Heme Oxygenase-1 Induction Does Not Improve Vascular Relaxation in Angiotensin II Hypertensive Mice

Stec, David E.; Vera, Trinity; McLemore, Gerald R.; Kelsen, Silvia; Rimoldi, John M.; Gadepalli, Rama S; Ryan, Michael J.

doi:10.1038/ajh.2007.29

Cited by 24 publications

(19 citation statements)

References 28 publications

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“…These observations are in line with the finding that induction of HO-1 did not improve NO-or CO-mediated vascular relaxations in angiotensin II-induced hypertensive mice, although it caused a reduction in arterial blood pressure. 19 However, the present findings diverge from previous observations, indicating that upregulation of HO-1 may …”

Section: Discussioncontrasting

confidence: 99%

Upregulation of Heme Oxygenase 1 by Hemin Impairs Endothelium-Dependent Contractions in the Aorta of the Spontaneously Hypertensive Rat

Wang

Vanhoutte

2011

Hypertension

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Abstract-Heme oxygenase converts heme to carbon monoxide, biliverdin (subsequently converted to bilirubin), and free iron. Pharmacological induction of heme oxygenase 1 has an antihypertensive effect in the spontaneously hypertensive rat. The present study investigated whether upregulation of heme oxygenase 1 by hemin reduces endothelial dysfunction in this animal. Thirty-six-week-old rats were divided into a hemin treatment (50 mg/kg, IP injection, once) and a control group. Aortas were isolated for the measurement of isometric tension, production of reactive oxygen species, and heme oxygenase activity, as well as gene and protein expressions. Hemin treatment augmented the expression and activity of heme oxygenase 1. This in vivo induction of heme oxygenase 1, but not in vitro incubation with the heme oxygenase products carbon monoxide or bilirubin, led to an improvement of endothelial function in that acetylcholine-induced relaxations were potentiated and acetylcholine-and calcium ionophore-induced contractions were attenuated. Free radical production was suppressed by hemin treatment, judging from the results of 2Ј,7Ј-dichlorodihydrofluoresein diacetate staining, dihydroethidium staining, and lucigenin chemiluminescence, which was explained by the decreased expressions of NADPH oxidase 2 and cyclooxygenase 1. The production of prostacyclin was decreased by heme oxygenase 1 induction, which was explained by a lower expression of cyclooxygenase 1. Contractions to vasoconstrictor concentrations of prostacyclin and its mimetic iloprost were attenuated, suggesting that the responsiveness of thromboxane-prostanoid receptors to prostacyclin was decreased in hemin-treated rats. The suppressed production of free radicals and prostacyclin and the decrease of thromboxane-prostanoid receptors sensitivity concur to explain the impairment of endothelium-dependent contractions caused by heme oxygenase 1 induction by hemin. Key Words: endothelial dysfunction Ⅲ endothelium-dependent contractions Ⅲ heme oxygenase 1 Ⅲ hemin Ⅲ prostacyclin Ⅲ reactive oxygen species Ⅲ spontaneously hypertensive rat Ⅲ thromboxane-prostanoid receptor T he endothelial cell layer contributes to the regulation of vascular tone by releasing vasodilators, in particular NO. 1 However, the endothelium becomes dysfunctional in aging, hypertension, and diabetes mellitus. 2 Endothelial dysfunction is characterized by a decreased production of NO, as well as an increased generation of vasoconstrictors, in particular cyclooxygenase (COX)-derived prostanoids and reactive oxygen species (ROS), termed endothelium-dependent contracting factors (EDCFs). 2 The production of EDCFs is a hallmark of endothelial dysfunction in the spontaneously hypertensive rat (SHR). 3 Indeed, in the endothelium of the SHR aorta, there is an increased expression of COX-1, increased intracellular calcium concentration, and enhanced production of ROS, endoperoxides, and other prostanoids, which underlies the greater occurrence of endotheliumdependent contractions. 3 The increase of end...

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Section: Discussioncontrasting

confidence: 99%

Upregulation of Heme Oxygenase 1 by Hemin Impairs Endothelium-Dependent Contractions in the Aorta of the Spontaneously Hypertensive Rat

Wang

Vanhoutte

2011

Hypertension

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“…We hypothesize that increases in both bilirubin and CO generation in the renal medulla mediate the blood pressure-lowering actions of HO-1 induction via improvement in renal pressure natriuresis. The role for a renal mechanism is supported by the observation that systemic induction of HO-1 does not improve vascular function in ANG II hypertensive mice despite lowering of blood pressure (23). The results of the present study further support the antioxidant role of HO-1 and its primary metabolites, bilirubin and CO, in the TALH.…”

Section: Discussionsupporting

confidence: 77%

Heme oxygenase attenuates angiotensin II-mediated superoxide production in cultured mouse thick ascending loop of Henle cells

