Real-time measurements of endogenous CO production from vascular cells using an ultrasensitive laser sensor

Morimoto, Yuji; Durante, William; Lancaster, David G.; Klattenhoff, Jens; Tittel, Frank K.

doi:10.1152/ajpheart.2001.280.1.h483

Cited by 70 publications

(49 citation statements)

References 21 publications

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“…In rat brain slices, electrical field stimulation leads to Ca 2ϩ waves spreading from the astrocytic soma to the end feet (11). In the present study, we observed that glutamate causes Ca 2ϩ transients at 10 CO production has been measured in neurons (16), vascular smooth muscle cells (21,29), endothelial cells (21), and astrocytes (this study). In the cerebral vasculature, glutamate stimulates CO production in astrocytes (26) and endothelial cells (21).…”

Section: Discussionsupporting

confidence: 66%

Glutamate-induced calcium signals stimulate CO production in piglet astrocytes

Tcheranova

Basuroy

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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Glutamate-stimulated, astrocyte-derived carbon monoxide (CO) causes cerebral arteriole dilation by activating smooth muscle cell large-conductance Ca 2ϩ -activated K ϩ channels. Here, we examined the hypothesis that glutamate activates heme oxygenase (HO)-2 and CO production via the intracellular Ca 2ϩ concentration ([Ca 2ϩ ]i)/ Ca 2ϩ -calmodulin signaling pathway in newborn pig astrocytes. The major findings are: 1) glutamate stimulated Ca 2ϩ transients and increased steady-state [Ca 2ϩ ]i in cerebral cortical astrocytes in primary culture, 2) in astrocytes permeabilized with ionomycin, elevation of [Ca 2ϩ ]i concentration-dependently increased CO production, 3) glutamate did not affect CO production at any [Ca 2ϩ ]i when the [Ca 2ϩ ]i was held constant, 4) thapsigargin, a sarco/endoplasmic reticulum Ca 2ϩ -ATPase blocker, decreased basal CO production and blocked glutamate-induced increases in CO, and 5) calmidazolium, a calmodulin inhibitor, blocked CO production induced by glutamate and by [Ca 2ϩ ]i elevation. Taken together, our data are consistent with the hypothesis that glutamate elevates [Ca 2ϩ ]i in astrocytes, leading to Ca 2ϩ -and calmodulin-dependent HO-2 activation, and CO production. cerebral circulation; heme oxygenase; calmodulin; gasotransmitter; neurovascular coupling IN THE NEUROVASCULAR UNIT, astrocytes act as intermediaries between neurons and arterioles to regulate vascular tone in response to neuronal activity. Release of glutamate from presynaptic neurons increases blood flow to match metabolic demands; such coupling is called functional hyperemia. Functional hyperemia has been investigated extensively, and many astrocyte-derived vasoactive mediators, including ADP (40, 41), ATP (34, 36), epoxyeicosatrienoic acids (1-3), K ϩ (11, 13, 33), and prostacyclin (42), appear to be involved, depending on experimental models. We have shown that carbon monoxide (CO) is another critical regulator of cerebrovascular tone in newborn piglets (19,24,26,31,39).CO dilates newborn pig pial arterioles (22,25). CO causes vasodilation by stimulating Ca 2ϩ sparks and large-conductance Ca 2ϩ -activated K ϩ (BK Ca ) channels and by increasing effective coupling between Ca 2ϩ sparks and BK Ca channels in arterial smooth muscle cells (17,18,25,38). Physiologically, CO is produced by heme oxygenase (HO)-catabolized breakdown of heme to CO, iron, and biliverdin (27). Of three HO isoforms, only HO-2 is expressed under basal conditions in newborn piglet brain (31, 32). In piglets, endogenous HO-2 can produce sufficient CO to induce cerebral arteriole dilation (23).Our previous studies in piglets demonstrated that glutamate stimulates astrocytic CO production in primary-cultured astrocytes and in vivo (24,26,31). We also demonstrated that astrocytes release CO and astrocyte-derived CO causes glutamate-induced pial arteriolar dilation in vivo (24), supporting a regulatory role for astrocytic CO in neurovascular coupling in the newborn brain. Indeed, in brain slices from newborn piglets, we demonstrated that glut...

