The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a major public health problem. Cardiovascular diseases, including hypertension and diabetes, are the most common comorbidities that are associated with severe illness and high case-fatality rates (CFR) in COVID-19 [
1,
2]. SARS-CoV-2 is a newly identified coronavirus with high genome similarity (89%) and identity (73%) of its receptor-binding domain (RBD) and similar ternary structure to SARS-CoV [
3‐
5]. Molecular modeling revealed that SARS-CoV-2 RBD has a stronger interaction with angiotensin-converting enzyme 2 (ACE2), as cell entry receptor, than SARS-CoV [
5]. ACE2 is a homologue of ACE but has physiological actions that oppose ACE [
6]. ACE cleaves angiotensin I to generate angiotensin II which binds and stimulates the AT1 receptor (AT1R) to increase blood pressure, in part, via arterial constriction and renal sodium retention [
7]. By contrast, ACE2 catalyzes the conversion of angiotensin (Ang) II into Ang1-7 which leads to vasodilatory, antiproliferative, and anti-inflammatory effects via the Mas receptor. Thus, ACE2 counterbalances the effects of Ang II and exhibits antihypertensive and cardioprotective effects in humans and several rodent models [
8].
AT1R blockers, such as losartan and olmesartan, are widely used in the therapy of hypertension. Urinary ACE2 levels are increased in hypertensive patients treated with the AT1R blocker (olmesartan), but not in patients treated with other AT1R blockers, such as losartan, candesartan, valsartan, and telminsartan [
9]. However, losartan and other AT1R blockers have been reported to increase ACE2 expression in the kidney of spontaneously hypertensive rat and heart of mice or rat with cardiac hypertrophy and dysfunction caused by transverse aortic constriction or coronary artery ligation [
10,
11]. It has been suggested that angiotensin receptor 1 (AT1R) blockers may be used to reduce the cardiac damage in SARS-CoV-2 infection [
12]. Retrospective studies found that hospitalized hypertensive patients with SARS-CoV-2 infection treated with ACE inhibitors or AT1R blockers have a lower risk of all-cause mortality than those treated with other drugs [
13]. A prospective cohort study also found that ACE inhibitors and AT1R blockers are associated with a reduced progression of COVID-19 and do not increase the risk of intensive care [
14]. However, due to ACE2 is critically important in the cellular entry of SARS and SARS-CoV-2, it is possible that hypertensive COVID-19 patients treated with drugs that increase ACE2, e.g., ACE inhibitors and AT1R blockers, are at a higher risk for the development and severity SARS-CoV-2 infection [
15]. Indeed, hypertensive patients taking ACE inhibitors or AT1R blockers may have higher all-cause mortalities than those taking other drugs [
16]. It has been suggested that ACE2-mediated inhibition of the AT1R pathway, which is beneficial in the treatment of hypertension, may also increase the susceptibility to pulmonary and cardiovascular disease in patients with COVID-19 [
17]. Human (h) ACE2 transgenic mice, intranasally inoculated with SARS-CoV-2, develop severe pulmonary pathology with viral replication in the lungs and intestines, at 1-day post infection (dpi) and severe pulmonary pathology 5 dpi. There is no viral load in other organs [
18]. The disease is more severe in aged mice [
19], similar to that seen in humans [
20]. The intranasal inoculation of SARS-CoV-2 in human (h) ACE2 transgenic mice results in 100% mortality within a few days [
21]. However, the effect of AT1R blockers in hypertensive hACE2 transgenic mice, induced by angiotensin II and infected with SARS-CoV-2, has not been studied. Therefore, we studied hospitalized COVID-19 hypertensive patients and hypertensive hACE2 transgenic mice to determine whether AT1R blockers protect or promote the development of COVID-19 [
17].