{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T18:42:48Z","timestamp":1788460968641,"version":"build-2803163510"},"reference-count":55,"publisher":"American Physiological Society","issue":"1","funder":[{"DOI":"10.13039\/501100000024","name":"Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de recherche en sant\u00e9 du Canada)","doi-asserted-by":"publisher","award":["MOP74765"],"award-info":[{"award-number":["MOP74765"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Heart and Circulatory Physiology"],"published-print":{"date-parts":[[2018,1,1]]},"abstract":"<jats:p>\n                    Doxorubicin is a widely used chemotherapeutic with deleterious cardiotoxic side effects. HDL has been shown to protect cardiomyocytes in vitro against doxorubicin-induced apoptosis. Scavenger receptor class B type 1 (SR-B1), a high-affinity HDL receptor, mediates cytoprotective signaling by HDL through Akt. Here, we assessed whether increased HDL levels protect against doxorubicin-induced cardiotoxicity in vivo and in cardiomyocytes in culture and explored the intracellular signaling mechanisms involved, particularly the role of SR-B1. Transgenic mice with increased HDL levels through overexpression of human apolipoprotein A1 (apoA1\n                    <jats:sup>Tg\/Tg<\/jats:sup>\n                    ) and wild-type mice (apoA1\n                    <jats:sup>+\/+<\/jats:sup>\n                    ) with normal HDL levels were treated repeatedly with doxorubicin. After treatment, apoA1\n                    <jats:sup>+\/+<\/jats:sup>\n                    mice displayed cardiac dysfunction, as evidenced by reduced left ventricular end-systolic pressure and +dP\/d t, and histological analysis revealed cardiomyocyte atrophy and increased cardiomyocyte apoptosis after doxorubicin treatment. In contrast, apoA1\n                    <jats:sup>Tg\/Tg<\/jats:sup>\n                    mice were protected against doxorubicin-induced cardiac dysfunction and cardiomyocyte atrophy and apoptosis. When SR-B1 was knocked out, however, overexpression of apoA1 did not protect against doxorubicin-induced cardiotoxicity. Using primary neonatal mouse cardiomyocytes and human immortalized ventricular cardiomyocytes in combination with genetic knockout, inhibitors, or siRNA-mediated knockdown, we demonstrated that SR-B1 is required for HDL-mediated protection of cardiomyocytes against doxorubicin-induced apoptosis in vitro via a pathway involving phosphatidylinositol 3-kinase and Akt1\/2. Our findings provide proof of concept that raising apoA1 to supraphysiological levels can dramatically protect against doxorubicin-induced cardiotoxicity via a pathway that is mediated by SR-B1 and involves Akt1\/2 activation in cardiomyocytes.\n                  <\/jats:p>\n                  <jats:p>NEW &amp; NOTEWORTHY We have identified an important role for the scavenger receptor class B type 1 in facilitating high-density lipoprotein-mediated protection of cardiomyocytes against stress-induced apoptosis and shown that increasing plasma high-density lipoprotein protects against the deleterious side effects of the chemotherapeutic and cardiotoxic drug doxorubicin.<\/jats:p>","DOI":"10.1152\/ajpheart.00521.2016","type":"journal-article","created":{"date-parts":[[2017,10,6]],"date-time":"2017-10-06T21:15:17Z","timestamp":1507324517000},"page":"H31-H44","source":"Crossref","is-referenced-by-count":27,"title":["HDL protects against doxorubicin-induced cardiotoxicity in a scavenger receptor class B type 1-, PI3K-, and Akt-dependent manner"],"prefix":"10.1152","volume":"314","author":[{"given":"Kristina K.","family":"Durham","sequence":"first","affiliation":[{"name":"Medical Sciences Graduate Program, McMaster University, Hamilton, Ontario, Canada"},{"name":"Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada"},{"name":"Thrombosis and Atherosclerosis Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin M.","family":"Chathely","sequence":"additional","affiliation":[{"name":"Medical Sciences Graduate Program, McMaster University, Hamilton, Ontario, Canada"},{"name":"Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada"},{"name":"Thrombosis and Atherosclerosis Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kei Cheng","family":"Mak","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada"},{"name":"Thrombosis and Atherosclerosis Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdul","family":"Momen","sequence":"additional","affiliation":[{"name":"Division of Cell and Molecular Biology, Toronto General Hospital Research Institute and Heart and Stroke\/Richard Lewar Centre of Excellence for Cardiovascular Research, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cyrus T.","family":"Thomas","sequence":"additional","affiliation":[{"name":"Thrombosis and Atherosclerosis Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, Ontario, 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