Sensitivity of human tissue heme oxygenase to a new synthetic metalloporphyrin

Chernick, Richard J.; Martásek, Pavel; Levere, Richard D.; Margreiter, Raimund; Abraham, Nader G.

doi:10.1002/hep.1840100320

Cited by 64 publications

(45 citation statements)

References 15 publications

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“…As previously reported, and confirmed in our study, heme and HO inhibitors such as ZnDPP are powerful inducers of HO-1 protein. 7,20 Importantly, the upregulation of HO-1 expression produced by these agents is unlikely to produce depletion of cellular heme, which could explain our finding that heme treatment increases and ZnDPP treatment is without effect on prostaglandin production in endothelial cells. Collectively, these observations support the notion that depletion of cellular heme is the connecting link between overexpression of HO-1 and diminished prostaglandin production in endothelial cells treated with SnCl 2 or transfected with the human HO-1 gene.…”

Section: Discussionmentioning

confidence: 86%

Heme Oxygenase Attenuates Angiotensin II-Mediated Increase in Cyclooxygenase-2 Activity in Human Femoral Endothelial Cells

et al. 2003

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Abstract-Heme oxygenase (HO) regulates cellular heme levels and catalyzes the formation of bilirubin and carbon monoxide. We hypothesize that the status of the endothelial HO system influences the angiotensin (Ang) II-induced increase in the endothelial production of prostaglandin I 2 (PGI 2 ) (measured as 6-keto-PGF 1␣ ) and prostaglandin E 2 (PGE 2 ), eicosanoids that modulate the vascular actions of Ang II. In the present study, we determined the effect of interventions that suppress HO activity or induce HO-1 gene expression on Ang II-mediated increase in 6-keto-PGF 1␣ and PGE 2 in cultures of human femoral artery endothelial cells. Incubation of endothelial cells with Ang II (100 ng/mL) for 24 hours increased the levels of both 6-keto-PGF 1␣ and PGE 2 in the culture media. Key Words: heme oxygenase Ⅲ cyclooxygenase activity Ⅲ prostaglandins Ⅲ angiotensin II Ⅲ endothelial cell Ⅲ gene transfer T he vascular endothelium manufactures prostaglandin E 2 (PGE 2 ) and/or I 2 (PGI 2 ) via a pathway that involves oxygenation of arachidonic acid by cyclooxygenase (COX)-1 and -2. 1-3 Angiotensin (Ang) II acutely stimulates prostaglandin synthesis in endothelial cells by promoting phospholipase-catalyzed deacylation of arachidonic acid, and thus increasing the amount of arachidonic acid available to COX, and also may induce COX-2 expression. 4 As prostaglandins produced by the vascular endothelium subserve mechanisms that counteract the actions of Ang II on the vasculature, 5 the interplay between endothelium-derived prostaglandins and Ang II has great functional relevance.COX-1 and COX-2 are heme proteins, 6 and it is well documented that the heme prosthetic group of both COX isoforms is essential for the expression of catalytic activity. 6 According to a recent study, prostaglandin synthesis in rabbit coronary and human endothelial cells decreases in response to interventions that upregulate the expression of heme oxygenase (HO)-1. 7,8 HO isoforms -1 and -2 catalyze the metabolisms of heme to biliverdin and carbon monoxide (CO), respectively, an antioxidant and a vasoactive mediator. 9,10 HO isoforms, particularly HO-1, play a critical role in the regulation of cellular heme levels, 11 which in turn may impact on the expression of catalytically active COX isoforms. 7,8 Previous studies have documented induction of vascular and renal HO-1 in response to Ang II in vivo. 12,13 It is conceivable, then, that Ang II-mediated upregulation of HO-1 creates a setting that does not favor Ang II-induced stimulation of prostaglandin synthesis. We tested this hypothesis by examining the effect of interventions that suppress HO activity, or induce HO-1 gene expression, on Ang II-induced prostaglandin synthesis in cultures of human femoral endothelial cells. Methods Cell Culture ConditionsHuman femoral artery endothelial cells were obtained from ATCC (Manassas, VA) and were grown in MCDB131 medium (GIBCO-BRL; passages 12 to 25) supplemented with 10% fetal bovine serum, 10 ng/mL endothelial growth factor (Sigma), and 1 g/mL hydrocorti...

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Section: Discussionmentioning

confidence: 86%

Heme Oxygenase Attenuates Angiotensin II-Mediated Increase in Cyclooxygenase-2 Activity in Human Femoral Endothelial Cells

et al. 2003

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“…HO activity assay and CO generation. HO activity was assayed in homogenates of various tissues or MSCs as previously described (27). 300 g protein was used for CO measurement in the presence and absence of heme and NADPH-generating system (28,29).…”

Section: Methodsmentioning

confidence: 99%

Treatment of Obese Diabetic Mice With a Heme Oxygenase Inducer Reduces Visceral and Subcutaneous Adiposity, Increases Adiponectin Levels, and Improves Insulin Sensitivity and Glucose Tolerance

