Modulation of cGMP by human HO-1 retrovirus gene transfer in pulmonary microvessel endothelial cells

Abraham, Nader G.; Quan, Shuo; Mieyal, Paul A.; Yang, Liming; Burke-Wolin, T.; Mingone, Christopher J.; Goodman, Alvin I.; Nasjletti, Alberto; Wolin, Michael S.

doi:10.1152/ajplung.00365.2001

Cited by 37 publications

(32 citation statements)

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“…Thus, genetic interventions result in a steady change of HO activity and heme content, which is regulated by an increase in the rate of heme synthesis. 36 In a recent study, we demonstrated that a moderate increase in HO-1 expression obtained by gene transfer as opposed to chemical inducers does not affect COX-1 37 or nitric oxide synthase 38 and significantly increases cGMP levels in microvessel endothelial cells. 38 Such effects may also contribute to increasing vasodepressor mechanisms that counteract Ang II actions.…”

Section: Discussionmentioning

confidence: 88%

“…36 In a recent study, we demonstrated that a moderate increase in HO-1 expression obtained by gene transfer as opposed to chemical inducers does not affect COX-1 37 or nitric oxide synthase 38 and significantly increases cGMP levels in microvessel endothelial cells. 38 Such effects may also contribute to increasing vasodepressor mechanisms that counteract Ang II actions. All of these direct and/or indirect changes, caused by overexpression of HO-1, might influence the responsiveness of MAP to Ang II.…”

Section: Discussionmentioning

confidence: 88%

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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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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 88%

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

Yang

Quan²,

Nasjletti³

et al. 2004

Hypertension

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“…The amount of CO was calculated from standard curves constructed with an abundance of ions m/z 28 and m/z 29 or m/z 31, as previously described. 28 …”

Section: Ho Activity/co Measurementmentioning

confidence: 99%

Heme Oxygenase-2 Is a Critical Determinant for Execution of an Acute Inflammatory and Reparative Response

Seta

Bellner

Rezzani

et al. 2006

The American Journal of Pathology

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120

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Heme oxygenase (HO) represents an intrinsic antiinflammatory system based on its ability to regulate leukocyte function and inhibit expression of proinflammatory cytokines. This anti-inflammatory function is linked to the inducible isoform HO-1; the role of the constitutive isoform HO-2 is unknown. The current study was undertaken to investigate the role of HO-2 in the regulation of the acute inflammatory and reparative response by using HO-2-null mice and well-established animal models of epithelial injury and antigen-induced peritonitis. Here we show that in vivo deletion of HO-2 disables execution of the acute inflammatory and reparative response after epithelial injury and leads to an exaggerated inflammatory response in antigen-induced peritonitis. HO-2 deletion was associated with impaired HO-1 induction, indicating that HO-2 is critical for HO-1 expression and that the subsequent failure to up-regulate the HO system may contribute to unresolved inflammation and the development of chronic inflammatory conditions. Indeed, supplementation with the HO bioactive product, biliverdin, rescued the acute inflammatory and reparative response in HO-2-null mice. Thus, HO-2 sets in place a basal tone of anti-inflammatory signals that may be a prerequisite for the ordered execution of an inflammatory and reparative response.

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“…8 Gene disruption of HO-1 increases sensitivity to overproduction of reactive oxygen species, inflammatory mediators or xenobiotic metabolism, whereas the gene transfer or CO inhalation under these circumstances suppresses such pathogenic responses. [7][8][9] However, direct mechanisms for the CO reception to trigger these adaptive responses of metabolism remain unknown.…”

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confidence: 99%

Cystathionine β-synthase as a carbon monoxide-sensitive regulator of bile excretion

et al. 2008

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Carbon monoxide (CO) is a stress-inducible gas generated by heme oxygenase (HO) eliciting adaptive responses against toxicants; however, mechanisms for its reception remain unknown. Serendipitous observation in metabolome analysis in CO-overproducing livers suggested roles of cystathionine ␤-synthase (CBS) that rate-limits transsulfuration pathway and H 2 S generation, for the gas-responsive receptor. Studies using recombinant CBS indicated that CO binds to the prosthetic heme, stabilizing 6-coordinated CO-Fe(II)-histidine complex to block the activity, whereas nitric oxide (NO) forms 5-coordinated structure without inhibiting it. The CO-overproducing livers down-regulated H 2 S to stimulate HCO 3 ؊ -dependent choleresis: these responses were attenuated by blocking HO C arbon monoxide (CO) is generated from inducible heme oxygenase 1 (HO-1) and constitutive heme oxygenase 2 (HO-2), respectively, and has the ability to regulate neurovascular functions, 1,2 apoptotic responses, 3,4 and metabolism of xenobiotics and toxicants. 5,6 This gas is overproduced through increased delivery of heme as a substrate and the HO-1 induction on exposure to stressors such as hypoxia and oxidative stress. Mechanisms by which CO regulates cell functions appear to involve an activation of soluble guanylate cyclase (sGC), the enzyme that allows the gas to bind to the prosthetic heme to synthesize cyclic guanosine monophosphate as a second messenger. 1 Distinct from nitric oxide (NO) that forms 5-coordinated NO-Fe(II) complex to trigger full activation of the enzyme, CO activates this enzyme only modestly because the gas binding stabilizes 6-coordinated CO-Fe(II)-histidine complex. 7 Mitogen-activated protein kinase has also been shown to serve as a CO-responsive signal transducer. 8 Gene disruption of HO-1 increases sensitivity to overproduction of reactive oxygen species, inflammatory mediators or xenobiotic metabolism, whereas the gene transfer or CO inhalation under these circumstances suppresses such pathogenic responses. 7-9 However, direct mechanisms for the CO reception to trigger these adaptive responses of metabolism remain unknown.Because this gas has the ability to inhibit ferrous form of the prosthetic heme of enzymes, tryptophan 2,3-dioxygenase or cytochromes P450 have been considered puta-

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Modulation of cGMP by human HO-1 retrovirus gene transfer in pulmonary microvessel endothelial cells

Cited by 37 publications

References 38 publications

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

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

Heme Oxygenase-2 Is a Critical Determinant for Execution of an Acute Inflammatory and Reparative Response

Cystathionine β-synthase as a carbon monoxide-sensitive regulator of bile excretion

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