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Activation of the renin\u2010angiotensin\u2010aldosterone system (RAAS) contributes to avid sodium retention, cardiac hypertrophy and oedema formation, including lung congestion. While the status of the classic components of RAAS such as renin, angiotensin converting enzyme (ACE), angiotensin II (Ang II) and angiotensin II receptor AT\u20101 is well studied in CHF, the expression of angiotensin converting enzyme\u20102 (ACE2), a key enzyme of angiotensin 1\u20107 (Ang 1\u20107) generation in the pulmonary, cardiac and renal systems has not been studied thoroughly in this clinical setting. This issue is of a special interest as Ang 1\u20107 counterbalance the vasoconstrictory, pro\u2010inflammatory and pro\u2010proliferative actions of Ang II. Furthermore, CHF predisposes to COVID\u201019 disease severity, while ACE2 also serves as the binding domain of SARS\u2010CoV\u20102 in human host\u2010cells, and acts in concert with furin, an important enzyme in the synthesis of BNP in CHF, in permeating viral functionality along TMPRSST2. ADAM17 governs ACE2 shedding from cell membranes. Therefore, the present study was designed to investigate the expression of ACE2, furin, TMPRSS2 and ADAM17 in the lung, heart and kidneys of rats with CHF to understand the exaggerated susceptibility of clinical CHF to COVID\u201019 disease. Heart failure was induced in male Sprague Dawley rats by the creation of a surgical aorto\u2010caval fistula. Sham\u2010operated rats served as controls. One week after surgery, the animals were subdivided into compensated and decompensated CHF according to urinary sodium excretion. Both groups and their controls were sacrificed, and their hearts, lungs and kidneys were harvested for assessment of tissue remodelling and ACE2, furin, TMPRSS2 and ADAM17 immunoreactivity, expression and immunohistochemical staining. ACE2 immunoreactivity and mRNA levels increased in pulmonary, cardiac and renal tissues of compensated, but not in decompensated CHF. Furin immunoreactivity was increased in both compensated and decompensated CHF in the pulmonary, cardiac tissues and renal cortex but not in the medulla. Interestingly, both the expression and abundance of pulmonary, cardiac and renal TMPRSS2 decreased in CHF in correlation with the severity of the disease. Pulmonary, cardiac and renal ADAM17 mRNA levels were also downregulated in decompensated CHF. Circulating furin levels increased in proportion to CHF severity, whereas plasma ACE2 remained unchanged. In summary, ACE2 and furin are overexpressed in the pulmonary, cardiac and renal tissues of compensated and to a lesser extent of decompensated CHF as compared with their sham controls. The increased expression of the ACE2 in heart failure may serve as a compensatory mechanism, counterbalancing the over\u2010activity of the deleterious isoform, ACE. Downregulated ADAM17 might enhance membranal ACE2 in COVID\u201019 disease, whereas the suppression of TMPRSS2 in CHF argues against its involvement in the exaggerated susceptibility of CHF patients to SARS\u2010CoV2.<\/jats:p>","DOI":"10.1111\/jcmm.16310","type":"journal-article","created":{"date-parts":[[2021,3,4]],"date-time":"2021-03-04T12:46:48Z","timestamp":1614862008000},"page":"3840-3855","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Pulmonary, cardiac and renal distribution of ACE2, furin, TMPRSS2 and ADAM17 in rats with heart failure: Potential implication for COVID\u201019 disease"],"prefix":"10.1111","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5545-8535","authenticated-orcid":false,"given":"Emad E.","family":"Khoury","sequence":"first","affiliation":[{"name":"Department of Physiology and Biophysics Rappaport Faculty of Medicine Technion\u2010Israel Institute of Technology Haifa Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yara","family":"Knaney","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics Rappaport Faculty of Medicine Technion\u2010Israel Institute of Technology Haifa Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmad","family":"Fokra","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics Rappaport Faculty of Medicine Technion\u2010Israel Institute of Technology Haifa Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Safa","family":"Kinaneh","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics Rappaport Faculty of Medicine Technion\u2010Israel Institute of Technology Haifa Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zaher","family":"Azzam","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Rambam Medical Center Haifa Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel N.","family":"Heyman","sequence":"additional","affiliation":[{"name":"Department of Medicine Hadassah Hebrew University Hospital Jerusalem Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7272-197X","authenticated-orcid":false,"given":"Zaid","family":"Abassi","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics Rappaport Faculty of Medicine Technion\u2010Israel Institute of Technology Haifa Israel"},{"name":"Laboratory Medicine Rambam Medical Center Haifa Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,3,4]]},"reference":[{"issue":"2","key":"e_1_2_9_2_1","first-page":"145","article-title":"The epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (COVID\u201019) in China","volume":"41","author":"Epidemiology Working Group for Ncip Epidemic Response CCfDC, Prevention","year":"2020","journal-title":"Zhonghua liu xing bing xue za zhi"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2004.04.001"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamacardio.2020.1105"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.120.047549"},{"issue":"6","key":"e_1_2_9_6_1","first-page":"E54","article-title":"Are patients with hypertension and diabetes mellitus at increased risk for COVID\u201019 infection? 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