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The impact of juvenile coxsackievirus infection on cardiac progenitor cells and postnatal heart development.

Sin J, Puccini JM, Huang C, Konstandin MH, Gilbert PE, Sussman MA, Gottlieb RA, Feuer R - PLoS Pathog. (2014)

Bottom Line: Chronic consequences of mild CVB infection are unknown, though there is an epidemiologic association between early subclinical infections and late heart failure, raising the possibility of subtle damage leading to late-onset dysfunction, or chronic ongoing injury due to inflammatory reactions during latent infection.Moreover, CVB3 efficiently infected juvenile c-kit+ cells, and cardiac progenitor cell numbers were reduced in the hearts of juvenile-infected adult mice.These results suggest that the exhausted cardiac progenitor cell pool following juvenile CVB3 infection may impair the heart's ability to increase capillary density to adapt to increased load.

View Article: PubMed Central - PubMed

Affiliation: Donald P. Shiley BioScience Center, San Diego State University, San Diego, California, United States of America.

ABSTRACT
Coxsackievirus B (CVB) is an enterovirus that most commonly causes a self-limited febrile illness in infants, but cases of severe infection can manifest in acute myocarditis. Chronic consequences of mild CVB infection are unknown, though there is an epidemiologic association between early subclinical infections and late heart failure, raising the possibility of subtle damage leading to late-onset dysfunction, or chronic ongoing injury due to inflammatory reactions during latent infection. Here we describe a mouse model of juvenile infection with a subclinical dose of coxsackievirus B3 (CVB3) which showed no evident symptoms, either immediately following infection or in adult mice. However following physiological or pharmacologically-induced cardiac stress, juvenile-infected adult mice underwent cardiac hypertrophy and dilation indicative of progression to heart failure. Evaluation of the vasculature in the hearts of adult mice subjected to cardiac stress showed a compensatory increase in CD31+ blood vessel formation, although this effect was suppressed in juvenile-infected mice. Moreover, CVB3 efficiently infected juvenile c-kit+ cells, and cardiac progenitor cell numbers were reduced in the hearts of juvenile-infected adult mice. These results suggest that the exhausted cardiac progenitor cell pool following juvenile CVB3 infection may impair the heart's ability to increase capillary density to adapt to increased load.

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Impaired vascular remodeling following beta-adrenergic stimulation-induced cardiac hypertrophy in adult mice infected with CVB3 at an early age.Three day-old mice were infected with eGFP-CVB3 (105 pfu IP) or mock-infected. After 13 weeks, a 10 day treatment with ISO was used to induce physiologic hypertrophy in infected or mock-infected mice. (A) Vascular changes were evaluated in the adult heart by immunostaining for CD31 (endothelial cell marker). A significant increase in CD31 staining was seen in mock-infected mice following ISO treatment (*p<0.05; two-way ANOVA). A Newman Keuls post hoc comparison test of the group×treatment interaction revealed that CD31 staining was significantly higher in the mock ISO group {6.36 (.13)} compared to the mock vehicle group {5.49 (.18)}. In contrast, a significant decrease in CD31 staining was observed in infected mice compared to mock-infected mice following ISO treatment (**p<0.01; two-way ANOVA). (B) A decrease in VEGF protein expression (western blot analysis) was observed in ISO-treated CVB3-infected mice (*p<0.05; Student's T-test). (C), (D) Heart sections from vehicle only controls and immunostained for CD31 showed no differences between mock-infected and CVB3-infected mice. (E) CD31 staining and vascularization near sites of fibrosis (Masson trichrome staining) was observed following ISO treatment in mock-infected mice. Regions of fibrosis were outlined in light purple. CD31 staining (light blue arrows) associated with vascularization (light yellow arrows) was observed at higher magnification. (F) In contrast, less CD31 staining and limited vascularization was seen following ISO treatment in CVB3-infected mice.
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ppat-1004249-g008: Impaired vascular remodeling following beta-adrenergic stimulation-induced cardiac hypertrophy in adult mice infected with CVB3 at an early age.Three day-old mice were infected with eGFP-CVB3 (105 pfu IP) or mock-infected. After 13 weeks, a 10 day treatment with ISO was used to induce physiologic hypertrophy in infected or mock-infected mice. (A) Vascular changes were evaluated in the adult heart by immunostaining for CD31 (endothelial cell marker). A significant increase in CD31 staining was seen in mock-infected mice following ISO treatment (*p<0.05; two-way ANOVA). A Newman Keuls post hoc comparison test of the group×treatment interaction revealed that CD31 staining was significantly higher in the mock ISO group {6.36 (.13)} compared to the mock vehicle group {5.49 (.18)}. In contrast, a significant decrease in CD31 staining was observed in infected mice compared to mock-infected mice following ISO treatment (**p<0.01; two-way ANOVA). (B) A decrease in VEGF protein expression (western blot analysis) was observed in ISO-treated CVB3-infected mice (*p<0.05; Student's T-test). (C), (D) Heart sections from vehicle only controls and immunostained for CD31 showed no differences between mock-infected and CVB3-infected mice. (E) CD31 staining and vascularization near sites of fibrosis (Masson trichrome staining) was observed following ISO treatment in mock-infected mice. Regions of fibrosis were outlined in light purple. CD31 staining (light blue arrows) associated with vascularization (light yellow arrows) was observed at higher magnification. (F) In contrast, less CD31 staining and limited vascularization was seen following ISO treatment in CVB3-infected mice.

