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However, this compound has poor selectivity for ADAM12, and the role of ADAM12 in cardiac dysfunction has not yet been investigated using genetic loss-of-function mice. We revealed that ADAM12 knockout mice showed significantly more advanced cardiac hypertrophy and higher mortality rates than wild-type mice 4 wk after TAC surgery. An ADAM12 deficiency resulted in significantly more expanded cardiac fibrosis accompanied by increased collagen-related gene expression in failing hearts. The results of a genome-wide transcriptional analysis suggested a strongly enhanced focal adhesion- and fibrosis-related signaling pathway in ADAM12 knockout hearts. The loss of ADAM12 increased the abundance of the integrin\u03b21 subunit and transforming growth factor (TGF)-\u03b2 receptor types I and III, and this was followed by the phosphorylation of focal adhesion kinase, Akt, mammalian target of rapamycin, ERK, and Smad2\/3 in the heart, which resulted in cardiac dysfunction. The present results revealed that the loss of ADAM12 enhanced focal adhesion and canonical TGF-\u03b2 signaling by regulating the abundance of the integrin\u03b21 and TGF-\u03b2 receptors. <\/jats:p><jats:p> NEW &amp; NOTEWORTHY In contrast to a long-believed cardio-damaging role of a disintegrin and metalloproteinase (ADAM)12, cardiac hypertrophy was more severe, cardiac function was lower, and mortality was higher in ADAM12 knockout mice than in wild-type mice after transverse aortic constriction surgery. The loss of ADAM12 enhanced focal adhesion- and fibrosis-related signaling pathways in the heart, which may compromise cardiac function. These results provide insights for the development of novel therapeutics that target ADAM12 to treat heart failure. <\/jats:p>","DOI":"10.1152\/ajpheart.00496.2019","type":"journal-article","created":{"date-parts":[[2019,11,27]],"date-time":"2019-11-27T13:06:26Z","timestamp":1574859986000},"page":"H238-H251","source":"Crossref","is-referenced-by-count":28,"title":["A disintegrin and metalloproteinase 12 prevents heart failure by regulating cardiac hypertrophy and fibrosis"],"prefix":"10.1152","volume":"318","author":[{"given":"Yuto","family":"Nakamura","sequence":"first","affiliation":[{"name":"Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan"},{"name":"Tokyo New Drug Laboratories, Kowa Company, Limited, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8937-0053","authenticated-orcid":false,"given":"Shunbun","family":"Kita","sequence":"additional","affiliation":[{"name":"Department 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