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Section: Discussionsupporting

confidence: 66%

Glutamate-induced calcium signals stimulate CO production in piglet astrocytes

Tcheranova

Basuroy

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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“…Pathological conditions (35), such as oxidative stress (2), diabetes (17), and salt-sensitive hypertension (21,22,48), induce HO-1 expression, which can lead to enhanced CO formation (38). However, HO-derived CO formation is normally limited by the availability of heme substrate (27), and HO activity can increase in the absence of enhanced HO-1 expression (38,54). In the current study, we did not find differences in thoracic aorta HO-1 protein levels between lean and obese ZR.…”

Section: Discussionmentioning

confidence: 99%

Metabolic syndrome increases endogenous carbon monoxide production to promote hypertension and endothelial dysfunction in obese Zucker rats

Johnson¹,

Johnson²,

Durante³

et al. 2006

American Journal of Physiology-Regulatory, Integrative and Comp

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Vascular heme oxygenase (HO) metabolizes heme to form carbon monoxide (CO). Increased heme-derived CO inhibits nitric oxide synthase and can contribute to hypertension via endothelial dysfunction in Dahl salt-sensitive rats. Obese Zucker rats (ZR) are models of metabolic syndrome. This study tests the hypothesis that endogenous CO formation is increased and contributes to hypertension and endothelial dysfunction in obese ZR. Awake obese ZR showed increased respiratory CO excretion, which was lowered by HO inhibitor administration [zinc deuteroporphyrin 2,4-bis glycol (ZnDPBG) 25 mol ⅐ kg Ϫ1 ⅐ 24 h Ϫ1 ip]. In awake obese ZR, chronically instrumented with femoral arterial catheters, blood pressure was elevated but was decreased by the HO inhibitor ZnDPBG. Body weight, blood glucose, glycated hemoglobin, plasma insulin, total and LDL cholesterol, oxidized LDL, and triglyceride levels were elevated in obese ZR, and, except for LDL cholesterol, were unchanged by HO inhibition. Total HO-1 protein levels were not different between lean and obese ZR aortas. In vitro experiments used isolated skeletal muscle arterioles with constant pressure and no flow, or constant midpoint, but altered endpoint pressures to establish graded levels of luminal flow. In obese ZR arterioles, responses to ACh and flow were attenuated. Acute in vitro pretreatment with an HO inhibitor, chromium mesoporphyrin, enhanced ACh and flow-induced dilation and abolished the differences between groups. Furthermore, exogenous CO prevented the restoration of flow-induced dilation by the HO inhibitor in obese ZR arterioles. These results suggest that HO-derived CO production is increased and promotes hypertension and arteriolar endothelial dysfunction in obese ZR with metabolic syndrome independent of affecting metabolic parameters. heme oxygenase; blood pressure; arterioles; vascular tone regulation METABOLIC SYNDROME IS CHARACTERIZED by upper body obesity, insulin resistance, hyperlipidemia, and hypertension, and it represents a major and growing health problem in the United States (11). Endothelial dysfunction due to impaired nitric oxide function, is a key feature promoting microvascular disease in resistance vessels, which contributes to hypertension during obesity (43) and metabolic syndrome. The obese Zucker rat (ZR) is a well established genetic model of obesity (58). Because of a nonfunctional leptin receptor gene (19) and the consequent hyperphagia, these animals develop obesity and metabolic syndrome, including insulin resistance (29), hyperlipidemia (29), and hypertension (13). Previous studies have shown impaired endothelium-derived nitric oxide-dependent vasodilation in various vascular beds of obese ZR (12,13,33,41), including skeletal muscle resistance vessels (12, 13).Metabolic syndrome represents a major cardiovascular risk factor, which is further enhanced by the increased chance of type 2 diabetes development (11). It is known that patients with type 2 diabetes show increased respiratory carbon monoxide (CO) levels (39). Although eleva...

