{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T03:11:16Z","timestamp":1785208276017,"version":"3.55.0"},"reference-count":26,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2022,8,1]],"date-time":"2022-08-01T00:00:00Z","timestamp":1659312000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005971","name":"Deutsche Herzstiftung","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005971","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010663","name":"European Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010663","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["dom-pubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Diabetes Obesity Metabolism"],"published-print":{"date-parts":[[2022,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aim<\/jats:title>\n                    <jats:p>To investigate cardiac signalling pathways connecting substrate utilization with left ventricular remodelling in a murine pressure overload model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Cardiac hypertrophy was induced by transverse aortic constriction surgery in 20\u2010week\u2010old C57BL\/6J mice treated with or without the sodium\u2010glucose co\u2010transporter 2 (SGLT2) inhibitor ertugliflozin (225\u2009mg\u2009kg\n                      <jats:sup>\u22121<\/jats:sup>\n                      chow diet) for 10\u2009weeks.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Ertugliflozin improved left ventricular function and reduced myocardial fibrosis. This occurred simultaneously with a fasting\u2010like response characterized by improved glucose tolerance and increased ketone body concentrations. While cardiac insulin signalling was reduced in response to SGLT2 inhibition, AMP\u2010activated protein kinase (AMPK) signalling was increased with induction of the fatty acid transporter cluster of differentiation 36 and phosphorylation of acetyl\u2010CoA carboxylase (ACC). Further, enzymes responsible for ketone body catabolism (\u03b2\u2010hydroxybutyrate dehydrogenase, succinyl\u2010CoA:3\u2010oxoacid\u2010CoA transferase and acetyl\u2010CoA acetyltransferase 1) were induced by SGLT2 inhibition. Ertugliflozin led to more cardiac abundance of fatty acids, tricarboxylic acid cycle metabolites and ATP. Downstream mechanistic target of rapamycin (mTOR) pathway, relevant for protein synthesis, cardiac hypertrophy and adverse cardiac remodelling, was reduced by SGLT2 inhibition, with alleviation of endoplasmic reticulum (ER) stress and unfolded protein response (UPR) providing a potential mechanism for abundant reduced left ventricular apoptosis and fibrosis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>SGLT2 inhibition reduced left ventricular fibrosis in a murine model of cardiac hypertrophy. Mechanistically, this was associated with reduced cardiac insulin and increased AMPK signalling as a potential mechanism for less cardiac mTOR activation with alleviation of downstream ER stress, UPR and apoptosis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/dom.14814","type":"journal-article","created":{"date-parts":[[2022,7,8]],"date-time":"2022-07-08T03:26:23Z","timestamp":1657250783000},"page":"2263-2272","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":52,"title":["The sodium\u2010glucose co\u2010transporter\u20102 inhibitor ertugliflozin modifies the signature of cardiac substrate metabolism and reduces cardiac\n                    <scp>mTOR<\/scp>\n                    signalling, endoplasmic reticulum stress and apoptosis"],"prefix":"10.1111","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8066-6114","authenticated-orcid":false,"given":"Julia","family":"Moellmann","sequence":"first","affiliation":[{"name":"Department of Internal Medicine I University Hospital Aachen, RWTH Aachen University  Aachen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pascal A.","family":"Mann","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I University Hospital Aachen, RWTH Aachen University  Aachen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ben A.","family":"Kappel","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I University Hospital Aachen, RWTH Aachen University  Aachen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Kahles","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I University Hospital Aachen, RWTH Aachen University  Aachen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara M.","family":"Klinkhammer","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University Hospital Aachen RWTH Aachen University  Aachen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Boor","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University Hospital Aachen RWTH Aachen University  Aachen Germany"},{"name":"Department of Nephrology and Clinical Immunology RWTH Aachen University  Aachen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael","family":"Kramann","sequence":"additional","affiliation":[{"name":"Department of Nephrology and Clinical Immunology RWTH Aachen University  Aachen Germany"},{"name":"Institute of Experimental Medicine and Systemsbiology, University Hospital Aachen RWTH Aachen University  Aachen 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