{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T22:52:29Z","timestamp":1784328749434,"version":"3.55.0"},"reference-count":43,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"8","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2017,8,2]]},"abstract":"<jats:sec xml:lang=\"en\">\n            <jats:title>Background<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              Compromised protein quality control causes the accumulation of misfolded proteins and intracellular aggregates, contributing to cardiac disease and heart failure. The development of therapeutics directed at proteotoxicity\u2010based pathology in heart disease is just beginning. The molecular tweezer\n              <jats:styled-content style=\"fixed-case\">CLR<\/jats:styled-content>\n              01 is a broad\u2010spectrum inhibitor of abnormal self\u2010assembly of amyloidogenic proteins, including amyloid \u03b2\u2010protein, tau, and \u03b1\u2010synuclein. This small molecule interferes with aggregation by binding selectively to lysine side chains, changing the charge distribution of aggregation\u2010prone proteins and thereby disrupting aggregate formation. However, the effects of\n              <jats:styled-content style=\"fixed-case\">CLR<\/jats:styled-content>\n              01 in cardiomyocytes undergoing proteotoxic stress have not been explored. Here we assess whether\n              <jats:styled-content style=\"fixed-case\">CLR<\/jats:styled-content>\n              01 can decrease cardiac protein aggregation catalyzed by cardiomyocyte\u2010specific expression of mutated \u03b1B\u2010crystallin (Cry\n              <jats:styled-content style=\"fixed-case\">\n                AB\n                <jats:sup>R<\/jats:sup>\n              <\/jats:styled-content>\n              <jats:sup>120G<\/jats:sup>\n              ).\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Methods and Results<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              A proteotoxic model of desmin\u2010related cardiomyopathy caused by cardiomyocyte\u2010specific expression of Cry\n              <jats:styled-content style=\"fixed-case\">\n                AB\n                <jats:sup>R<\/jats:sup>\n              <\/jats:styled-content>\n              <jats:sup>120G<\/jats:sup>\n              was used to test the efficacy of\n              <jats:styled-content style=\"fixed-case\">CLR<\/jats:styled-content>\n              01 therapy in the heart. Neonatal rat cardiomyocytes were infected with adenovirus expressing either wild\u2010type Cry\n              <jats:styled-content style=\"fixed-case\">AB<\/jats:styled-content>\n              or Cry\n              <jats:styled-content style=\"fixed-case\">\n                AB\n                <jats:sup>R<\/jats:sup>\n              <\/jats:styled-content>\n              <jats:sup>120G<\/jats:sup>\n              . Subsequently, the cells were treated with different doses of\n              <jats:styled-content style=\"fixed-case\">CLR<\/jats:styled-content>\n              01 or a closely related but inactive derivative,\n              <jats:styled-content style=\"fixed-case\">CLR<\/jats:styled-content>\n              03.\n              <jats:styled-content style=\"fixed-case\">CLR<\/jats:styled-content>\n              01 decreased aggregate accumulation and attenuated cytotoxicity caused by Cry\n              <jats:styled-content style=\"fixed-case\">\n                AB\n                <jats:sup>R<\/jats:sup>\n              <\/jats:styled-content>\n              <jats:sup>120G<\/jats:sup>\n              expression in a dose\u2010dependent manner, whereas\n              <jats:styled-content style=\"fixed-case\">CLR<\/jats:styled-content>\n              03 had no effect. Ubiquitin\u2010proteasome system function was analyzed using a ubiquitin\u2010proteasome system reporter protein consisting of a short degron,\n              <jats:styled-content style=\"fixed-case\">CL<\/jats:styled-content>\n              1, fused to the\n              <jats:styled-content style=\"fixed-case\">COOH<\/jats:styled-content>\n              \u2010terminus of green fluorescent protein.\n              <jats:styled-content style=\"fixed-case\">CLR<\/jats:styled-content>\n              01 improved proteasomal function in Cry\n              <jats:styled-content style=\"fixed-case\">\n                AB\n                <jats:sup>R<\/jats:sup>\n              <\/jats:styled-content>\n              <jats:sup>120G<\/jats:sup>\n              cardiomyocytes but did not alter autophagic flux. In vivo,\n              <jats:styled-content style=\"fixed-case\">CLR<\/jats:styled-content>\n              01 administration also resulted in reduced protein aggregates in Cry\n              <jats:styled-content style=\"fixed-case\">\n                AB\n                <jats:sup>R<\/jats:sup>\n              <\/jats:styled-content>\n              <jats:sup>120G<\/jats:sup>\n              transgenic mice.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              <jats:styled-content style=\"fixed-case\">CLR<\/jats:styled-content>\n              01 can inhibit Cry\n              <jats:styled-content style=\"fixed-case\">\n                AB\n                <jats:sup>R<\/jats:sup>\n              <\/jats:styled-content>\n              <jats:sup>120G<\/jats:sup>\n              aggregate formation and decrease cytotoxicity in cardiomyocytes undergoing proteotoxic stress, presumably through clearance of the misfolded protein via increased proteasomal function.\n              <jats:styled-content style=\"fixed-case\">CLR<\/jats:styled-content>\n              01 or related\u00a0compounds may be therapeutically useful in treating the pathogenic sequelae resulting from proteotoxic heart disease.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/jaha.117.006182","type":"journal-article","created":{"date-parts":[[2017,9,1]],"date-time":"2017-09-01T18:25:38Z","timestamp":1504290338000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":16,"title":["Inhibition of Mutant \u03b1B Crystallin\u2010Induced Protein Aggregation by a Molecular Tweezer"],"prefix":"10.1161","volume":"6","author":[{"given":"Na","family":"Xu","sequence":"first","affiliation":[{"name":"Division of Molecular Cardiovascular Biology, the Heart Institute, Cincinnati Children's Hospital, Cincinnati, OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gal","family":"Bitan","sequence":"additional","affiliation":[{"name":"Department of Neurology, David Geffen School of Medicine, Brain Research Institute, and Molecular Biology Institute, University of California at Los Angeles, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Schrader","sequence":"additional","affiliation":[{"name":"Faculty of Chemistry, University of Duisburg\u2010Essen, Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank\u2010Gerrit","family":"Kl\u00e4rner","sequence":"additional","affiliation":[{"name":"Faculty of Chemistry, University of Duisburg\u2010Essen, Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanna","family":"Osinska","sequence":"additional","affiliation":[{"name":"Division of Molecular Cardiovascular Biology, the Heart Institute, Cincinnati Children's Hospital, Cincinnati, OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey","family":"Robbins","sequence":"additional","affiliation":[{"name":"Division of Molecular Cardiovascular Biology, the Heart Institute, Cincinnati Children's Hospital, Cincinnati, OH"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2015.01.016"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1106180"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2015.02.002"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biochem-060208-092442"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0401900101"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.107.750232"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2993"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1017\/S1462399407000385"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/1300"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200003163421104"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.108.193516"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.105.572552"},{"key":"e_1_3_3_14_2","first-page":"390","article-title":"Protein quality control in protection against systolic overload cardiomyopathy: the long term role of small heat shock proteins","volume":"2","author":"Kumarapeli AR","year":"2010","unstructured":"Kumarapeli AR, Horak K, Wang X. 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