ADP-ribose-acceptor hydrolase 2(Arh2) deficiency results in cardiac dysfunction, tumorigenesis, inflammation, and decreased survival

Abstract

AbstractADP-ribosylation is a reversible reaction with ADP-ribosyltransferases catalyzing the forward reaction and ADP-ribose-acceptor hydrolases (ARHs) hydrolyzing the ADP-ribose acceptor bond. ARH2 is a member of the 39-kDa ARH family (ARH1-3), which is expressed in heart and skeletal muscle. ARH2 failed to exhibit any in vitro enzymatic activity. To determine its possible in vivo activities,Arh2-knockout (KO) and - heterozygous (Het) mice were generated using CRISPR-Cas9.Arh2-KO mice exhibited decreased cardiac contractility by MRI, echocardiography and dobutamine stress with cardiomegaly and abnormal motor function.Arh2-Het mice showed results similar to those seen inArh2-KO mice except for cardiomegaly.Arh2-KO and -Het mice and mouse embryonic fibroblasts (MEFs) developed spontaneous tumors and subcutaneous tumors in nude mice. We identified 13 mutations inArh2-Het MEFs and heterozygous tumors, corresponding to humanARH2mutations in cancers obtained from COSMIC. Of interest, the L116R mutation inArh2gene plays a critical role in aggressive tumorigenesis in nude mice, corresponding to humanARH2mutations in stomach adenocarcinoma. Both genders ofArh2-KO and -Het mice showed increased unexpectedly deaths and decreased survival rate during a 24-month observation, caused by tumor, inflammation, non-inflammation (e.g., cardiomegaly, dental dysplasia), and congenital diseases. Thus,Arh2plays a pivotal role in cardiac function, tumorigenesis, inflammation, and overall survival.