| Content Provider |
World Health Organization (WHO)-Global Index Medicus |
| Author |
Gorham, Joshua M. Lee, Richard T. Burgon, Patrick G. O'meara, Caitlin C. Seidman, J. G. Onoue, Kenji Wakimoto, Hiroko Mcconnell, Bradley K. Seidman, Christine E. Jiang, Jianming Fomovsky, Gregory |
| Description |
Author Affiliation: Jiang J ( Department of Genetics, Harvard Medical School, Boston, MA 02115); Burgon PG ( Department of Genetics, Harvard Medical School, Boston, MA 02115); Wakimoto H ( Department of Genetics, Harvard Medical School, Boston, MA 02115); Onoue K ( Department of Genetics, Harvard Medical School, Boston, MA 02115); Gorham JM ( Department of Genetics, Harvard Medical School, Boston, MA 02115); O'Meara CC ( Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA 02115); Fomovsky G ( Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA 02115); McConnell BK ( Department of Genetics, Harvard Medical School, Boston, MA 02115); Lee RT ( Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA 02115); Seidman JG ( Department of Genetics, Harvard Medical School, Boston, MA 02115); Seidman CE ( Department of Genetics, Harvard Medical School, Boston, MA 02115); |
| Abstract |
Homozygous cardiac myosin binding protein C-deficient (Mybpc(t/t)) mice develop dramatic cardiac dilation shortly after birth; heart size increases almost twofold. We have investigated the mechanism of cardiac enlargement in these hearts. Throughout embryogenesis myocytes undergo cell division while maintaining the capacity to pump blood by rapidly disassembling and reforming myofibrillar components of the sarcomere throughout cell cycle progression. Shortly after birth, myocyte cell division ceases. Cardiac MYBPC is a thick filament protein that regulates sarcomere organization and rigidity. We demonstrate that many Mybpc(t/t) myocytes undergo an additional round of cell division within 10 d postbirth compared with their wild-type counterparts, leading to increased numbers of mononuclear myocytes. Short-hairpin RNA knockdown of Mybpc3 mRNA in wild-type mice similarly extended the postnatal window of myocyte proliferation. However, adult Mybpc(t/t) myocytes are unable to fully regenerate the myocardium after injury. MYBPC has unexpected inhibitory functions during postnatal myocyte cytokinesis and cell cycle progression. We suggest that human patients with homozygous MYBPC3-null mutations develop dilated cardiomyopathy, coupled with myocyte hyperplasia (increased cell number), as observed in Mybpc(t/t) mice. Human patients, with heterozygous truncating MYBPC3 mutations, like mice with similar mutations, have hypertrophic cardiomyopathy. However, the mechanism leading to hypertrophic cardiomyopathy in heterozygous MYBPC3(+/-) individuals is myocyte hypertrophy (increased cell size), whereas the mechanism leading to cardiac dilation in homozygous Mybpc3(-/-) mice is primarily myocyte hyperplasia. |
| ISSN |
00278424 |
| e-ISSN |
10916490 |
| Journal |
Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number |
29 |
| Volume Number |
112 |
| Language |
English |
| Publisher |
National Academy of Sciences |
| Publisher Date |
2015-07-01 |
| Publisher Place |
United States |
| Access Restriction |
Open |
| Subject Keyword |
Carrier Proteins Metabolism Cytokinesis Myocardium Myocytes, Cardiac Animals Animals, Newborn Aurora Kinases Biological Markers Calcium Cell Count Cell Differentiation Cell Proliferation Dependovirus Endothelial Cells Gene Expression Regulation Heart Ventricles Histones Indoles Mice Models, Biological Cytology Phosphorylation RNA, Small Interfering Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type |
Text |
| Resource Type |
Article |
| Subject |
Multidisciplinary |
