Heme Oxygenase-1 Gene Expression Modulates Angiotensin II–Induced Increase in Blood Pressure

Yang, Liming; Quan, Shuo; Nasjletti, Alberto; Laniado−Schwartzman, Michal; Abraham, Nader G.

doi:10.1161/01.hyp.0000126287.62060.e6

Cited by 91 publications

(66 citation statements)

References 44 publications

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“…Our data demonstrate that moderate hyperbilirubinemia is capable of decreasing vascular oxidative stress and increasing plasma NO x levels, suggesting a role for increased NO bioavailability in antihypertensive actions of moderate hyperbilirubinemia. Previous studies have indicated that induction of HO-1 attenuates ANG II-dependent hypertension by decreasing oxidative stress (11,21,29). The current study provides additional evidence that increased bilirubin might mediate part of the antihypertensive and antioxidant effects of HO-1 induction in these models.…”

supporting

confidence: 64%

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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supporting

confidence: 64%

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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“…[4][5][6][7][8][9] Despite these results, the mechanism by which systemic induction of HO-1 lowers blood pressure is not known. We have previously shown that kidney-specific induction of HO-1 through renal medullary interstitial infusion of cobalt protoporphyrin attenuates the development of Ang II-dependent hypertension.…”

Section: Discussionmentioning

confidence: 99%

“…[4][5][6][7][8][9] Recently, we reported that kidney-specific induction of HO-1 by renal medullary interstitial infusion of cobalt protoporphyrin attenuated the development of angiotension II (Ang II) -dependent hypertension. 10 Although that work was the first to report that renal-specific induction of HO-1 could attenuate Ang II-dependent hypertension, the importance of vascular versus tubular induction of HO-1 could not be distinguished in this model.…”

mentioning

confidence: 99%

Expression of Heme Oxygenase-1 in Thick Ascending Loop of Henle Attenuates Angiotensin II-Dependent Hypertension

Stec

Drummond

Gousette

et al. 2012

Journal of the American Society of Nephrology

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Kidney-specific induction of heme oxygenase-1 (HO-1) attenuates the development of angiotensin II (Ang II) -dependent hypertension, but the relative contribution of vascular versus tubular induction of HO-1 is unknown. To determine the specific contribution of thick ascending loop of Henle (TALH) -derived HO-1, we generated a transgenic mouse in which the uromodulin promoter controlled expression of human HO-1. Quantitative RT-PCR and confocal microscopy confirmed successful localization of the HO-1 transgene to TALH tubule segments. Medullary HO activity, but not cortical HO activity, was significantly higher in transgenic mice than control mice. Enhanced TALH HO-1 attenuated the hypertension induced by Ang II delivered by an osmotic minipump for 10 days (13963 versus 15362 mmHg in the transgenic and control mice, respectively; P,0.05). The lower blood pressure in transgenic mice associated with a 60% decrease in medullary NKCC2 transporter expression determined by Western blot. Transgenic mice also exhibited a 36% decrease in ouabain-sensitive sodium reabsorption and a significantly attenuated response to furosemide in isolated TALH segments,. In summary, these results show that increased levels of HO-1 in the TALH can lower blood pressure by a mechanism that may include alterations in NKCC2-dependent sodium reabsorption. Heme oxygenase (HO) is the rate-limiting enzyme in the catabolism of heme to biliverdin, during which both carbon monoxide (CO) gas and free iron are released. Biliverdin is then reduced to bilirubin by the ubiquitous enzyme biliverdin reductase. There are two major isoforms of HO that are responsible for the breakdown of heme, HO-1 and HO-2. HO-2 is the constitutively expressed isoform, whereas HO-1 is inducible by a wide variety of stimuli, including hypoxia, metals, ischemia, and oxidative stress. In the kidney, both isoforms of HO are present, with the highest level of expression of both isoforms in the renal medulla under basal conditions. 1,2 HO enzymes are not only expressed in the renal medulla, but their metabolites, CO and bilirubin, play an important role in the regulation of both renal vascular and tubular function. Renal medullary infusion of the general HO inhibitor, zinc deuteroporphyrin 2,4-bis glycol, results in a significant decrease in renal medullary blood flow. 1 In the renal tubules, increases in perfusion pressure increase CO levels, and inhibition of HO activity results in significant attenuation of pressure natriuresis and development of salt-sensitive hypertension. 3

