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Pharmacological induction of vascular extracellular superoxide dismutase expression in vivo.

Oppermann M, Balz V, Adams V, Dao VT, Bas M, Suvorava T, Kojda G - J. Cell. Mol. Med. (2008)

Bottom Line: These effects are associated with decreased vascular superoxide production, but the underlying molecular mechanisms remain unknown.A similar increase was found in aortic homogenates. eNOS(++) lung cytosols showed an increase of ecSOD protein level of 142 +/- 10.5% as compared with transgene-negative littermates (P < 0.05), which was abolished by N(omega)-nitro-L-arginine treatment.Up-regulation of vascular ecSOD may contribute to the reported antioxidative and anti-atherosclerotic effects of PETN.

View Article: PubMed Central - PubMed

Affiliation: Institute for Pharmacology and Clinical Pharmacology, Heinrich-Heine-University, Duesseldorf, Germany.

ABSTRACT
Pentaerythritol tetranitrate (PETN) treatment reduces progression of atherosclerosis and endothelial dysfunction and decreases oxidation of low-density lipoprotein (LDL) in rabbits. These effects are associated with decreased vascular superoxide production, but the underlying molecular mechanisms remain unknown. Previous studies demonstrated that endogenous nitric oxide could regulate the expression of extracellular superoxide dismutase (ecSOD) in conductance vessels in vivo. We investigated the effect of PETN and overexpression of endothelial nitric oxide synthase (eNOS(++)) on the expression and activity of ecSOD. C57BL/6 mice were randomized to receive placebo or increasing doses of PETN for 4 weeks and eNOS(++) mice with a several fold higher endothelial-specific eNOS expression were generated. The expression of ecSOD was determined in the lung and aortic tissue by real-time PCR and Western blot. The ecSOD activity was measured using inhibition of cytochrome C reduction. There was no effect of PETN treatment or eNOS overexpression on ecSOD mRNA in the lung tissue, whereas ecSOD protein expression increased from 2.5-fold to 3.6-fold (P < 0.05) by 6 mg PETN/kg body weight (BW)/day and 60 mg PETN/kg BW/day, respectively. A similar increase was found in aortic homogenates. eNOS(++) lung cytosols showed an increase of ecSOD protein level of 142 +/- 10.5% as compared with transgene-negative littermates (P < 0.05), which was abolished by N(omega)-nitro-L-arginine treatment. In each animal group, the increase of ecSOD expression was paralleled by an increase of ecSOD activity. Increased expression and activity of microvascular ecSOD are likely induced by increased bioavailability of vascular nitric oxide. Up-regulation of vascular ecSOD may contribute to the reported antioxidative and anti-atherosclerotic effects of PETN.

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ecSOD mRNA levels. (A) Treatment of C57Bl/6 mice with 6 mg/kg/day (PETN-6) or 60 mg/kg/day (PETN-60) PETN induced no changes in lung ecSOD mRNA expression relative to HPRT (P > 0.05 versus PETN-0). (B) eNOS++ mice induced no changes in lung ecSOD mRNA expression relative to HPRT (P > 0.05 versus eNOSn). (C) eNOS++ mice induced no changes in aortic ecSOD mRNA expression relative to SMA (P > 0.05 versus eNOSn), irrespective of oral treatment with L-NA.
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fig02: ecSOD mRNA levels. (A) Treatment of C57Bl/6 mice with 6 mg/kg/day (PETN-6) or 60 mg/kg/day (PETN-60) PETN induced no changes in lung ecSOD mRNA expression relative to HPRT (P > 0.05 versus PETN-0). (B) eNOS++ mice induced no changes in lung ecSOD mRNA expression relative to HPRT (P > 0.05 versus eNOSn). (C) eNOS++ mice induced no changes in aortic ecSOD mRNA expression relative to SMA (P > 0.05 versus eNOSn), irrespective of oral treatment with L-NA.

Mentions: The mRNA expression of lung ecSOD relative to HPRT did not show significant changes in the PETN-treated groups compared with the PETN-0-treated groups (each n= 6, P= 0.7558, anova; Fig. 2A). In eNOS++ mice, ecSOD mRNA expression (0.522 ± 0.080) was not significant different from eNOSn mice (0.637 ± 0.156, n= 6, P= 0.5238; Fig. 2B). Likewise, eNOS++ aortic ecSOD mRNA levels were unchanged. Similar results on aortic ecSOD mRNA were obtained after treatment with L-NA and when SMA and 18S rRNA were used as standards (Fig. 2C).


