Vascular Smooth Muscle Cell Heme Oxygenases Generate Guanylyl Cyclase–Stimulatory Carbon Monoxide

Christodoulides, Nicolaos; Durante, William; Kroll, Michael H.; Schafer, Andrew I.

doi:10.1161/01.cir.91.9.2306

Cited by 230 publications

(146 citation statements)

References 11 publications

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“…CO appears to block vascular SMC growth by increasing the intracellular levels of guanosine 3 0 -5 0 -cyclic monophosphate (cGMP). CO activates both crude and purified preparations of soluble guanylate cyclase and elevates cGMP levels in vascular SMCs (Ramos et al, 1989;Brune et al, 1990;Stone and Marletta, 1994;Christodoulides et al, 1995;. Furthermore, inhibition of soluble guanylate cyclase by ODQ blocks the rise in cGMP and the antiproliferative action of HO-1 (Duckers et al, 2001).…”

Section: Ho-1 and Cell Proliferationmentioning

confidence: 99%

Heme oxygenase‐1 in growth control and its clinical application to vascular disease

Durante

2003

Journal Cellular Physiology

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143

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Heme oxygenase-1 (HO-1) catalyzes the degradation of heme to carbon monoxide (CO), iron, and biliverdin. Biliverdin is subsequently metabolized to bilirubin by the enzyme biliverdin reductase. Although interest in HO-1 originally centered on its heme-degrading function, recent findings indicate that HO-1 exerts other biologically important actions. Emerging evidence suggests that HO-1 plays a critical role in growth regulation. Deletion of the HO-1 gene or inhibition of HO-1 activity results in growth retardation and impaired fetal development, whereas HO-1 overexpression increases body size. Although the mechanisms responsible for the growth promoting properties of HO-1 are not well established, HO-1 can indirectly influence growth by regulating the synthesis of growth factors and by modulating the delivery of oxygen or nutrients to specific target tissues. In addition, HO-1 exerts important effects on critical determinants of tissue size, including cell proliferation, apoptosis, and hypertrophy. However, the actions of HO-1 are highly variable and may reflect a role for HO-1 in maintaining tissue homeostasis. Considerable evidence supports a crucial role for HO-1 in blocking the growth of vascular smooth muscle cells (SMCs). This antiproliferative effect of HO-1 is mediated primarily via the release of CO, which inhibits vascular SMC growth via multiple pathways. Pharmacologic or genetic approaches targeting HO-1 or CO to the blood vessel wall may represent a promising, novel therapeutic approach in treating vascular proliferative disorders.

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Section: Ho-1 and Cell Proliferationmentioning

confidence: 99%

Heme oxygenase‐1 in growth control and its clinical application to vascular disease

Durante

2003

Journal Cellular Physiology

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143

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“…Aortic NOS activity was detected by calculating the concentration of 3H-citrulline converted from 3H-arginine 7…”

Section: Detection Of Aortic No and Co Contentsmentioning

confidence: 99%

Effect of the haeme oxygenase-1/endogenous carbon monoxide system on atherosclerotic plaque formation in rabbits

Liu¹,

Fang²,

Wu³

et al. 2010

CardioVascular Journal of Africa

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ObjectiveTo investigate the effect of the haeme oxygenase-1/carbon monoxide (HO-1/CO) system on atherosclerotic plaque formation and its possible mechanism.MethodsFor 12 weeks, rabbits were given a 1.5% cholesterol diet (Ch group, n = 8) or a 1.5% cholesterol diet plus an HO-1 inducer, haemin (Hm group, n = 8), or an HO-1 inhibitor, zinc protoporphyrin IX (Znpp-IX, Zn group, n = 8) by intraperitoneal injection.ResultsCompared with the normal control group (C group, n = 8), serum levels of lipids and oxidised low-density lipoproteins (ox-LDL) increased significantly in all experimental groups (p < 0.01). However, no significant differences were observed among the three experimental groups (p > 0.01). Compared with the control group, aortic nitric oxide (NO) production and nitric oxide synthase (cNOS) activity decreased markedly, whereas carbon monoxide (CO) production and HO-1 activity increased markedly in the Ch group (p < 0.01). This was associated with an increase in the area of aortic plaque of 54.00 ± 4.16%. Compared with the Ch group, CO production and HO-1 activity increased markedly, while aortic HO activity and CO production decreased significantly in the Hm group. The area of aortic plaque was significantly reduced in the Hm group (17.88 ± 3.01%), whereas the area of aortic plaque was significantly increased in the Zn group (61.13 ± 3.50%). Compared with the Ch group, aortic endothlin-1 expression in the Hm group reduced significantly, while in the Zn group it was significantly higher than in the Ch group (p < 0.01).ConclusionThe HO-1/CO system plays an inhibitory role in atherosclerotic plaque formation. This role was not mediated by regulating serum lipids and ox-LDL, but was related to the reciprocal relationship between the HO-1/CO and NOS/NO systems in atherosclerosis and the down-regulated expression of endothlin-1 (ET-1), which inhibits the proliferation of vascular smooth muscle cells.

