Journal
CELL DEATH & DISEASE
Volume 5, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/cddis.2014.181
Keywords
PLC; cardiomyocyte; cardiac dilation; remodeling
Categories
Funding
- Takeda Science Foundation
- Medical Research Foundation
- Uehara Memorial Foundation
- Japan Society of the Promotion of Sciences
- Funding Program for Next Generation World-Leading Researchers
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Ono Medical Research Foundation
- Grants-in-Aid for Scientific Research [23590115, 26293071, 11J08751, 26650038] Funding Source: KAKEN
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Phospholipase C (PLC) is a key enzyme in phosphoinositide turnover. Among 13 PLC isozymes, PLC delta 1 and PLC delta 3 share high sequence homology and similar tissue distribution, and are expected to have functional redundancy in many tissues. We previously reported that the simultaneous loss of PLC delta 1 and PLC delta 3 caused embryonic lethality because of excessive apoptosis and impaired vascularization of the placenta. Prenatal death of PLC delta 1/PLC delta 3 double-knockout mice hampered our investigation of the roles of these genes in adult animals. Here, we generated PLC delta 1/PLC delta 3 double-knockout mice that expressed PLC delta 1 in extra-embryonic tissues (cDKO mice) to escape embryonic lethality. The cDKO mice were born at the expected Mendelian ratio, which indicated that the simultaneous loss of PLC delta 1 and PLC delta 3 in the embryo proper did not impair embryonic development. However, half of the cDKO mice died prematurely. In addition, the surviving cDKO mice spontaneously showed cardiac abnormalities, such as increased heart weight/tibial length ratios, impaired cardiac function, cardiac fibrosis, dilation, and hypertrophy. Predating these abnormalities, excessive apoptosis of their cardiomyocytes was observed. In addition, siRNA-mediated simultaneous silencing of PLC delta 1 and PLC delta 3 increased apoptosis in differentiated-H9c2 cardiomyoblasts. Activation of Akt and protein kinase C (PKC) theta was impaired in the hearts of the cDKO mice. siRNA-mediated simultaneous silencing of PLC delta 1 and PLC delta 3 also decreased activated Akt and PKC theta in differentiated-H9c2 cardiomyoblasts. These results indicate that PLC delta 1 and PLC delta 3 are required for cardiomyocyte survival and normal cardiac function.
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