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Inducible nitric oxide synthase, Nos2, does not mediate optic neuropathy and retinopathy in the DBA/2J glaucoma model.

Libby RT, Howell GR, Pang IH, Savinova OV, Mehalow AK, Barter JW, Smith RS, Clark AF, John SW - BMC Neurosci (2007)

Bottom Line: The expression of Nos2 in the optic nerve head was analyzed at both the RNA and protein levels at different stages of disease pathogenesis.Optic nerve head Nos2 RNA levels varied and increased during moderate but decreased at early and severe stages of disease.Additionally, neither Nos2 deficiency nor aminoguanidine had any detectable affect on the glaucomatous optic nerve damage.

View Article: PubMed Central - HTML - PubMed

Affiliation: The Jackson Laboratory, Bar Harbor, ME 04609, USA. Richard_Libby@URMC.rochester.edu

ABSTRACT

Background: Nitric oxide synthase 2 (NOS2) contributes to neural death in some settings, but its role in glaucoma remains controversial. NOS2 is implicated in retinal ganglion cell degeneration in a rat glaucoma model in which intraocular pressure (IOP) is experimentally elevated by blood vessel cauterization, but not in a rat glaucoma model where IOP was elevated by injection of hypertonic saline. To test the importance of NOS2 for an inherited glaucoma, in this study we both genetically and pharmacologically decreased NOS2 activity in the DBA/2J mouse glaucoma model.

Methods: The expression of Nos2 in the optic nerve head was analyzed at both the RNA and protein levels at different stages of disease pathogenesis. To test the involvement of Nos2 in glaucomatous neurodegeneration, a allele of Nos2 was backcrossed into DBA/2J mice and the incidence and severity of glaucoma was assessed in mice of each Nos2 genotype. Additionally, DBA/2J mice were treated with the NOS2 inhibitor aminoguanidine and the disease compared to untreated mice.

Results: Optic nerve head Nos2 RNA levels varied and increased during moderate but decreased at early and severe stages of disease. Despite the presence of a few NOS2 positive cells in the optic nerve head, NOS2 protein was not substantially increased during the glaucoma. Genetic deficiency of Nos2 or aminoguanidine treatment did not alter the IOP profile of DBA/2J mice. Additionally, neither Nos2 deficiency nor aminoguanidine had any detectable affect on the glaucomatous optic nerve damage.

Conclusion: Glaucomatous neurodegeneration in DBA/2J mice does not require NOS2 activity. Further experiments involving various models are needed to assess the general importance of Nos2 in glaucoma.

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NOS2 deficiency does not alter IOP. The IOP distributions of mice of each genotype overlap extensively. The boxes show the upper and lower quartiles and the bars show the extremes including outliers. The centerline of each diamond is the mean with the upper and lower points of each diamond representing the 95% confidence intervals of the mean. Mean ± s.e.m in mm Hg, number of eyes examined; 3.5 months, Nos+/+ 12.6 ± 0.24, 18; Nos+/- 11.9 ± 0.30, 19; Nos-/- 12.2 ± 0.19, 19; P value for all comparisons > 0.08; 10–11 months, Nos+/+ 21.9 ± 0.87, 39; Nos+/- 21.0 ± 0.95, 32; Nos-/- 23.6 ± 1.3, 30, P value for all comparisons >0.09.
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Figure 2: NOS2 deficiency does not alter IOP. The IOP distributions of mice of each genotype overlap extensively. The boxes show the upper and lower quartiles and the bars show the extremes including outliers. The centerline of each diamond is the mean with the upper and lower points of each diamond representing the 95% confidence intervals of the mean. Mean ± s.e.m in mm Hg, number of eyes examined; 3.5 months, Nos+/+ 12.6 ± 0.24, 18; Nos+/- 11.9 ± 0.30, 19; Nos-/- 12.2 ± 0.19, 19; P value for all comparisons > 0.08; 10–11 months, Nos+/+ 21.9 ± 0.87, 39; Nos+/- 21.0 ± 0.95, 32; Nos-/- 23.6 ± 1.3, 30, P value for all comparisons >0.09.

Mentions: To investigate the involvement of Nos2, a allele of Nos2 (Nos2tm1Lau [Nos2tm1Lau; [48]]) was backcrossed into the DBA/2J strain for greater than 13 generations. The genetic removal of Nos2 ensures that there is no enzymatic activity throughout life. Glaucoma in DBA/2J mice is the result of elevated IOP that is secondary to an iris disease. Preventing or lessening the iris disease alleviates IOP elevation and prevents the subsequent neurodegeneration [38,49,50]. Therefore, it is necessary to determine whether Nos2 genotype altered the iris disease or IOP profile. Slit lamp examination at various time points throughout the experiment showed that Nos2 genotype had no affect on the age of onset, progression, or severity of the iris disease (data not shown). Importantly, Nos2 genotype did not alter IOP in either young or aged mice (Fig. 2), and mice of all genotypes had a glaucomatous IOP elevation at 10–11 months of age (Fig. 2, P < 0.001, ANOVA, for all comparisons compared to young mice).


