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Cardiomyopathy in the mouse model of Duchenne muscular dystrophy caused by disordered secretion of vascular endothelial growth factor.

Nowak D, Kozlowska H, Gielecki JS, Rowinski J, Zurada A, Goralczyk K, Bozilow W - Med. Sci. Monit. (2011)

Bottom Line: Duchenne muscular dystrophy (DMD) is a genetic neuromuscular disorder that affects skeletal muscles and cardiac muscle tissue.In the heart, the total level of VEGF depends on VEGF expression in myocardium, not in vessel endothelium, and our research demonstrates that the expression of VEGF is dystrophin-dependent.Disordered secretion of VEGF-A in hypoxic myocardium caused the total level of this factor to be impaired in the heart.

View Article: PubMed Central - PubMed

Affiliation: Department of Histology and Embryology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Torun, Poland. dareknowak15@wp.pl

ABSTRACT

Background: Duchenne muscular dystrophy (DMD) is a genetic neuromuscular disorder that affects skeletal muscles and cardiac muscle tissue. In some cases, myocardial injury secondary to hypoxia can lead to dilative cardiomyopathy (DCM). A genetic defect in the dystrophin gene may increase the susceptibility of myocardium to hypoxia. Available data suggest that this may be caused by impaired secretion of NO, which is bound with secretion of VEGF-A.

Material/methods: Male mice C57BI/10ScSn mdx (animal model of DMD) and healthy mice C57BI/10ScSn were exposed to hypobaric hypoxia in low-pressure chambers. Their hearts were harvested immediately after and 1, 3, 7, and 21 days after exposure to hypoxia. Normobaric mice were used as controls. The expression of VEGF-A in myocardium and cardiac vessel walls was evaluated using immunohistochemistry, Western blotting, and in situ hybridization.

Results: VEGF-A expression in myocardium and vessel walls of healthy mice peaked 24 hours after exposure to hypoxia. The expression of VEGF-A in vessel walls was similar in dystrophic and healthy mice; however, VEGF-A expression in the myocardium of dystrophic mice was impaired, peaking around day 7. In the heart, the total level of VEGF depends on VEGF expression in myocardium, not in vessel endothelium, and our research demonstrates that the expression of VEGF is dystrophin-dependent.

Conclusions: Disordered secretion of VEGF-A in hypoxic myocardium caused the total level of this factor to be impaired in the heart. This factor, which in normal situations protect against hypoxia, promotes the gradual progression of cardiomyopathy.

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(A) Heart’s specimen from normal mice obtained 1 day after exposure to hypoxia. Increased expression of VEGF in both myocardium and vessel walls. (B) Heart’s specimen from mdx mice obtained 1 day after exposure to hypoxia. Low expression of VEGF in myocardium and an enhanced signal in vessel walls. Scale bar =100 μm.
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f5-medscimonit-17-11-br332: (A) Heart’s specimen from normal mice obtained 1 day after exposure to hypoxia. Increased expression of VEGF in both myocardium and vessel walls. (B) Heart’s specimen from mdx mice obtained 1 day after exposure to hypoxia. Low expression of VEGF in myocardium and an enhanced signal in vessel walls. Scale bar =100 μm.

Mentions: There were also differences in the expression of VEGF-A protein expression between the normal and mdx mice. In the case of endothelium, there were no difference in VEGF-A concentrations in normal and mdx mice (Figure 4A). In the case of myocardial cells, the initial control levels (99±7% vs. 92±6%, respectively) and those measured immediately following hypoxia (104±7% vs. 96±4%, respectively) did not differ between normal and mdx mice (p>0.05) (Figure 4B). Differences in VEGF-A protein concentration became apparent 1 day after hypoxia in the normal group. In these animals, there was an increase in optical density up to 168% (±9%) of the control level (Figure 5A). In dystrophic mdx mice, the protein concentration remained constant at 95±7% (p<0.05) (Figure 5B). After 3 days, the concentration of VEGF-A in normal mice fell to 120% (±7%), but remained elevated relative to the initial level. In the mdx mice, the concentration of VEGF remained stable at 86±8% (p<0.05). After 7 days, the VEGF-A concentration in normal mice returned to the initial value (99±4%) (Figure 6A), whereas in the mdx mice, the level of VEGF-A protein began to increase, reaching 135±9% (p<0.05) (Figure 6B). After 21 days, there was a clear difference between the 2 groups in terms of VEGF concentration. In control mice, the VEGF concentration remained at its initial level (103±7%) but had decreased in mdx mice (76±8%) (p<0.05).


