Key result
ADAM12 knockout mice showed significantly more advanced cardiac hypertrophy, higher mortality rates, and expanded cardiac fibrosis than wild-type mice 4 weeks after transverse aortic constriction.
Why the study?
Small-molecule inhibitors suggested ADAM12 promotes cardiac dysfunction, but compounds lack selectivity and the role of ADAM12 had not been investigated using genetic loss-of-function mice.
Genetic loss of ADAM12 exacerbates cardiac hypertrophy, fibrosis, and mortality in a pressure overload mouse model, suggesting a protective rather than damaging role in heart failure.
Challenges prior nonselective inhibitor data in TAC; leaves open ADAM12's role in cardiac dysfunction.
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 integrinβ1 subunit and transforming growth factor (TGF)-β 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-β signaling by regulating the abundance of the integrinβ1 and TGF-β 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.
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Nakamura et al. (2019) studied Cardiac hypertrophy and heart failure. ADAM12 knockout vs. Wild-type mice was evaluated on Cardiac hypertrophy, mortality, and cardiac fibrosis. ADAM12 knockout mice showed significantly more advanced cardiac hypertrophy, higher mortality rates, and expanded cardiac fibrosis than wild-type mice 4 weeks after transverse aortic constriction.
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