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“…In addition, recent studies suggest that sGC heme oxidation and loss could be an important factor in aging and multiple vascular disease models (31) Heme oxygenase (HO) activity is a key regulator of cellular heme levels (2), and the carbon monoxide (CO) product of heme degradation by this enzyme is also known to bind the heme of sGC in a manner which causes a modest stimulation of cGMP generation (6,32). The induction of HO-1 in cultured vascular smooth muscle cells was observed to cause an increase in cGMP production through a mechanism that appeared to involve CO generation (7). However, a prolonged exposure of sGC to increased levels of HO-1 in cultured rat pulmonary microvascular endothelial cells was associated with a depletion of heme, a loss of CO production and decreased sGC activity, suggesting heme availability was a factor which controlled sGC activity (3).…”

Section: Introductionmentioning

confidence: 99%

Heme oxygenase-1 induction depletes heme and attenuates pulmonary artery relaxation and guanylate cyclase activation by nitric oxide

Mingone¹,

Ahmad²,

Gupte³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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This study examines in endothelium-denuded bovine pulmonary arteries the effects of increasing heme oxygenase-1 (HO-1) activity on relaxation and soluble guanylate cyclase (sGC) activation by nitric oxide (NO). A 24 hour organ culture with 0.1 mM cobalt chloride (CoCl 2 ) or 30 μM Coprotoporphyrin IX was developed as a method of increasing HO-1 expression. These treatments increased HO-1 expression and HO activity by ~2-4 fold, and lowered heme levels by 40-45%. Induction of HO-1 was associated with an attenuation of pulmonary arterial relaxation to the NOdonor spermine-NONOate. The presence of a HO-1 inhibitor 30 μM chromium mesoporphyrin during the 24 hour organ culture (but, not acute treatment with this agent) reversed the attenuation of relaxation to NO seen in arteries co-cultured with agents that increased HO-1. Relaxation to isoproterenol, which is thought to be mediated through cAMP, was not altered in arteries with increased HO-1. Inducers of HO-1 did not appear to alter basal sGC activity in arterial homogenates or expression of the β1-subunit of sGC. However, the increase in activity seen in the presence of 1 μM spermine-NONOate was attenuated in homogenates obtained from arteries with increased HO-1. Since arteries with increased HO-1 had decreased levels of superoxide detected by the chemiluminescence of 5 μM lucigenin, superoxide did not appear to be mediating the attenuation of relaxation to NO. These data suggest that increasing HO-1 activity depletes heme, and this is associated with an attenuation of pulmonary artery relaxation and sGC activation responses to NO.

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Vascular Smooth Muscle Cell Heme Oxygenases Generate Guanylyl Cyclase–Stimulatory Carbon Monoxide

Abstract: These results indicate that vascular SMCs have both constitutive and inducible HO activity, and they respond to specific stimuli to generate guanylyl cyclase-stimulatory CO in the same SMCs and in coincubated platelets.

Cited by 230 publications

References 11 publications

Heme oxygenase‐1 in growth control and its clinical application to vascular disease

Heme oxygenase‐1 in growth control and its clinical application to vascular disease

Effect of the haeme oxygenase-1/endogenous carbon monoxide system on atherosclerotic plaque formation in rabbits

Heme oxygenase-1 induction depletes heme and attenuates pulmonary artery relaxation and guanylate cyclase activation by nitric oxide

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