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“…A number of studies have examined the effect of modulating the HO system on models of systemic hypertension. For example, upregulation of human HO-1 by a retroviral approach reduces the hypertensive effect of ANG II (43). Similarly, systemic hypertension induced by ANG II is lessened when HO-1 is induced by cobalt protoporphyrin in vivo (41,42), the latter not affecting the vascular reactivity ex vivo (37).…”

Section: Discussionmentioning

confidence: 99%

Heme oxygenase activity as a determinant of the renal hemodynamic response to low-dose ANG II

Nath

Hernandez

Croatt

et al. 2010

American Journal of Physiology-Regulatory, Integrative and Comp

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II causes renal injury through hemodynamic and other effects, and pressor doses of ANG II induce heme oxygenase-1 (HO-1) as a protective response. The present studies examined the hemodynamic effects of more clinically relevant, lower doses of ANG II and the role of HO activity in influencing these effects. Under euvolemic conditions, ANG II increased arterial pressure and renal vascular resistance. ANG II did not induce oxidative stress, inflammation/injury-related gene expression, or proteinuria and did not alter extrarenal vascular reactivity. At these doses, ANG II failed to increase HO-1 or HO-2 mRNA expression or HO activity. Inhibiting HO activity in ANG II-treated rats by tin mesoporphyrin further increased renal vascular resistances, decreased renal blood flow, and blunted the rise in arterial pressure without inducing oxidative stress or altering expression of selected vasoactive/ injury/inflammation-related genes; tin mesoporphyrin did not alter vasorelaxation of mesenteric resistor vessels. We conclude that in this model renal vasoconstriction occurs without the recognized adverse effects of ANG II on glomerular filtration rate, renal blood flow, oxidative stress, vascular reactivity, proteinuria, and injury-related gene expression; renal HO activity is essential in preserving perfusion of the ANG II-exposed kidney. These findings represent an uncommon example wherein function of a stressed organ (by ANG II), but not that of the unstressed organ, requires intact renal HO activity, even when the imposed stress neither induces HO-1 nor HO activity. These findings may be germane to conditions attended by heightened ANG II levels, ineffective renal perfusion, and susceptibility to acute kidney injury. tin mesoporphyrin; ischemia ANG II IS A MAJOR CONTRIBUTOR to chronic kidney disease by virtue of its hemodynamic, proinflammatory, and profibrotic effects. Indeed, agents that interrupt the generation of ANG II and the engagement of ANG II with its receptor comprise a fundamental therapeutic approach in the management of patients with chronic kidney disease (12,20,22). Such therapies, however, reduce but do not abort the progression of chronic kidney disease, and thus complementary strategies that can synergize with these therapies would be of interest. In this regard, a fundamental basis for the injurious effects of ANG II involves the imposition of oxidant stress via NADPH oxidase (35). Studies by us and others have demonstrated that ANG II induces the antioxidant gene heme oxygenase-1 (HO-1) (3, 4, 11) in the kidney in vivo and in vitro and that such induction of HO-1, by virtue of its antioxidant, anti-inflammatory, and vasorelaxant properties (1,2,15,24), is implicated as an adaptive, protective mechanism that can reduce the severity of ANG II-induced renal injury.An established approach employed in studying the pathogenetic basis for ANG II-induced renal injury utilizes the chronic administration of ANG II by osmotic minipumps. Such studies demonstrate that ANG II, so administered, provokes markedly i...

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Heme Oxygenase-1 Gene Expression Modulates Angiotensin II–Induced Increase in Blood Pressure

Cited by 91 publications

References 44 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

Expression of Heme Oxygenase-1 in Thick Ascending Loop of Henle Attenuates Angiotensin II-Dependent Hypertension

Heme oxygenase activity as a determinant of the renal hemodynamic response to low-dose ANG II

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