| First Author | Nakamura Y | Year | 2020 |
| Journal | Am J Physiol Heart Circ Physiol | Volume | 318 |
| Issue | 2 | Pages | H238-H251 |
| PubMed ID | 31774689 | Mgi Jnum | J:293713 |
| Mgi Id | MGI:6450403 | Doi | 10.1152/ajpheart.00496.2019 |
| Citation | Nakamura Y, et al. (2020) A disintegrin and metalloproteinase 12 prevents heart failure by regulating cardiac hypertrophy and fibrosis. Am J Physiol Heart Circ Physiol 318(2):H238-H251 |
| abstractText | A disintegrin and metalloproteinase (ADAM)12 is considered to promote cardiac dysfunction based on the finding that a small-molecule ADAM12 inhibitor, KB-R7785, ameliorated cardiac function in a transverse aortic constriction (TAC) model by inhibiting the proteolytic activation of heparin-binding-EGF signaling. 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 integrinbeta1 subunit and transforming growth factor (TGF)-beta 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-beta signaling by regulating the abundance of the integrinbeta1 and TGF-beta receptors.NEW & 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. |