Pharmacological induction of vascular extracellular superoxide dismutase expression in vivo.

Oppermann M, Balz V, Adams V, Dao VT, Bas M, Suvorava T, Kojda G - J. Cell. Mol. Med. (2008)

ecSOD mRNA levels. (A) Treatment of C57Bl/6 mice with 6 mg/kg/day (PETN-6) or 60 mg/kg/day (PETN-60) PETN induced no changes in lung ecSOD mRNA expression relative to HPRT (P > 0.05 versus PETN-0). (B) eNOS++ mice induced no changes in lung ecSOD mRNA expression relative to HPRT (P > 0.05 versus eNOSn). (C) eNOS++ mice induced no changes in aortic ecSOD mRNA expression relative to SMA (P > 0.05 versus eNOSn), irrespective of oral treatment with L-NA.
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Related In: Results  -  Collection

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fig02: ecSOD mRNA levels. (A) Treatment of C57Bl/6 mice with 6 mg/kg/day (PETN-6) or 60 mg/kg/day (PETN-60) PETN induced no changes in lung ecSOD mRNA expression relative to HPRT (P > 0.05 versus PETN-0). (B) eNOS++ mice induced no changes in lung ecSOD mRNA expression relative to HPRT (P > 0.05 versus eNOSn). (C) eNOS++ mice induced no changes in aortic ecSOD mRNA expression relative to SMA (P > 0.05 versus eNOSn), irrespective of oral treatment with L-NA.
Mentions: The mRNA expression of lung ecSOD relative to HPRT did not show significant changes in the PETN-treated groups compared with the PETN-0-treated groups (each n= 6, P= 0.7558, anova; Fig. 2A). In eNOS++ mice, ecSOD mRNA expression (0.522 ± 0.080) was not significant different from eNOSn mice (0.637 ± 0.156, n= 6, P= 0.5238; Fig. 2B). Likewise, eNOS++ aortic ecSOD mRNA levels were unchanged. Similar results on aortic ecSOD mRNA were obtained after treatment with L-NA and when SMA and 18S rRNA were used as standards (Fig. 2C).

Bottom Line: These effects are associated with decreased vascular superoxide production, but the underlying molecular mechanisms remain unknown.A similar increase was found in aortic homogenates. eNOS(++) lung cytosols showed an increase of ecSOD protein level of 142 +/- 10.5% as compared with transgene-negative littermates (P < 0.05), which was abolished by N(omega)-nitro-L-arginine treatment.Up-regulation of vascular ecSOD may contribute to the reported antioxidative and anti-atherosclerotic effects of PETN.

View Article: PubMed Central - PubMed

Affiliation: Institute for Pharmacology and Clinical Pharmacology, Heinrich-Heine-University, Duesseldorf, Germany.

ABSTRACT
Pentaerythritol tetranitrate (PETN) treatment reduces progression of atherosclerosis and endothelial dysfunction and decreases oxidation of low-density lipoprotein (LDL) in rabbits. These effects are associated with decreased vascular superoxide production, but the underlying molecular mechanisms remain unknown. Previous studies demonstrated that endogenous nitric oxide could regulate the expression of extracellular superoxide dismutase (ecSOD) in conductance vessels in vivo. We investigated the effect of PETN and overexpression of endothelial nitric oxide synthase (eNOS(++)) on the expression and activity of ecSOD. C57BL/6 mice were randomized to receive placebo or increasing doses of PETN for 4 weeks and eNOS(++) mice with a several fold higher endothelial-specific eNOS expression were generated. The expression of ecSOD was determined in the lung and aortic tissue by real-time PCR and Western blot. The ecSOD activity was measured using inhibition of cytochrome C reduction. There was no effect of PETN treatment or eNOS overexpression on ecSOD mRNA in the lung tissue, whereas ecSOD protein expression increased from 2.5-fold to 3.6-fold (P < 0.05) by 6 mg PETN/kg body weight (BW)/day and 60 mg PETN/kg BW/day, respectively. A similar increase was found in aortic homogenates. eNOS(++) lung cytosols showed an increase of ecSOD protein level of 142 +/- 10.5% as compared with transgene-negative littermates (P < 0.05), which was abolished by N(omega)-nitro-L-arginine treatment. In each animal group, the increase of ecSOD expression was paralleled by an increase of ecSOD activity. Increased expression and activity of microvascular ecSOD are likely induced by increased bioavailability of vascular nitric oxide. Up-regulation of vascular ecSOD may contribute to the reported antioxidative and anti-atherosclerotic effects of PETN.

Show MeSH
Related in: MedlinePlus