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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) Western analysis of VEGF expression in the heart following hypoxia normal mice. Control group (1); immediately after (2); 1 day after (3); 3 days after (4); 7 days after (5), and 21 days after (6) hypoxia. (B) Western analysis of VEGF expression in the heart following hypobaric hypoxia in dystrophic mice. Control group (1); immediately after (2); 1 day after (3); 3 days after (4); 7 days after (5), and 21 days after (6) hypoxia. (C) Quantitative analysis of western blot signals in normal and mdx mice. Note the difference in the timing of maximum VEGF expression between normal and mdx mice. The control group signal is set to 100%. * Statistically significant compared to healthy mice. In each group was 10 mice.
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f2-medscimonit-17-11-br332: (A) Western analysis of VEGF expression in the heart following hypoxia normal mice. Control group (1); immediately after (2); 1 day after (3); 3 days after (4); 7 days after (5), and 21 days after (6) hypoxia. (B) Western analysis of VEGF expression in the heart following hypobaric hypoxia in dystrophic mice. Control group (1); immediately after (2); 1 day after (3); 3 days after (4); 7 days after (5), and 21 days after (6) hypoxia. (C) Quantitative analysis of western blot signals in normal and mdx mice. Note the difference in the timing of maximum VEGF expression between normal and mdx mice. The control group signal is set to 100%. * Statistically significant compared to healthy mice. In each group was 10 mice.

Mentions: There were significant differences in cardiac VEGF expression in response to hypoxia between mdx and normal mice (Figure 2). During the first days following hypoxia, expression of VEGF in the hearts of the control group did not differ from that observed in the hearts of the normal and mdx mice (102±3% vs. 99±4%, respectively) (p>0.05) (Figure 2C). Immediately after exposure to hypoxia, VEGF expression was 98±5% and 96±6% in normal and mdx mice, respectively (p>0.05). One day later, the changes in VEGF concentrations were similar in normal (168±8%) and mdx mice (172±9%) (p>0.05). Statistically significant differences became apparent on the third day following hypoxia (p<0.05). The decrease in VEGF expression was markedly greater among the mdx mice (113±7%) than the normal mice (133±5%) (p<0.05). This trend reversed on day 7 – VEGF expression in normal mice continued to decrease (107±5%), whereas it increased in mdx mice, reaching 147±6% (p<0.05). The differences between the groups were statistically significant. After day 21, VEGF expression began to decline in both groups, reaching its initial concentration in normal mice (104±6%) and falling below the initial concentration in mdx mice (70±4%) (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) Western analysis of VEGF expression in the heart following hypoxia normal mice. Control group (1); immediately after (2); 1 day after (3); 3 days after (4); 7 days after (5), and 21 days after (6) hypoxia. (B) Western analysis of VEGF expression in the heart following hypobaric hypoxia in dystrophic mice. Control group (1); immediately after (2); 1 day after (3); 3 days after (4); 7 days after (5), and 21 days after (6) hypoxia. (C) Quantitative analysis of western blot signals in normal and mdx mice. Note the difference in the timing of maximum VEGF expression between normal and mdx mice. The control group signal is set to 100%. * Statistically significant compared to healthy mice. In each group was 10 mice.
© Copyright Policy
Related In: Results  -  Collection

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

f2-medscimonit-17-11-br332: (A) Western analysis of VEGF expression in the heart following hypoxia normal mice. Control group (1); immediately after (2); 1 day after (3); 3 days after (4); 7 days after (5), and 21 days after (6) hypoxia. (B) Western analysis of VEGF expression in the heart following hypobaric hypoxia in dystrophic mice. Control group (1); immediately after (2); 1 day after (3); 3 days after (4); 7 days after (5), and 21 days after (6) hypoxia. (C) Quantitative analysis of western blot signals in normal and mdx mice. Note the difference in the timing of maximum VEGF expression between normal and mdx mice. The control group signal is set to 100%. * Statistically significant compared to healthy mice. In each group was 10 mice.
Mentions: There were significant differences in cardiac VEGF expression in response to hypoxia between mdx and normal mice (Figure 2). During the first days following hypoxia, expression of VEGF in the hearts of the control group did not differ from that observed in the hearts of the normal and mdx mice (102±3% vs. 99±4%, respectively) (p>0.05) (Figure 2C). Immediately after exposure to hypoxia, VEGF expression was 98±5% and 96±6% in normal and mdx mice, respectively (p>0.05). One day later, the changes in VEGF concentrations were similar in normal (168±8%) and mdx mice (172±9%) (p>0.05). Statistically significant differences became apparent on the third day following hypoxia (p<0.05). The decrease in VEGF expression was markedly greater among the mdx mice (113±7%) than the normal mice (133±5%) (p<0.05). This trend reversed on day 7 – VEGF expression in normal mice continued to decrease (107±5%), whereas it increased in mdx mice, reaching 147±6% (p<0.05). The differences between the groups were statistically significant. After day 21, VEGF expression began to decline in both groups, reaching its initial concentration in normal mice (104±6%) and falling below the initial concentration in mdx mice (70±4%) (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