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Cellular entry of SARS-CoV-2 is mainly via the angiotensin-converting enzyme 2 (ACE2) receptor, which is highly expressed in normal hearts. There is a disagreement regarding the effect of factors such as obesity and diabetes on ACE2 expression in the human heart and whether treatment with renin\u2013angiotensin system inhibitors or anti-diabetic medications increases ACE2 expression and subsequently the susceptibility to infection. We designed this study to elucidate factors that control ACE2 expression in human serum, human heart biopsies, and mice.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Right atrial appendage biopsies were collected from 79 patients that underwent coronary artery bypass graft (CABG) surgery. We investigated the alteration in <jats:italic>ACE2<\/jats:italic> mRNA and protein expression in heart tissue and serum. <jats:italic>ACE2<\/jats:italic> expression was compared with clinical risk factors: diabetes, obesity and different anti-hypertensive or anti-diabetic therapies. WT or db\/db mice were infused with Angiotensin II (ATII), treated with different anti-diabetic drugs (Metformin, GLP1A and SGLT2i) were also tested.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p><jats:italic>ACE2<\/jats:italic> gene expression was increased in diabetic hearts compared to non-diabetic hearts and was positively correlated with glycosylated hemoglobin (HbA1c), body mass index (BMI), and activation of the renin angiotensin system (RAS), and negatively correlated with ejection fraction. <jats:italic>ACE2<\/jats:italic> was not differentially expressed in patients who were on angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs) prior to the operation. We found no correlation between plasma free <jats:italic>ACE2<\/jats:italic> and cardiac tissue <jats:italic>ACE2<\/jats:italic> expression. Transmembrane serine protease 2 (<jats:italic>TMPRSS2),<\/jats:italic> metalloprotease <jats:italic>ADAM10<\/jats:italic> and <jats:italic>ADAM17<\/jats:italic> that facilitate viral-<jats:italic>ACE2<\/jats:italic> complex entry and degradation were increased in diabetic hearts. <jats:italic>ACE2<\/jats:italic> expression in mice was increased with ATII infusion and attenuated following anti-diabetic drugs treatment.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>Patients with uncontrolled diabetes or obesity with RAS activation have higher ACE2 expressions therefore are at higher risk for severe infection. Since ACEi or ARBs show no effect on <jats:italic>ACE2<\/jats:italic> expression in the heart further support their safety.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12933-021-01275-w","type":"journal-article","created":{"date-parts":[[2021,4,27]],"date-time":"2021-04-27T15:06:41Z","timestamp":1619536001000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["Expression of the SARS-CoV-2 receptorACE2 in human heart is associated with uncontrolled diabetes, obesity, and activation of the renin angiotensin system"],"prefix":"10.1186","volume":"20","author":[{"given":"Michal","family":"Herman-Edelstein","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tali","family":"Guetta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amir","family":"Barnea","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maayan","family":"Waldman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naomi","family":"Ben-Dor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaron D.","family":"Barac","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ran","family":"Kornowski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Arad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edith","family":"Hochhauser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Aravot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,4,27]]},"reference":[{"issue":"4","key":"1275_CR1","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1016\/j.tem.2004.03.001","volume":"15","author":"LM Burrell","year":"2004","unstructured":"Burrell LM, Johnston CI, Tikellis C, Cooper ME. 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