et al. 2008

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OBJECTIVE-We hypothesized that the induction of heme oxygenase (HO)-1 and increased HO activity, which induces arterial antioxidative enzymes and vasoprotection in a mouse and a rat model of diabetes, would ameliorate insulin resistance, obesity, and diabetes in the ob mouse model of type 2 diabetes.RESEARCH DESIGN AND METHODS-Lean and ob mice were intraperitoneally administered the HO-1 inducer cobalt protoporphyrin (3 mg/kg CoPP) with and without the HO inhibitor stannous mesoporphyrin (2 mg/100 g SnMP) once a week for 6 weeks. Body weight, blood glucose, and serum cytokines and adiponectin were measured. Aorta, adipose tissue, bone marrow, and mesenchymal stem cells (MSCs) were isolated and assessed for HO expression and adipogenesis.RESULTS-HO activity was reduced in ob mice compared with age-matched lean mice. Administration of CoPP caused a sustained increase in HO-1 protein, prevented weight gain, decreased visceral and subcutaneous fat content (P Ͻ 0.03 and 0.01, respectively, compared with vehicle animals), increased serum adiponectin, and decreased plasma tumor necrosis factor-␣ (TNF-␣), interleukin (IL)-6, and IL-1␤ levels (P Ͻ 0.05). HO-1 induction improved insulin sensitivity and glucose tolerance and decreased insulin levels. Upregulation of HO-1 decreased adipogenesis in bone marrow in vivo and in cultured MSCs and increased adiponectin levels in the culture media. Inhibition of HO activity decreased adiponectin and increased secretion of TNF-␣, IL-6, and IL-1␤ levels in ob mice.CONCLUSIONS-This study provides strong evidence for the existence of an HO-1-adiponectin regulatory axis that can be manipulated to ameliorate the deleterious effects of obesity and the metabolic syndrome associated with cardiovascular disease and diabetes. Diabetes 57:1526-1535, 2008

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“…Each rat was anesthetized with sodium pentobarbital (65 mg/kg IP), and arterial and venous catheters were implanted for blood pressure determination and Ang II or tin mesoporphyrin (SnMP) administration, respectively. 22 The arterial catheter (PE-50), filled with heparinized normal saline, was introduced through the femoral artery and advanced into the lower abdominal aorta. The venous catheter was implanted into the femoral vein.…”

Section: Animalsmentioning

confidence: 99%

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

Yang

Quan²,

Nasjletti³

et al. 2004

Hypertension

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Abstract-The heme-heme oxygenase (HO) system has been implicated in the regulation of vascular reactivity and blood pressure. This study examines the notion that overexpression of HO decreases pressor responsiveness to angiotensin II (Ang II). Five-day-old Sprague-Dawley rats received an intraleft ventricular injection of Ϸ5ϫ10 9 cfu/mL of retroviruses containing human HO-1 sense (LSN-HHO-1), rat HO-1 antisense (LSN-RHO-1-AS), or control retrovirus (LXSN). Three months later, rats were instrumented with femoral arterial and venous catheters for mean arterial pressure (MAP) determination and Ang II administration, respectively. Rats injected with LSN-HHO-1, but not with LXSN, expressed human HO-1 mRNA and protein in several tissues. BP increased with administration of Ang II in rats expressing and not expressing human HO-1. However, the Ang II-induced pressor response (mm Hg) in LSN-HHO-1 rats (16Ϯ3, 27Ϯ3, and 38Ϯ3 at 0.5, 2, and 10 ng) was surpassed (PϽ0.05) in LXSN rats (23Ϯ1, 37Ϯ2, and 52Ϯ2 at 0.5, 2, and 10 ng). Importantly, treating LSN-HHO-1 rats with the HO inhibitor tin mesoporphyrin (SnMP) enhanced (PϽ0.05) the Ang II-induced pressor response to a level not different from that observed in LXSN rats. Rats injected with LSN-RHO-1-AS showed a decrease in renal HO-1 protein expression and HO activity relative to control LXSN rats. Administration of Ang II (0.1 to 2 ng) caused small (4 to 5 mm Hg) but significant increases in MAP in rats injected with LSN-RHO-1-AS (PϽ0.05) compared with rats injected with LXSN. These data demonstrate that overexpression of HO-1 brings about a reduction in pressor responsiveness to Ang II, which is most likely due to increased generation of an HO-1 product, presumably CO, with the ability to inhibit vascular reactivity to constrictor stimuli. Key Words: blood pressure Ⅲ retrovirus Ⅲ genes Ⅲ angiotensin II Ⅲ oxidative stress H eme oxygenases (HO) are a family of enzymes involved in the enzymatic conversion of heme to CO and biliverdin, which is further metabolized by biliverdin reductase to the antioxidant bilirubin. 1 HO activity arises primarily from two distinct genes, the inducible HO-1 and the constitutively expressed HO-2. 1,2 Among the metabolic products of heme, CO has many functions, including vascular relaxation, 3,4 inhibition of platelet aggregation, 5 and modulation of the NO-cGMP signaling system. 6 Exogenous administration of CO relaxes isolated blood vessels 7,8 and treatment with heme decreases blood pressure in hypertensive rats, 9 whereas the administration of HO inhibitors increases arterial pressure in normotensive rats. 3 These observations suggest that one or more HO-derived products play a role in the regulation of vascular tone and arterial blood pressure.Previous studies have documented induction of vascular, cardiac, and renal HO-1 in response to angiotensin II (Ang II) in vitro and in vivo. 10 -12 HO-1 expression is markedly increased in aortic adventitial and endothelial cells from rats with Ang II-induced hypertension; treatment with losartan, a s...

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Sensitivity of human tissue heme oxygenase to a new synthetic metalloporphyrin

Cited by 64 publications

References 15 publications

Heme Oxygenase Attenuates Angiotensin II-Mediated Increase in Cyclooxygenase-2 Activity in Human Femoral Endothelial Cells

Heme Oxygenase Attenuates Angiotensin II-Mediated Increase in Cyclooxygenase-2 Activity in Human Femoral Endothelial Cells

Treatment of Obese Diabetic Mice With a Heme Oxygenase Inducer Reduces Visceral and Subcutaneous Adiposity, Increases Adiponectin Levels, and Improves Insulin Sensitivity and Glucose Tolerance

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

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