Cardiomyopathy in the mouse model of Duchenne muscular dystrophy caused by disordered secretion of vascular endothelial growth factor.

Nowak D, Kozlowska H, Gielecki JS, Rowinski J, Zurada A, Goralczyk K, Bozilow W - Med. Sci. Monit. (2011)

(A) Heart’s specimen from normal mice obtained 1 day after exposure to hypoxia. Increased expression of VEGF in both myocardium and vessel walls. (B) Heart’s specimen from mdx mice obtained 1 day after exposure to hypoxia. Low expression of VEGF in myocardium and an enhanced signal in vessel walls. Scale bar =100 μm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3539494&req=5

f5-medscimonit-17-11-br332: (A) Heart’s specimen from normal mice obtained 1 day after exposure to hypoxia. Increased expression of VEGF in both myocardium and vessel walls. (B) Heart’s specimen from mdx mice obtained 1 day after exposure to hypoxia. Low expression of VEGF in myocardium and an enhanced signal in vessel walls. Scale bar =100 μm.
Mentions: There were also differences in the expression of VEGF-A protein expression between the normal and mdx mice. In the case of endothelium, there were no difference in VEGF-A concentrations in normal and mdx mice (Figure 4A). In the case of myocardial cells, the initial control levels (99±7% vs. 92±6%, respectively) and those measured immediately following hypoxia (104±7% vs. 96±4%, respectively) did not differ between normal and mdx mice (p>0.05) (Figure 4B). Differences in VEGF-A protein concentration became apparent 1 day after hypoxia in the normal group. In these animals, there was an increase in optical density up to 168% (±9%) of the control level (Figure 5A). In dystrophic mdx mice, the protein concentration remained constant at 95±7% (p<0.05) (Figure 5B). After 3 days, the concentration of VEGF-A in normal mice fell to 120% (±7%), but remained elevated relative to the initial level. In the mdx mice, the concentration of VEGF remained stable at 86±8% (p<0.05). After 7 days, the VEGF-A concentration in normal mice returned to the initial value (99±4%) (Figure 6A), whereas in the mdx mice, the level of VEGF-A protein began to increase, reaching 135±9% (p<0.05) (Figure 6B). After 21 days, there was a clear difference between the 2 groups in terms of VEGF concentration. In control mice, the VEGF concentration remained at its initial level (103±7%) but had decreased in mdx mice (76±8%) (p<0.05).

Bottom Line: Duchenne muscular dystrophy (DMD) is a genetic neuromuscular disorder that affects skeletal muscles and cardiac muscle tissue.In the heart, the total level of VEGF depends on VEGF expression in myocardium, not in vessel endothelium, and our research demonstrates that the expression of VEGF is dystrophin-dependent.Disordered secretion of VEGF-A in hypoxic myocardium caused the total level of this factor to be impaired in the heart.

View Article: PubMed Central - PubMed

Affiliation: Department of Histology and Embryology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Torun, Poland. dareknowak15@wp.pl

ABSTRACT

Background: Duchenne muscular dystrophy (DMD) is a genetic neuromuscular disorder that affects skeletal muscles and cardiac muscle tissue. In some cases, myocardial injury secondary to hypoxia can lead to dilative cardiomyopathy (DCM). A genetic defect in the dystrophin gene may increase the susceptibility of myocardium to hypoxia. Available data suggest that this may be caused by impaired secretion of NO, which is bound with secretion of VEGF-A.

Material/methods: Male mice C57BI/10ScSn mdx (animal model of DMD) and healthy mice C57BI/10ScSn were exposed to hypobaric hypoxia in low-pressure chambers. Their hearts were harvested immediately after and 1, 3, 7, and 21 days after exposure to hypoxia. Normobaric mice were used as controls. The expression of VEGF-A in myocardium and cardiac vessel walls was evaluated using immunohistochemistry, Western blotting, and in situ hybridization.

Results: VEGF-A expression in myocardium and vessel walls of healthy mice peaked 24 hours after exposure to hypoxia. The expression of VEGF-A in vessel walls was similar in dystrophic and healthy mice; however, VEGF-A expression in the myocardium of dystrophic mice was impaired, peaking around day 7. In the heart, the total level of VEGF depends on VEGF expression in myocardium, not in vessel endothelium, and our research demonstrates that the expression of VEGF is dystrophin-dependent.

Conclusions: Disordered secretion of VEGF-A in hypoxic myocardium caused the total level of this factor to be impaired in the heart. This factor, which in normal situations protect against hypoxia, promotes the gradual progression of cardiomyopathy.

Show MeSH
Related in: MedlinePlus