Mentions: To examine if cardiac vasculature was affected by loss of progenitor cells due to prior CVB3 infection, we stained heart sections from ISO-treated animals for the blood vessel marker, CD31. In mice treated with vehicle alone, no significant differences in CD31+ blood vessel density was observed between infected and mock-infected animals (Figure 8A). As expected, treatment with ISO in mock-infected mice resulted in increased CD31 expression consistent with increased vascular remodeling in response to the increased workload imposed by beta adrenergic stress (*p<0.05). In contrast, no corresponding increase in CD31 expression was observed in juvenile-infected mice after ISO exposure (**p<0.01). These data indicate that under increased load, the heart remodels its vasculature to meet demand, but juvenile CVB3 infection impairs this compensatory function.


The impact of juvenile coxsackievirus infection on cardiac progenitor cells and postnatal heart development.

Sin J, Puccini JM, Huang C, Konstandin MH, Gilbert PE, Sussman MA, Gottlieb RA, Feuer R - PLoS Pathog. (2014)

Impaired vascular remodeling following beta-adrenergic stimulation-induced cardiac hypertrophy in adult mice infected with CVB3 at an early age.Three day-old mice were infected with eGFP-CVB3 (105 pfu IP) or mock-infected. After 13 weeks, a 10 day treatment with ISO was used to induce physiologic hypertrophy in infected or mock-infected mice. (A) Vascular changes were evaluated in the adult heart by immunostaining for CD31 (endothelial cell marker). A significant increase in CD31 staining was seen in mock-infected mice following ISO treatment (*p<0.05; two-way ANOVA). A Newman Keuls post hoc comparison test of the group×treatment interaction revealed that CD31 staining was significantly higher in the mock ISO group {6.36 (.13)} compared to the mock vehicle group {5.49 (.18)}. In contrast, a significant decrease in CD31 staining was observed in infected mice compared to mock-infected mice following ISO treatment (**p<0.01; two-way ANOVA). (B) A decrease in VEGF protein expression (western blot analysis) was observed in ISO-treated CVB3-infected mice (*p<0.05; Student's T-test). (C), (D) Heart sections from vehicle only controls and immunostained for CD31 showed no differences between mock-infected and CVB3-infected mice. (E) CD31 staining and vascularization near sites of fibrosis (Masson trichrome staining) was observed following ISO treatment in mock-infected mice. Regions of fibrosis were outlined in light purple. CD31 staining (light blue arrows) associated with vascularization (light yellow arrows) was observed at higher magnification. (F) In contrast, less CD31 staining and limited vascularization was seen following ISO treatment in CVB3-infected mice.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4117602&req=5

