PUUO displayed increased mRNA expression of Nox2 (1.68±0.23) and p22phox (2.82±0.51) compared with control rats, and this was normalized by renal denervation (0.81±0.43) (p<0.05). In conclusion, renal denervation of the hydronephrotic kidney attenuates hypertension and salt-sensitivity, and restores renal excretion pattern. Mechanistically, this is associated with reduced renal NADPH oxidase activity and expression.

Download Full-text

Comparative effects of N-acetyl-l-cysteine and ramipril on arterial hypertension, insulin resistance, and oxidative stress in chronically glucose-fed rats

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y08-090 ◽

2008 ◽

Vol 86 (11) ◽

pp. 752-760 ◽

Cited By ~ 25

Author(s):

Adil El Midaoui ◽

Mahmoud Ali Ismael ◽

Huogen Lu ◽

I. George Fantus ◽

Jacques de Champlain ◽

...

Keyword(s):

Oxidative Stress ◽

Insulin Resistance ◽

Blood Pressure ◽

Nadph Oxidase ◽

Plasma Levels ◽

Superoxide Anion ◽

Oxidase Activity ◽

Therapeutic Effects ◽

Superoxide Anion Production ◽

Nadph Oxidase Activity

Beneficial effects of an antioxidant (N-acetyl-l-cysteine, NAC) and an angiotensin I-converting enzyme (ACE) inhibitor (ramipril) were assessed in a rat model of insulin resistance induced by 10% glucose feeding for 20 weeks. Treatments with NAC (2 g/kg per day) and ramipril (1 mg/kg per day) were initiated at 16 weeks in the drinking fluid. Systolic blood pressure, plasma levels of insulin and glucose, and insulin resistance were significantly higher in rats treated with glucose for 20 weeks. This was associated with a higher production of superoxide anion and NADPH oxidase activity in aorta and liver and with a marked reduction in protein expression of skeletal muscle insulin receptor substrate-1 (IRS-1) in the gastrocnemius muscle. NAC prevented all these alterations. Although ramipril also reversed high blood pressure, it had a lesser effect on insulin resistance (including IRS-1) and blocked superoxide anion production only in aorta. Ramipril, in contrast to NAC, did not reduce NADPH oxidase activity in aorta and liver or plasma levels of 4-hydroxynonenal and malondialdehyde. Results suggest that the inhibition of the oxidative stress in hypertensive and insulin-resistant states contributes to the therapeutic effects of NAC and ramipril. Whereas NAC exerts effective antioxidant activity in multiple tissues, ramipril appears to preferentially target the vasculature.

Download Full-text

Abstract P063: Pitavastatin Has Antihypertensive and Renoprotective Effects With Upregulation of No System and Down-regulation of Oxidative Stress in the Kidney of Spontaneously Hypertensive Rats

Hypertension ◽

10.1161/hyp.66.suppl_1.p063 ◽

2015 ◽

Vol 66 (suppl_1) ◽

Author(s):

Gaizun Hu ◽

Osamu Ito ◽

Rong Rong ◽

Bin Xu ◽

Akihiro Sakuyama ◽

...

Keyword(s):

Oxidative Stress ◽

Blood Pressure ◽

Nadph Oxidase ◽

Oxidase Activity ◽

Active Form ◽

Thiobarbituric Acid ◽

Down Regulation ◽

Spontaneously Hypertensive ◽

Nadph Oxidase Activity ◽

Enos Phosphorylation

Clinical trials have demonstrated renoprotective effects of atorvastatin (ATV) and pitavastatin (PTV), which belong to the strong statins, are more potent than other statins. We reported previously that ATV attenuated the development of hypertension in SHR with increasing the endothelial and neuronal NO synthases (eNOS, nNOS) expressions in the kidney, whereas ATV inhibited the eNOS phosphorylation at serin1177 (J Hypertes 28: 2278-2288, 2010). To clarify the mechanisms of renoprotective effects of PTV, the present study examined the effects of PTV on blood pressure, renal functions, NOS and oxidative stress in the kidney of SHR. Five-week-old, male SHR were given orally PTV (2mg/kg/day) or vehicle for 8 weeks. The systolic blood pressure (SBP) was measured. The NOS expression and eNOS phosphorylation were analyzed by Western blot. The NADPH oxidase activity was measured by the lucigenin-enhanced chemiluminescence method. PTV attenuated the progression of hypertension (220 ± 8 vs. 177± 4 mmHg, P<0.01) and albuminuria (684 ± 66 vs. 398 ± 42 mg/day, P<0.01) without changing plasma total cholesterol or creatinine. PTV increased the eNOS and nNOS expressions in the outer and inner medulla of the kidney (eNOS; by 182% and 186%, nNOS; by 315% and 194%, P<0.01). PTV significantly stimulated the eNOS phosphorylation at serin1177 in the inner medulla and inhibited the eNOS phosphorylation at threonine495 in the outer and inner medulla. PTV decreased hydrogen peroxide (13.4 ± 2.1 vs. 6.1 ± 1.2 nmol/day, P<0.05) and thiobarbituric acid reactive substances (TBARS) (236.6 ± 12.4 vs. 198.3 ± 10.6 nmol/day, P<0.05) in the urine and the NADPH oxidase activity (42681± 2515 vs. 32381 ± 1995 c.p.m/mg protein, P<0.01) in the renal cortex. These results indicate that PTV attenuates the development of hypertension and albuminuria in SHR with increasing the eNOS and nNOS expressions, changing the eNOS phosphorylation to an active form and mitigating oxidative stress in the kidney. The antihypertensive and renoprotective effects of PTV may be mediated in part by an upregulation of NO system and down-regulation of oxidative stress in the kidney.

Download Full-text

Epicatechin lowers blood pressure, restores endothelial function, and decreases oxidative stress and endothelin-1 and NADPH oxidase activity in DOCA-salt hypertension

Free Radical Biology and Medicine ◽

10.1016/j.freeradbiomed.2011.09.015 ◽

2012 ◽

Vol 52 (1) ◽

pp. 70-79 ◽

Cited By ~ 104

Author(s):

Manuel Gómez-Guzmán ◽

Rosario Jiménez ◽

Manuel Sánchez ◽

María José Zarzuelo ◽

Pilar Galindo ◽

...

Keyword(s):

Oxidative Stress ◽

Blood Pressure ◽

Nadph Oxidase ◽

Endothelial Function ◽

Oxidase Activity ◽

Nadph Oxidase Activity ◽

Endothelin 1 ◽

Salt Hypertension

Download Full-text

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.

Download Full-text

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

Circulation ◽

10.1161/circ.116.suppl_16.ii_283-c ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Dongmei Liu ◽

Lie Gao ◽

Kurtis G Cornish ◽

Irving H Zucker

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Angiotensin Ii ◽

Nadph Oxidase ◽

Oxidase Activity ◽

Neuronal Cell ◽

Activator Protein 1 ◽

Ang Ii ◽

Nadph Oxidase Activity ◽

Activator Protein

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.

Download Full-text

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.

Download Full-text