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“…Figure 4A is a Western blot showing that both HO-1 and HO-2 are expressed in the endothelial cells in 4 experiments. We then used hemin, the substrate of HO, 23 to examine whether stimulation of endogenous CO production was able to increase BK channel activity in HUVECs. Data summarized in Figure 4B demonstrate that application of 20 mol/L of hemin significantly stimulated BK channels by 478% (nϭ5), and increasing hemin concentration to 40 mol/L augmented the channel further to 4000% (nϭ7) of the control value.…”

Section: Co Stimulates Bk In Huvecsmentioning

confidence: 99%

Carbon Monoxide Stimulates the Ca ²⁺ –Activated Big Conductance K Channels in Cultured Human Endothelial Cells

et al. 2007

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Abstract-We used the whole-cell patch-clamp technique to study K channels in the human umbilical vein endothelial cells and identified a 201 pS K channel, which was blocked by tetraethylammonium and iberiotoxin but not by TRAM34 and apamin. This suggests that the Ca 2ϩ -activated big-conductance K channel (BK) is expressed in endothelial cells. Application of carbon monoxide (CO) or tricarbonylchloro(glycinato)ruthenium(II), a water soluble CO donor, stimulated the BK channels. Moreover, application of hemin, a substrate of heme oxygenase, mimicked the effect of CO and increased the BK channel activity. The stimulatory effect of hemin was significantly diminished by tin mesoporphyrin, an inhibitor of heme oxygenase. To determine whether the stimulatory effect of CO on the BK channel was mediated by NO and the cGMP-dependent pathway, we examined the effect of CO on BK channels in cells treated with, N G -nitro-L-arginine methyl ester, 1H(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one, an inhibitor of soluble guanylate cyclase, or KT5823, an inhibitor of protein kinase G. Addition of either diethylamine NONOate or sodium nitroprusside significantly increased BK channel activity. Inhibition of endogenous NO synthesis with N G -nitro-L-arginine methyl ester, blocking soluble guanylate cyclase or protein kinase G, delayed but did not prevent the CO-induced activation of BK channels. Finally, application of an antioxidant agent, ebselen, had no effect on CO-mediated stimulation of BK channels in human umbilical vein endothelial cells. We conclude that BK channels are expressed in human umbilical vein endothelial cells and that they are activated by both CO and NO. CO activates BK channels directly, as well as via a mechanism involving NO or the cGMP-dependent pathway.

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Real-time measurements of endogenous CO production from vascular cells using an ultrasensitive laser sensor

Cited by 70 publications

References 21 publications

Glutamate-induced calcium signals stimulate CO production in piglet astrocytes

Glutamate-induced calcium signals stimulate CO production in piglet astrocytes

Metabolic syndrome increases endogenous carbon monoxide production to promote hypertension and endothelial dysfunction in obese Zucker rats

Carbon Monoxide Stimulates the Ca ²⁺ –Activated Big Conductance K Channels in Cultured Human Endothelial Cells

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Real-time measurements of endogenous CO production from vascular cells using an ultrasensitive laser sensor

Cited by 70 publications

References 21 publications

Glutamate-induced calcium signals stimulate CO production in piglet astrocytes

Glutamate-induced calcium signals stimulate CO production in piglet astrocytes

Metabolic syndrome increases endogenous carbon monoxide production to promote hypertension and endothelial dysfunction in obese Zucker rats

Carbon Monoxide Stimulates the Ca 2+ –Activated Big Conductance K Channels in Cultured Human Endothelial Cells

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Carbon Monoxide Stimulates the Ca ²⁺ –Activated Big Conductance K Channels in Cultured Human Endothelial Cells