Increased Aortic NADPH Oxidase Activity in Rats With Genetically High Angiotensin-Converting Enzyme Levels

Jalil, Jorge; Pérez, Alfonso; Ocaranza, María Paz; Bargetto, Jorge; Galaz, Alfonso; Lavandero, Sergio

doi:10.1161/01.hyp.0000188980.57312.63

Cited by 34 publications

(23 citation statements)

References 55 publications

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“…Previous studies have shown that ANG IIdependent hypertension is associated with increases in superoxide production (7,11,18). The increased superoxide produced can then interact with nitric oxide (NO) to form ) for 12 days before the plasma samples were collected and analyzed.…”

mentioning

confidence: 99%

Inhibition of bilirubin metabolism induces moderate hyperbilirubinemia and attenuates ANG II-dependent hypertension in mice

Vera

Granger²,

Stec³

2009

American Journal of Physiology-Regulatory, Integrative and Comp

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-Population studies indicate that moderate hyperbilirubinemia is associated with reduced incidence of cardiovascular diseases, including hypertension. Despite this correlative evidence, no studies have directly tested the hypothesis that moderate increases in plasma bilirubin levels can attenuate the development of hypertension. This hypothesis was tested by treating mice with Indinavir, a drug that competes with bilirubin for metabolism by UDP-glucuronosyltransferase 1A1 (UGT1A1). Treatment of mice with Indinavir (500 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 , gavage) resulted in a twofold increase in plasma unconjugated bilirubin levels. Next, we determined the effect of Indinavir-induced changes in plasma bilirubin on the development of ANG II-dependent hypertension. Moderate hyperbilirubinemia was induced 3 days before the implantation of an osmotic minipump that delivered ANG II at a rate of 1 g ⅐ kg Ϫ1 ⅐ min Ϫ1 . ANG II infusion increased mean arterial pressure (MAP) by 20 mmHg in control mice but by only 6 mmHg in mice treated with Indinavir (n ϭ 6). Similar to Indinavir treatment, direct infusion of bilirubin (37.2 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 iv) resulted in a twofold increase in plasma bilirubin levels and also attenuated the development of ANG II-dependent hypertension. Moderate hyperbilirubinemia resulted in an increase in plasma nitrate/nitrite levels, which averaged 36 Ϯ 2 vs. 50 Ϯ 7 M in ANG II vehicle vs. Indinavir-treated mice (n ϭ 5). Moderate hyperbilirubinemia resulted in attenuation of vascular oxidative stress as determined by dihydroethidium staining of aortic segments. These results indicate that moderate hyperbilirubinemia prevents ANG IIdependent hypertension by a mechanism that may involve decreases in vascular oxidative stress. bilirubin; angiotensin II hypertension; uridine 5Ј-triphosphate-glucuronosyltransferase 1A1, heme oxygenase BILIRUBIN IS ONE of the by-products of heme catabolism by heme oxygenase (HO). Bilirubin is initially produced as biliverdin, which is rapidly converted by biliverdin reductase (BVR). HO and BVR are ubiquitous enzymes that render all mammalian cell types capable of producing bilirubin; however, the majority of circulating bilirubin is derived from the breakdown of hemoglobin by the reticuloendothelial system. The resultant bilirubin circulates bound to albumin to the liver where its entry into hepatocytes is mediated by the organic anion transporting polypeptide 2 (OATP2). Once in the hepatocyte, bilirubin is glucoronidated by UDP-glucuronyltransferase 1A1 (UGT1A1) and subsequently eliminated in the bile ducts through the multidrug resistance protein 2. The conjugated bilirubin is excreted via the common bile duct in the intestines as one of the components of bile salts.Recent population studies have revealed that elevated plasma bilirubin levels are associated with reduced incidence of cardiovascular diseases, including hypertension, coronary artery disease, atherosclerosis, and preeclampsia (5,6,17,19). More recent data from a study of Framingham offspring revealed that individuals ...

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confidence: 99%

Inhibition of bilirubin metabolism induces moderate hyperbilirubinemia and attenuates ANG II-dependent hypertension in mice

Vera

Granger²,

Stec³

2009

American Journal of Physiology-Regulatory, Integrative and Comp

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“…In this experimental model, ROCK activation was associated with increased expression of genes and proteins that promote vascular remodeling and high oxidative stress. In BN rats (with genetically high ACE and Ang II levels and low Ang-1-7 levels), [31][32][33] the aortic mRNA and protein levels of TGF-␤ 1 , PAI-1, and MCP-1 were significantly higher compared with the "control" Lewis rats (with genetically low levels of ACE and Ang II and high levels of Ang-1-7) and were "normalized" to levels observed in Lewis rats by the ROCK inhibitor fasudil.…”

Section: Discussionmentioning

confidence: 99%

“…NADPH oxidase activity was measured by a luminescence assay containing lucigenin as the electron acceptor and NADPH as the substrate. 31 To verify the specificity of the signal, each assay was performed with and without apocynin (2.5 mmol/L), and the counts were subtracted to determine the final counts. …”