Inducible nitric oxide synthase, Nos2, does not mediate optic neuropathy and retinopathy in the DBA/2J glaucoma model.

Libby RT, Howell GR, Pang IH, Savinova OV, Mehalow AK, Barter JW, Smith RS, Clark AF, John SW - BMC Neurosci (2007)

NOS2 deficiency does not alter IOP. The IOP distributions of mice of each genotype overlap extensively. The boxes show the upper and lower quartiles and the bars show the extremes including outliers. The centerline of each diamond is the mean with the upper and lower points of each diamond representing the 95% confidence intervals of the mean. Mean ± s.e.m in mm Hg, number of eyes examined; 3.5 months, Nos+/+ 12.6 ± 0.24, 18; Nos+/- 11.9 ± 0.30, 19; Nos-/- 12.2 ± 0.19, 19; P value for all comparisons > 0.08; 10–11 months, Nos+/+ 21.9 ± 0.87, 39; Nos+/- 21.0 ± 0.95, 32; Nos-/- 23.6 ± 1.3, 30, P value for all comparisons >0.09.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC2211487&req=5

Figure 2: NOS2 deficiency does not alter IOP. The IOP distributions of mice of each genotype overlap extensively. The boxes show the upper and lower quartiles and the bars show the extremes including outliers. The centerline of each diamond is the mean with the upper and lower points of each diamond representing the 95% confidence intervals of the mean. Mean ± s.e.m in mm Hg, number of eyes examined; 3.5 months, Nos+/+ 12.6 ± 0.24, 18; Nos+/- 11.9 ± 0.30, 19; Nos-/- 12.2 ± 0.19, 19; P value for all comparisons > 0.08; 10–11 months, Nos+/+ 21.9 ± 0.87, 39; Nos+/- 21.0 ± 0.95, 32; Nos-/- 23.6 ± 1.3, 30, P value for all comparisons >0.09.
Mentions: To investigate the involvement of Nos2, a allele of Nos2 (Nos2tm1Lau [Nos2tm1Lau; [48]]) was backcrossed into the DBA/2J strain for greater than 13 generations. The genetic removal of Nos2 ensures that there is no enzymatic activity throughout life. Glaucoma in DBA/2J mice is the result of elevated IOP that is secondary to an iris disease. Preventing or lessening the iris disease alleviates IOP elevation and prevents the subsequent neurodegeneration [38,49,50]. Therefore, it is necessary to determine whether Nos2 genotype altered the iris disease or IOP profile. Slit lamp examination at various time points throughout the experiment showed that Nos2 genotype had no affect on the age of onset, progression, or severity of the iris disease (data not shown). Importantly, Nos2 genotype did not alter IOP in either young or aged mice (Fig. 2), and mice of all genotypes had a glaucomatous IOP elevation at 10–11 months of age (Fig. 2, P < 0.001, ANOVA, for all comparisons compared to young mice).

Bottom Line: The expression of Nos2 in the optic nerve head was analyzed at both the RNA and protein levels at different stages of disease pathogenesis.Optic nerve head Nos2 RNA levels varied and increased during moderate but decreased at early and severe stages of disease.Additionally, neither Nos2 deficiency nor aminoguanidine had any detectable affect on the glaucomatous optic nerve damage.

View Article: PubMed Central - HTML - PubMed

Affiliation: The Jackson Laboratory, Bar Harbor, ME 04609, USA. Richard_Libby@URMC.rochester.edu

ABSTRACT

Background: Nitric oxide synthase 2 (NOS2) contributes to neural death in some settings, but its role in glaucoma remains controversial. NOS2 is implicated in retinal ganglion cell degeneration in a rat glaucoma model in which intraocular pressure (IOP) is experimentally elevated by blood vessel cauterization, but not in a rat glaucoma model where IOP was elevated by injection of hypertonic saline. To test the importance of NOS2 for an inherited glaucoma, in this study we both genetically and pharmacologically decreased NOS2 activity in the DBA/2J mouse glaucoma model.

Methods: The expression of Nos2 in the optic nerve head was analyzed at both the RNA and protein levels at different stages of disease pathogenesis. To test the involvement of Nos2 in glaucomatous neurodegeneration, a allele of Nos2 was backcrossed into DBA/2J mice and the incidence and severity of glaucoma was assessed in mice of each Nos2 genotype. Additionally, DBA/2J mice were treated with the NOS2 inhibitor aminoguanidine and the disease compared to untreated mice.

Results: Optic nerve head Nos2 RNA levels varied and increased during moderate but decreased at early and severe stages of disease. Despite the presence of a few NOS2 positive cells in the optic nerve head, NOS2 protein was not substantially increased during the glaucoma. Genetic deficiency of Nos2 or aminoguanidine treatment did not alter the IOP profile of DBA/2J mice. Additionally, neither Nos2 deficiency nor aminoguanidine had any detectable affect on the glaucomatous optic nerve damage.

Conclusion: Glaucomatous neurodegeneration in DBA/2J mice does not require NOS2 activity. Further experiments involving various models are needed to assess the general importance of Nos2 in glaucoma.

Show MeSH
Related in: MedlinePlus