{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T19:31:40Z","timestamp":1768505500522,"version":"3.49.0"},"posted":{"date-parts":[[2023,2,7]]},"group-title":"Molecular Biology","reference-count":33,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,2,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Aims<\/jats:title>\n                  <jats:p>\n                    Patients with\n                    <jats:italic>ADP-ribose-acceptor hydrolase 3<\/jats:italic>\n                    (\n                    <jats:italic>ARH3<\/jats:italic>\n                    ) deficiency exhibit stress-induced childhood-onset neurodegeneration with ataxia and seizures (CONDSIAS). ARH3 degrades protein-linked poly(ADP- ribose) (PAR) synthesized by poly(ADP-ribose)polymerase (PARP)-1 during oxidative stress, leading to cleavage of the ADP-ribose linked to protein.\n                    <jats:italic>ARH3<\/jats:italic>\n                    deficiency leads to excess accumulation of PAR, resulting in PAR-dependent cell death or parthanatos. Approximately one-third of patients with homozygous mutant\n                    <jats:italic>ARH3<\/jats:italic>\n                    die from cardiac arrest, which has been described as neurogenic, suggesting that ARH3 may play an important role in maintaining myocardial function. To address this question, cardiac function was monitored in\n                    <jats:italic>Arh3<\/jats:italic>\n                    -knockout (KO) and - heterozygous (HT) mice.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods and results<\/jats:title>\n                  <jats:p>\n                    <jats:italic>Arh3<\/jats:italic>\n                    -KO male mice displayed cardiac hypertrophy by histopathology and decreased cardiac contractility assessed by MRI. In addition, both genders of\n                    <jats:italic>Arh3<\/jats:italic>\n                    -KO and -HT mice showed decreased cardiac contractility by dobutamine stress test assessed by echocardiography. A direct role of ARH3 on myocardial function was seen with a Langendorff-perfused isolated heart model\n                    <jats:italic>. Arh3<\/jats:italic>\n                    -KO male mouse hearts showed decreased post-ischemic rate pressure products, increased size of ischemia-reperfusion (IR) infarcts, and elevated PAR levels. Consistently,\n                    <jats:italic>in vivo<\/jats:italic>\n                    IR injury showed enhanced infarct size in\n                    <jats:italic>Arh3<\/jats:italic>\n                    -KO mice in both genders. In addition,\n                    <jats:italic>Arh3<\/jats:italic>\n                    -HT male mice showed increased size of\n                    <jats:italic>in vivo<\/jats:italic>\n                    IR infarcts. Treatment with an FDA-approved PARP inhibitor, rucaparib, improved cardiac contractility during dobutamine-induced stress and exhibited reduced size of\n                    <jats:italic>in vivo<\/jats:italic>\n                    IR infarcts. To understand better the role of ARH3, CRISPR-Cas9 was used to generate different\n                    <jats:italic>Arh3<\/jats:italic>\n                    genotypes of myoblasts and myotubes. Incubation with H2O2 decreased viability of\n                    <jats:italic>Arh3<\/jats:italic>\n                    -KO and -HT myoblasts and myotubes, resulting in PAR-dependent cell death that was reduced by PARP inhibitors or by transfection with the\n                    <jats:italic>Arh3<\/jats:italic>\n                    gene.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>\n                    ARH3 regulates PAR homeostasis in myocardium to preserve function and protect against oxidative stress; PARP inhibitors reduce the myocardial dysfunction seen with\n                    <jats:italic>Arh3<\/jats:italic>\n                    mutations.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Graphical Abstract<\/jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"527369v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>","DOI":"10.1101\/2023.02.07.527369","type":"posted-content","created":{"date-parts":[[2023,2,7]],"date-time":"2023-02-07T23:50:11Z","timestamp":1675813811000},"source":"Crossref","is-referenced-by-count":1,"title":["A PARP inhibitor, rucaparib, improves cardiac dysfunction in\n                  <i>ADP-ribose-acceptor hydrolase 3<\/i>\n                  (\n                  <i>Arh3<\/i>\n                  ) 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