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Decreased Yes-Associated Protein-1 (YAP1) Expression in Pediatric Hearts with Ventricular Septal Defects.

Ye L, Yin M, Xia Y, Jiang C, Hong H, Liu J - PLoS ONE (2015)

Bottom Line: Animal studies have suggested that the downregulation of Yes-associated protein 1 (YAP1) during embryonic development causes VSD-associated CHDs.However, how YAP1 contributes to isolated VSD (iVSD) is unclear.Concomitantly, mRNA levels of YAP1 downstream targets CTGF and AXL were also significantly decreased in iVSD specimens.

View Article: PubMed Central - PubMed

Affiliation: Department of Thoracic and Cardiovascular Surgery, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China; Institute of Pediatric Translational Medicine, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China; Shanghai Pediatric Congenital Heart Disease Institute, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China.

ABSTRACT

Background: Ventricular septal defects (VSDs) are the most common and simplest type of congenital heart diseases (CHDs). Animal studies have suggested that the downregulation of Yes-associated protein 1 (YAP1) during embryonic development causes VSD-associated CHDs. However, how YAP1 contributes to isolated VSD (iVSD) is unclear.

Methods and results: Twenty right atrial specimens were obtained from iVSD patients during routine congenital cardiac surgery and we assessed YAP1 expression in these specimens. For controls, six right atrial specimens were obtained from normal hearts of children without heart disease, three of whom died from cerebral palsy, and three who underwent heart transplants. YAP1 mRNA and protein levels and nuclear localization were significantly reduced in iVSD specimens compared to normal heart specimens. Concomitantly, mRNA levels of YAP1 downstream targets CTGF and AXL were also significantly decreased in iVSD specimens. Although Ki67-positive cardiomyocytes in iVSD specimens were comparable to normal heart specimens, Ki67-positive non-cardiomyocytes were significantly decreased.

Conclusions: YAP1 expression was markedly decreased in hearts of iVSD children. Given the important role of YAP1 during heart development, downregulation of YAP1 expression may contribute to iVSD and affect the proliferation of non-cardiomyocytes.

No MeSH data available.


Related in: MedlinePlus

Proliferation of iVSD cardiomyocytes analyzed via confocal microscopy.Confocal microscopy of tissue sections using Ki67 and troponin indicate that non-cardiomyocyte cell proliferation is decreased in iVSD tissues compared to controls. (A) Representative Ki67-positive cells in normal hearts. (B) Representative Ki67-positive cells in iVSD hearts. (C) Quantification of Ki67-positive cardiomyocytes. (D) Quantification of Ki67-positive non-cardiomyocytes (iVSD group: n = 20; control group: n = 6. Data presented as means ± SD; ***p<0.001. Cardiac troponin T (red), Ki67 (green), and DAPI (blue) staining are shown. Arrow indicates proliferating cardiomyocytes and the triangle indicates non-cardiomyocytes.
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pone.0139712.g006: Proliferation of iVSD cardiomyocytes analyzed via confocal microscopy.Confocal microscopy of tissue sections using Ki67 and troponin indicate that non-cardiomyocyte cell proliferation is decreased in iVSD tissues compared to controls. (A) Representative Ki67-positive cells in normal hearts. (B) Representative Ki67-positive cells in iVSD hearts. (C) Quantification of Ki67-positive cardiomyocytes. (D) Quantification of Ki67-positive non-cardiomyocytes (iVSD group: n = 20; control group: n = 6. Data presented as means ± SD; ***p<0.001. Cardiac troponin T (red), Ki67 (green), and DAPI (blue) staining are shown. Arrow indicates proliferating cardiomyocytes and the triangle indicates non-cardiomyocytes.

Mentions: To confirm the flow cytometry data, we quantified proliferating cardiomyocytes in tissue sections using confocal microscopy. Data revealed that the percentage of Ki67-positive cardiomyocytes in normal and iVSD hearts were 0.11 ± 0.05 (number of Ki67- positive cardiomyocytes: 9±3, number of total counted cells: 9782±1873, n = 20) and 0.10 ± 0.02 (number of Ki67- positive cardiomyocytes: 8±2, number of total counted cells: 9886±1451, n = 6), respectively (p = ns), while the percentage of Ki67-positive non-cardiomyocytes in both groups were 0.35 ± 0.05 (number of Ki67- positive non-cardiomyocytes: 33±5) and 0.12 ± 0.02 (number of Ki67- positive non-cardiomyocytes: 12±4), respectively (p < 0.01; Fig 6). Proliferating cells measured with staining correlated well with flow cytometry data from isolated cardiac cells, confirming that non-cardiomyocyte proliferation activity was reduced significantly in iVSD patients.


