A disintegrin and metalloproteinase 12 prevents heart failure by regulating cardiac hypertrophy and fibrosis

Author:

Nakamura Yuto12,Kita Shunbun13ORCID,Tanaka Yoshimitsu1,Fukuda Shiro1,Obata Yoshinari1,Okita Tomonori1,Kawachi Yusuke1,Tsugawa-Shimizu Yuri1,Fujishima Yuya1ORCID,Nishizawa Hitoshi1,Miyagawa Shigeru4,Sawa Yoshiki45,Sehara-Fujisawa Atsuko6,Maeda Norikazu17,Shimomura Iichiro1

Affiliation:

1. Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan

2. Tokyo New Drug Laboratories, Kowa Company, Limited, Tokyo, Japan

3. Department of Adipose Management, Graduate School of Medicine, Osaka University, Osaka, Japan

4. Department of Cardiovascular Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan

5. Medical Center for Translational Research, Osaka University Hospital, Osaka, Japan

6. Department of Growth Regulation, Institute for Frontier 11 Medical Sciences, Kyoto University, Kyoto, Japan

7. Department of Metabolism and Atherosclerosis, Graduate School of Medicine, Osaka University, Osaka, Japan

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 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.

Funder

Japan Science and Technology Agency

Publisher

American Physiological Society

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine,Physiology

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