A Disintegrin and Metalloproteinase 12 prevents heart failure by regulating cardiac hypertrophy and fibrosis.

A Disintegrin and Metalloproteinase 12 prevents heart failure by regulating cardiac hypertrophy and fibrosis. Am J Physiol Heart Circ Physiol. 2019 Nov 27;: Authors: Nakamura Y, Kita S, Tanaka Y, Fukuda S, Obata Y, Okita T, Kawachi Y, Tsugawa-Shimizu Y, Fujishima Y, Nishizawa H, Miyagawa S, Sawa Y, Sehara-Fujisawa A, Maeda N, Shimomura I Abstract 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 HB-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 weeks 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 TGF-β receptor types I and III, and this was followed by the phosphorylation...
Source: American Journal of Physiology. Heart and Circulatory Physiology - Category: Physiology Authors: Tags: Am J Physiol Heart Circ Physiol Source Type: research