ppat-1004249-g008: Impaired vascular remodeling following beta-adrenergic stimulation-induced cardiac hypertrophy in adult mice infected with CVB3 at an early age.Three day-old mice were infected with eGFP-CVB3 (105 pfu IP) or mock-infected. After 13 weeks, a 10 day treatment with ISO was used to induce physiologic hypertrophy in infected or mock-infected mice. (A) Vascular changes were evaluated in the adult heart by immunostaining for CD31 (endothelial cell marker). A significant increase in CD31 staining was seen in mock-infected mice following ISO treatment (*p<0.05; two-way ANOVA). A Newman Keuls post hoc comparison test of the group×treatment interaction revealed that CD31 staining was significantly higher in the mock ISO group {6.36 (.13)} compared to the mock vehicle group {5.49 (.18)}. In contrast, a significant decrease in CD31 staining was observed in infected mice compared to mock-infected mice following ISO treatment (**p<0.01; two-way ANOVA). (B) A decrease in VEGF protein expression (western blot analysis) was observed in ISO-treated CVB3-infected mice (*p<0.05; Student's T-test). (C), (D) Heart sections from vehicle only controls and immunostained for CD31 showed no differences between mock-infected and CVB3-infected mice. (E) CD31 staining and vascularization near sites of fibrosis (Masson trichrome staining) was observed following ISO treatment in mock-infected mice. Regions of fibrosis were outlined in light purple. CD31 staining (light blue arrows) associated with vascularization (light yellow arrows) was observed at higher magnification. (F) In contrast, less CD31 staining and limited vascularization was seen following ISO treatment in CVB3-infected mice.
Mentions: To examine if cardiac vasculature was affected by loss of progenitor cells due to prior CVB3 infection, we stained heart sections from ISO-treated animals for the blood vessel marker, CD31. In mice treated with vehicle alone, no significant differences in CD31+ blood vessel density was observed between infected and mock-infected animals (Figure 8A). As expected, treatment with ISO in mock-infected mice resulted in increased CD31 expression consistent with increased vascular remodeling in response to the increased workload imposed by beta adrenergic stress (*p<0.05). In contrast, no corresponding increase in CD31 expression was observed in juvenile-infected mice after ISO exposure (**p<0.01). These data indicate that under increased load, the heart remodels its vasculature to meet demand, but juvenile CVB3 infection impairs this compensatory function.

Bottom Line: Chronic consequences of mild CVB infection are unknown, though there is an epidemiologic association between early subclinical infections and late heart failure, raising the possibility of subtle damage leading to late-onset dysfunction, or chronic ongoing injury due to inflammatory reactions during latent infection.Moreover, CVB3 efficiently infected juvenile c-kit+ cells, and cardiac progenitor cell numbers were reduced in the hearts of juvenile-infected adult mice.These results suggest that the exhausted cardiac progenitor cell pool following juvenile CVB3 infection may impair the heart's ability to increase capillary density to adapt to increased load.

View Article: PubMed Central - PubMed

Affiliation: Donald P. Shiley BioScience Center, San Diego State University, San Diego, California, United States of America.

ABSTRACT
Coxsackievirus B (CVB) is an enterovirus that most commonly causes a self-limited febrile illness in infants, but cases of severe infection can manifest in acute myocarditis. Chronic consequences of mild CVB infection are unknown, though there is an epidemiologic association between early subclinical infections and late heart failure, raising the possibility of subtle damage leading to late-onset dysfunction, or chronic ongoing injury due to inflammatory reactions during latent infection. Here we describe a mouse model of juvenile infection with a subclinical dose of coxsackievirus B3 (CVB3) which showed no evident symptoms, either immediately following infection or in adult mice. However following physiological or pharmacologically-induced cardiac stress, juvenile-infected adult mice underwent cardiac hypertrophy and dilation indicative of progression to heart failure. Evaluation of the vasculature in the hearts of adult mice subjected to cardiac stress showed a compensatory increase in CD31+ blood vessel formation, although this effect was suppressed in juvenile-infected mice. Moreover, CVB3 efficiently infected juvenile c-kit+ cells, and cardiac progenitor cell numbers were reduced in the hearts of juvenile-infected adult mice. These results suggest that the exhausted cardiac progenitor cell pool following juvenile CVB3 infection may impair the heart's ability to increase capillary density to adapt to increased load.

Show MeSH
Related in: MedlinePlus