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Among 13 PLC isozymes, PLC<jats:italic>\u03b4<\/jats:italic>1 and PLC<jats:italic>\u03b4<\/jats:italic>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<jats:italic>\u03b4<\/jats:italic>1 and PLC<jats:italic>\u03b4<\/jats:italic>3 caused embryonic lethality because of excessive apoptosis and impaired vascularization of the placenta. Prenatal death of PLC<jats:italic>\u03b4<\/jats:italic>1\/PLC<jats:italic>\u03b4<\/jats:italic>3 double-knockout mice hampered our investigation of the roles of these genes in adult animals. Here, we generated PLC<jats:italic>\u03b4<\/jats:italic>1\/PLC<jats:italic>\u03b4<\/jats:italic>3 double-knockout mice that expressed PLC<jats:italic>\u03b4<\/jats:italic>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<jats:italic>\u03b4<\/jats:italic>1 and PLC<jats:italic>\u03b4<\/jats:italic>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<jats:italic>\u03b4<\/jats:italic>1 and PLC<jats:italic>\u03b4<\/jats:italic>3 increased apoptosis in differentiated-H9c2 cardiomyoblasts. Activation of Akt and protein kinase C (PKC) <jats:italic>\u03b8<\/jats:italic> was impaired in the hearts of the cDKO mice. siRNA-mediated simultaneous silencing of PLC<jats:italic>\u03b4<\/jats:italic>1 and PLC<jats:italic>\u03b4<\/jats:italic>3 also decreased activated Akt and PKC<jats:italic>\u03b8<\/jats:italic> in differentiated-H9c2 cardiomyoblasts. These results indicate that PLC<jats:italic>\u03b4<\/jats:italic>1 and PLC<jats:italic>\u03b4<\/jats:italic>3 are required for cardiomyocyte survival and normal cardiac function.<\/jats:p>","DOI":"10.1038\/cddis.2014.181","type":"journal-article","created":{"date-parts":[[2014,5,8]],"date-time":"2014-05-08T12:59:47Z","timestamp":1399553987000},"page":"e1215-e1215","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Simultaneous loss of phospholipase C\u03b41 and phospholipase C\u03b43 causes cardiomyocyte apoptosis and cardiomyopathy"],"prefix":"10.1038","volume":"5","author":[{"given":"Y","family":"Nakamura","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K","family":"Kanemaru","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R","family":"Kojima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y","family":"Hashimoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T","family":"Marunouchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N","family":"Oka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T","family":"Ogura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K","family":"Tanonaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K","family":"Fukami","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2014,5,8]]},"reference":[{"key":"BFcddis2014181_CR1","doi-asserted-by":"publisher","first-page":"856","DOI":"10.1161\/01.RES.85.9.856","volume":"85","author":"S Guerra","year":"1999","unstructured":"Guerra S, Leri A, Wang X, Finato N, Di Loreto C, Beltrami CA et al. 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