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Abstract
Angiotensin-converting enzyme 2 (ACE2) is an important factor in coronavirus disease (COVID-19) interactions. Losartan (LOS) belongs to the angiotensin receptor blocker (ARB) family. Additionally, the protective role of ACE2 restored by LOS has been suggested and clinically examined in the treatment of COVID-19 patients. Furthermore, clinical trials with LOS have been conducted. However, the mechanism through which LOS enhances ACE2 expression remains unclear. In addition, the response of ACE2 to LOS differs among patients. Our LOS-treated patient data revealed a correlated mechanism of ACE2 with components of the renin-angiotensinogen system. We observed a significant positive regulation of MAS1 and ACE2 expression. In the context of LOS treatment of COVID-19, ACE2 expression could depend on LOS regulated MAS1. Thus, MAS1 expression could predict the COVID-19 treatment response of LOS.

 Losartan produces controversial response to ACE2. We observed that the response of ACE2 to losartan differed among patients. We suspect the possible ACE2 upregulation after Losartan treatment was via ACE2/MAS1 axis. We have performed the individual patients ACE2 and components of Renin-angiotensinogen system like AT1R, AGT, AT2R and MAS1 expression level at baseline and after 6 weeks of losartan treatment. 77% patient shows synchronized expression of ACE2 and MAS1 after 6 weeks of treatment. We also performed the correlation analysis among component of Renin-angiotensinogen system after Losartan treatment. Since AT1R is receptor of losartan so we find negative correlation among ACE2, AGT AT2R and MAS1 with AT1R after drug treatment. MAS1 and AT1R showed moderate corelation of r = 0.53 but is higher than rest of the component. Similarly we performed correlation analysis among ACE2 with AT2R and MAS1, and AGT with AT2R and MAS1. Both AGT (r = 0.82) and ACE2 (r = 0.92) show strong positive pearson correlation coefficient with MAS1. That could point towards upregulated ACE2 after losartan could be related to ACE2/MAS1 axis. It also points that ACE2 expression is associated with MAS1. MAS1 expression could predict the COVID-19 treatment response of losartan. SARS-CoV-2 binds to ACE2, enabling cell entry thus determining MAS1 expression could predict the response to SARS-CoV-2 viral load for patients who are already on losartan medication for a pre-existing condition .  

Affiliations
1 Division of RI Application, Korea Institute of Radiological and Medical Sciences, 75 Nowon-Gil, Gongneung-Dong, Nowon-Gu, Seoul, 01812, Korea.
2 Radiological and Medico-Oncological Sciences, University of Science and Technology (UST), Seoul, 01812, Korea.
3 Division of RI Application, Korea Institute of Radiological and Medical Sciences, 75 Nowon-Gil, Gongneung-Dong, Nowon-Gu, Seoul, 01812, Korea. kjs@kirams.re.kr.
4 Radiological and Medico-Oncological Sciences, University of Science and Technology (UST), Seoul, 01812, Korea. kjs@kirams.re.kr.