Kelsen

Patel²,

Parker³

et al. 2008

American Journal of Physiology-Renal Physiology

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2 , respectively. To determine which metabolite of HO-1 is responsible for reducing ANG II-mediated increases in superoxide production in mTALH cells, cells were preincubated with bilirubin or carbon monoxide (CO)-releasing molecule (CORM)-A1 (each at 100 M) before exposure to ANG II. DHE fluorescence averaged 80 Ϯ 7 RFU/m 2 after incubation with ANG II and was significantly decreased to 55 Ϯ 7 and 53 Ϯ 4 RFU/m 2 after pretreatment with bilirubin and CORM-A1. These results demonstrate that induction of HO-1 in mTALH cells reduces the levels of ANG II-mediated superoxide production through the production of both bilirubin and CO. bilirubin; carbon monoxide; carbon monoxide-releasing molecule A1RECENT STUDIES HAVE DEMONSTRATED the importance of superoxide generation in the development and maintenance of angiotensin II (ANG II)-dependent hypertension (1,14,35). ANG II can increase the production of superoxide by direct activation of NADPH oxidase (6, 7). In the kidney, ANG II-mediated increases in superoxide production have been demonstrated to mediate renal vasoconstriction, cortical hypoxia, and reduced efficiency of O 2 usage for sodium transport (10, 13, 31). Increased superoxide production in the thick ascending loop of Henle (TALH) has been reported to stimulate sodium reabsorption by decreasing the levels of nitric oxide (NO) (19,20).ANG II-mediated increases in superoxide production in the TALH have also been reported to limit NO availability to vasa recta, which could lead to decreases in medullary blood flow, blunting of pressure natriuresis, and hypertension (16). In line with this hypothesis, enhanced expression of NADPH oxidase and increased superoxide production in the medulla have been demonstrated to cause hypertension in normal rats and may contribute to salt-sensitive hypertension in Dahl salt-sensitive rats (17,26).Heme oxygenase (HO)-1 is an important cellular defense protein that is induced by a variety of stimulants including hypoxia and heavy metals. In the rat kidney, HO-1 is mainly expressed in the renal medulla, where it plays an important role in maintaining the blood flow to the renal medulla (36). Increases in HO-1 levels have also been shown to be protective against oxidant damage in tissues such as brain and liver (2, 9). In agreement with these observations, induction of HO-1 in TALH cells was found to limit ANG II-induced oxidative damage (21).While increases in HO-1 levels have been found to limit oxidative damage, the mechanism responsible for this protection is unknown. HO-1 metabolites carbon monoxide (CO) and bilirubin have antioxidant properties that may protect cells against excessive superoxide production. Bilirubin is an antioxidant molecule that can decrease superoxide production by direct actions as well as inhibition of NAD(P)H oxidase activity (11,12,24). CO also can inhibit NAD(P)H oxidase by interactions with the heme-containing subunits (25). We previously reported (29) that induction of HO-1 was associated with a decrease in ANG II-mediated superoxide production in ...

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“…In addition, our conclusion that induction of HO-1 may improve FFA-induced endothelial dysfunction is based upon studies in which we examined the acute effects of induction of HO-1 on endothelial function. This conclusion contrasts with previous studies in which transgenic mice overexpressing either HO-1 or CoPP were subjected to longer periods of HO-1 induction; these studies demonstrated that the induction of HO-1 did not improve endothelial function [36,37]. It is possible that the acute induction of HO-1 in these vessels may have had a different effect on vascular relaxation compared with chronic induction of HO-1.…”

Section: Discussioncontrasting

confidence: 63%

Induction of Haemeoxygenase-1 Improves FFA-Induced Endothelial Dysfunction in Rat Aorta

Han

Hui²,

Zhang³

et al. 2015

Cell Physiol Biochem

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Background: The induction of haemeoxygenase-1 (HO-1) exerts beneficial effects in the setting of endothelial dysfunction in obesity. High free fatty acid (FFA) levels are a common feature of obesity and are the primary cause of endothelial dysfunction. The objective of our study was to explore the effects of HO-1 induction on FFA-induced endothelial dysfunction in rats. Methods: Rats received FFA treatment with either cobalt protoporphyrin (CoPP) to induce HO-1 or stannous protoporphyrin (SnPP) to inhibit HO-1. Endothelial function was determined by measuring endothelium-dependent vasodilatation (EDV). Nitric oxide (NO) production, superoxide production and nuclear factor (NF)-κB expression in the aorta were each determined. The levels of adenosine monophosphate (AMP)-activated kinase (AMPK) and endothelial nitric oxide synthase (eNOS) expression in endothelial cells were determined via Western blotting. Results: Induction of HO-1 by CoPP decreased circulating FFA, high-sensitivity C-reactive protein and malondialdehyde levels and increased serum adiponectin and glutathione levels compared with the FFA group (P<0.05). High FFA levels resulted in EDV impairment, which was improved by HO-1 induction (P<0.05). Induction of HO-1 increased NO levels and reduced aortic superoxide production and NF-κB expression compared with the FFA group. The FFA group exhibited decreased AMPK expression and eNOS phosphorylation, both of which were enhanced via HO-1 induction (P<0.05). The beneficial effects of CoPP on EDV were partially attenuated in vitro in the presence of inhibitors of AMPK, phosphatidylinositol 3-kinase (PI3K), and eNOS. Conclusions: HO-1 induction with CoPP improves FFA-induced endothelial dysfunction in the rat aorta. The protective mechanism appears to be related to the activation of the AMPK-PI3K-eNOS pathway as a result of increased adiponectin levels as well as decreased inflammation and oxidative stress.

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Heme Oxygenase-1 Induction Does Not Improve Vascular Relaxation in Angiotensin II Hypertensive Mice

Abstract: These results suggest that induction of HO-1 lowers Ang II-dependent hypertension through a mechanism independent of improved vascular relaxation.

Cited by 24 publications

References 28 publications

Upregulation of Heme Oxygenase 1 by Hemin Impairs Endothelium-Dependent Contractions in the Aorta of the Spontaneously Hypertensive Rat

Upregulation of Heme Oxygenase 1 by Hemin Impairs Endothelium-Dependent Contractions in the Aorta of the Spontaneously Hypertensive Rat

Heme oxygenase attenuates angiotensin II-mediated superoxide production in cultured mouse thick ascending loop of Henle cells

Induction of Haemeoxygenase-1 Improves FFA-Induced Endothelial Dysfunction in Rat Aorta

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