Decreased Yes-Associated Protein-1 (YAP1) Expression in Pediatric Hearts with Ventricular Septal Defects.

Ye L, Yin M, Xia Y, Jiang C, Hong H, Liu J - PLoS ONE (2015)

Proliferation of iVSD cardiomyocytes analyzed via confocal microscopy.Confocal microscopy of tissue sections using Ki67 and troponin indicate that non-cardiomyocyte cell proliferation is decreased in iVSD tissues compared to controls. (A) Representative Ki67-positive cells in normal hearts. (B) Representative Ki67-positive cells in iVSD hearts. (C) Quantification of Ki67-positive cardiomyocytes. (D) Quantification of Ki67-positive non-cardiomyocytes (iVSD group: n = 20; control group: n = 6. Data presented as means ± SD; ***p<0.001. Cardiac troponin T (red), Ki67 (green), and DAPI (blue) staining are shown. Arrow indicates proliferating cardiomyocytes and the triangle indicates non-cardiomyocytes.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4591351&req=5

pone.0139712.g006: Proliferation of iVSD cardiomyocytes analyzed via confocal microscopy.Confocal microscopy of tissue sections using Ki67 and troponin indicate that non-cardiomyocyte cell proliferation is decreased in iVSD tissues compared to controls. (A) Representative Ki67-positive cells in normal hearts. (B) Representative Ki67-positive cells in iVSD hearts. (C) Quantification of Ki67-positive cardiomyocytes. (D) Quantification of Ki67-positive non-cardiomyocytes (iVSD group: n = 20; control group: n = 6. Data presented as means ± SD; ***p<0.001. Cardiac troponin T (red), Ki67 (green), and DAPI (blue) staining are shown. Arrow indicates proliferating cardiomyocytes and the triangle indicates non-cardiomyocytes.
Mentions: To confirm the flow cytometry data, we quantified proliferating cardiomyocytes in tissue sections using confocal microscopy. Data revealed that the percentage of Ki67-positive cardiomyocytes in normal and iVSD hearts were 0.11 ± 0.05 (number of Ki67- positive cardiomyocytes: 9±3, number of total counted cells: 9782±1873, n = 20) and 0.10 ± 0.02 (number of Ki67- positive cardiomyocytes: 8±2, number of total counted cells: 9886±1451, n = 6), respectively (p = ns), while the percentage of Ki67-positive non-cardiomyocytes in both groups were 0.35 ± 0.05 (number of Ki67- positive non-cardiomyocytes: 33±5) and 0.12 ± 0.02 (number of Ki67- positive non-cardiomyocytes: 12±4), respectively (p < 0.01; Fig 6). Proliferating cells measured with staining correlated well with flow cytometry data from isolated cardiac cells, confirming that non-cardiomyocyte proliferation activity was reduced significantly in iVSD patients.

Bottom Line: Animal studies have suggested that the downregulation of Yes-associated protein 1 (YAP1) during embryonic development causes VSD-associated CHDs.However, how YAP1 contributes to isolated VSD (iVSD) is unclear.Concomitantly, mRNA levels of YAP1 downstream targets CTGF and AXL were also significantly decreased in iVSD specimens.

View Article: PubMed Central - PubMed

Affiliation: Department of Thoracic and Cardiovascular Surgery, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China; Institute of Pediatric Translational Medicine, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China; Shanghai Pediatric Congenital Heart Disease Institute, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China.

ABSTRACT

Background: Ventricular septal defects (VSDs) are the most common and simplest type of congenital heart diseases (CHDs). Animal studies have suggested that the downregulation of Yes-associated protein 1 (YAP1) during embryonic development causes VSD-associated CHDs. However, how YAP1 contributes to isolated VSD (iVSD) is unclear.

Methods and results: Twenty right atrial specimens were obtained from iVSD patients during routine congenital cardiac surgery and we assessed YAP1 expression in these specimens. For controls, six right atrial specimens were obtained from normal hearts of children without heart disease, three of whom died from cerebral palsy, and three who underwent heart transplants. YAP1 mRNA and protein levels and nuclear localization were significantly reduced in iVSD specimens compared to normal heart specimens. Concomitantly, mRNA levels of YAP1 downstream targets CTGF and AXL were also significantly decreased in iVSD specimens. Although Ki67-positive cardiomyocytes in iVSD specimens were comparable to normal heart specimens, Ki67-positive non-cardiomyocytes were significantly decreased.

Conclusions: YAP1 expression was markedly decreased in hearts of iVSD children. Given the important role of YAP1 during heart development, downregulation of YAP1 expression may contribute to iVSD and affect the proliferation of non-cardiomyocytes.

No MeSH data available.


Related in: MedlinePlus