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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 rate of cardiomyocytes in iVSD hearts is comparable to control hearts, while proliferating non-cardiomyocytes are significantly reduced in iVSD hearts.Flow cytometry analysis showed that the percentage of Ki67-positive cardiomyocytes was similar in hearts of iVSD patients compared to control hearts and that Ki67-positive non-cardiomyocytes were significantly reduced in iVSD patients compared to control hearts. (A) Representative Ki67-positive cells in control 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<0.01.
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pone.0139712.g005: Proliferation rate of cardiomyocytes in iVSD hearts is comparable to control hearts, while proliferating non-cardiomyocytes are significantly reduced in iVSD hearts.Flow cytometry analysis showed that the percentage of Ki67-positive cardiomyocytes was similar in hearts of iVSD patients compared to control hearts and that Ki67-positive non-cardiomyocytes were significantly reduced in iVSD patients compared to control hearts. (A) Representative Ki67-positive cells in control 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<0.01.

Mentions: Because YAP1 has been shown to affect cardiac cell proliferation and contributes to ventricular septal closure in mice, we compared cardiac cell proliferation in iVSD hearts to control hearts to determine whether YAP1 was still functional in the postnatal period. We chose to analyze Ki67 expression because Ki67 is present during all active phases of the cell cycle (G1, S, G2 and mitosis), which makes it an excellent marker of proliferation. Using flow cytometry, the number of proliferating cardiomyocytes was assessed in both groups. Based on the combination of Ki67- and troponin-positive staining, the number of proliferating cardiomyocytes (Fig 5) were similar in the iVSD group compared to the control group (14 ±6 in iVSD vs. 20±8 in control group; p = ns). A total of 10,124 ±2452 cells were counted from the iVSD group (n = 20), and 12,344 ±3463 cells were counted from the normal group (n = 6) (The percentage of Ki67-positive cardiomyocytes in iVSD group and control group were 0.11± 0.02 and 0.12 ± 0.02, respectively; p = ns). For Ki67-positive non- cardiomyocytes, in the iVSD group 12 ±4 and normal control 41 ±6 cells were counted (p<0.01) (The percentage of Ki67-positive non-cardiomyocytes in iVSD group and control group were 0.13± 0.02 and 0.38 ± 0.06, respectively; p<0.01). The results indicate that YAP1 expression primarily affected the non- cardiomyocyte cell proliferation activity in the postnatal iVSD heart.


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 rate of cardiomyocytes in iVSD hearts is comparable to control hearts, while proliferating non-cardiomyocytes are significantly reduced in iVSD hearts.Flow cytometry analysis showed that the percentage of Ki67-positive cardiomyocytes was similar in hearts of iVSD patients compared to control hearts and that Ki67-positive non-cardiomyocytes were significantly reduced in iVSD patients compared to control hearts. (A) Representative Ki67-positive cells in control 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<0.01.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0139712.g005: Proliferation rate of cardiomyocytes in iVSD hearts is comparable to control hearts, while proliferating non-cardiomyocytes are significantly reduced in iVSD hearts.Flow cytometry analysis showed that the percentage of Ki67-positive cardiomyocytes was similar in hearts of iVSD patients compared to control hearts and that Ki67-positive non-cardiomyocytes were significantly reduced in iVSD patients compared to control hearts. (A) Representative Ki67-positive cells in control 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<0.01.
Mentions: Because YAP1 has been shown to affect cardiac cell proliferation and contributes to ventricular septal closure in mice, we compared cardiac cell proliferation in iVSD hearts to control hearts to determine whether YAP1 was still functional in the postnatal period. We chose to analyze Ki67 expression because Ki67 is present during all active phases of the cell cycle (G1, S, G2 and mitosis), which makes it an excellent marker of proliferation. Using flow cytometry, the number of proliferating cardiomyocytes was assessed in both groups. Based on the combination of Ki67- and troponin-positive staining, the number of proliferating cardiomyocytes (Fig 5) were similar in the iVSD group compared to the control group (14 ±6 in iVSD vs. 20±8 in control group; p = ns). A total of 10,124 ±2452 cells were counted from the iVSD group (n = 20), and 12,344 ±3463 cells were counted from the normal group (n = 6) (The percentage of Ki67-positive cardiomyocytes in iVSD group and control group were 0.11± 0.02 and 0.12 ± 0.02, respectively; p = ns). For Ki67-positive non- cardiomyocytes, in the iVSD group 12 ±4 and normal control 41 ±6 cells were counted (p<0.01) (The percentage of Ki67-positive non-cardiomyocytes in iVSD group and control group were 0.13± 0.02 and 0.38 ± 0.06, respectively; p<0.01). The results indicate that YAP1 expression primarily affected the non- cardiomyocyte cell proliferation activity in the postnatal iVSD heart.

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