Section: Nadph Oxidase Activity and O 2 ⅐؊ Productionmentioning

confidence: 99%

“…[27][28][29] In the BN rats, normal blood pressure, high circulating and tissue levels of ACE, high plasma Ang II levels, and low Ang-1-7 levels are observed. 30 -34 Compared with rats with genetically low ACE levels (Lewis rats), the BN rats have higher levels of vascular oxidative stress 31 and develop higher levels of chronic hypertension in response to experimental renal artery stenosis. 32 There are no studies assessing the role of genetically increased ACE expression and Ang II levels on the Rho/ROCK pathway activation.…”

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confidence: 99%

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Rho Kinase Activation and Gene Expression Related to Vascular Remodeling in Normotensive Rats With High Angiotensin I–Converting Enzyme Levels

Rivera

Ocaranza²,

Lavandero³

et al. 2007

Hypertension

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Abstract-The RhoA/Rho kinase (ROCK) pathway is a new mechanism of remodeling and vasoconstriction. Few data are available regarding ROCK activation when angiotensin I-converting enzyme is high and blood pressure is normal. We hypothesized that ROCK is activated in the vascular wall in normotensive rats with genetically high angiotensin Iconverting enzyme levels, and it causes increased vascular expression of genes promoting vascular remodeling and also oxidative stress. Aortic ROCK activation, mRNA and protein levels (of monocyte chemoattractant protein-1, transforming growth factor [TGF]-␤ 1 , and plasminogen activator inhibitor-1 [PAI-1]), NADPH oxidase activity, and O 2 ⅐Ϫ production were measured in normotensive rats with genetically high (Brown Norway [BN]) and low (Lewis) angiotensin-I-converting enzyme levels and in BN rats treated with the ROCK antagonist fasudil (100 mg/kg per day) for 7 days. ROCK activation was 12-fold higher in BN versus Lewis rats (PϽ0.05) and was reduced with fasudil by 100% (PϽ0.05). Aortic TGF-␤1, PAI-1, and monocyte chemoattractant protein-1 mRNA levels were higher in BN versus Lewis rats by 300%, 180%, and 1000%, respectively (PϽ0.05). Aortic TGF-␤1, PAI-1, and monocyte chemoattractant protein-1 protein levels were higher in BN versus Lewis rats (PϽ0,05). Fasudil reduced TGF-␤1 and PAI-1 mRNA and TGF-␤1, PAI-1, and monocyte chemoattractant protein-1 protein aortic levels to those observed in Lewis rats. Aortic reduced nicotinamide-adenine dinucleotide phosphate oxidase activity and . O 2 Ϫ production were increased by 88% and 300%, respectively, in BN rats (PϽ0.05) and normalized by fasudil. In conclusion, ROCK is significantly activated in the aortic wall in normotensive rats with genetically high angiotensin-I-converting enzyme and angiotensin II, and it causes activation of genes that promote vascular remodeling and also increases vascular oxidative stress.

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“…12,13 However, the studies cited above with Ang II infusion resulting in high circulating Ang II sufficient to increase BP show that BP was reduced by targeting Nox sources of O 2 Ϫ or O 2 Ϫ scavenging. 8 -11 Relevant to this issue is the study by Jalil et al, 14 who showed that Brown Norway rats have elevated angiotensin-converting enzyme and circulating Ang II without hypertension. However, O 2 Ϫ production was higher in aorta from Brown Norway rats compared with those from the control Lewis rats and was substantially reduced by candesartan, an AT 1 R antagonist.…”

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confidence: 99%

Angiotensin II–Dependent Superoxide

Welch

2008

Hypertension

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A ngiotensin (Ang) II generates reactive oxygen species (ROS) by activation of Ang II type 1 receptors (AT 1 Rs). The resulting ROS mediates many of the actions of Ang II, including constriction of vascular smooth muscles, increased systemic blood pressure (BP), endothelial dysfunction, vascular remodeling, and sodium retention. Ang II has its greatest effect on superoxide anion (O 2 Ϫ ), which may be an important signaling element of the hypertensive rats and other deleterious actions of Ang II. The mechanisms of ROS actions are not fully understood, yet effective antioxidant therapy often attenuates hypertension and other vascular effects of Ang II. Currently many studies use Ang II-infused animal models to investigate the role of ROS and interacting systems, not only on hypertension, but endothelial dysfunction, renal disease, heart disease, and other pathologies. This review focuses on the recent reports of Ang II-generated ROS and how it impacts hypertension and its vascular consequences.

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Increased Aortic NADPH Oxidase Activity in Rats With Genetically High Angiotensin-Converting Enzyme Levels

Cited by 34 publications

References 55 publications

Inhibition of bilirubin metabolism induces moderate hyperbilirubinemia and attenuates ANG II-dependent hypertension in mice

Inhibition of bilirubin metabolism induces moderate hyperbilirubinemia and attenuates ANG II-dependent hypertension in mice

Rho Kinase Activation and Gene Expression Related to Vascular Remodeling in Normotensive Rats With High Angiotensin I–Converting Enzyme Levels

Angiotensin II–Dependent Superoxide

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