{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T06:46:58Z","timestamp":1790664418336,"version":"4.1.0"},"reference-count":27,"publisher":"The Company of Biologists","license":[{"start":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T00:00:00Z","timestamp":1621296000000},"content-version":"am","delay-in-days":2329,"URL":"http:\/\/creativecommons.org\/licenses\/by\/3.0"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2015,1,1]]},"abstract":"<jats:p>Oxidative stress in cardiac fibroblasts (CF) promotes transformation to myofibroblasts and collagen synthesis leading to myocardial fibrosis, a precursor to heart failure (HF). NADPH oxidase 4 (Nox4) is a major source of cardiac reactive oxygen species (ROS), however, mechanisms of Nox4 regulation are unclear. \u03b2-arrestins are scaffold proteins which signal in G protein-dependent and independent manners including ERK activation. We hypothesize that \u03b2-arrestins regulate oxidative stress in a Nox4-dependent manner and increase fibrosis in HF. CF were isolated from normal and failing adult human left ventricles. Mitochondrial ROS\/superoxide production was quantitated using MitoSox. \u03b2-arrestin and Nox4 expression were manipulated using adenoviral overexpression or siRNA-mediated knockdown. Mitochondrial oxidative stress and Nox4 expression in CF are significantly increased in HF. Nox4 knockdown resulted in significant inhibition of mitochondrial superoxide production and decreased basal and TGF-\u03b2 stimulated collagen and \u03b1-SMA expression. CF \u03b2-arrestin expression is upregulated 4-fold in HF. \u03b2-arrestin knockdown in failing CF decreased ROS and Nox4 expression by 50%. \u03b2-arrestin overexpression in normal CF increased mitochondrial superoxide production 2-fold. These effects were inhibited by Nox or ERK inhibition. Upregulation of Nox4 appears to be a primary mechanism for increased ROS production in failing CF, which stimulates collagen deposition. \u03b2-arrestin expression is upregulated in HF and plays an important and novel role in regulating mitochondrial superoxide production via Nox4. The mechanism for this effect appears to be ERK-mediated. Targeted inhibition of \u03b2-arrestins in CF may decrease oxidative stress as well as pathological cardiac fibrosis.<\/jats:p>","DOI":"10.1242\/dmm.019968","type":"journal-article","created":{"date-parts":[[2015,10,9]],"date-time":"2015-10-09T01:28:52Z","timestamp":1444354132000},"source":"Crossref","is-referenced-by-count":18,"title":["Regulation of mitochondrial oxidative stress by \u03b2-arrestins in cardiac fibroblasts"],"prefix":"10.1242","author":[{"given":"Jennifer L.","family":"Philip","sequence":"first","affiliation":[{"name":"Department of Surgery, Division of Cardiothoracic Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Md. 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