Because of increased ACE2 expression in patients with chronic treatment with ACEi/ARB, it is suggested that these patients might have a higher risk of SARS-CoV-2 infection and severe COVID-19 [72]. by the imbalance between ADAM metallopeptidase domain 17 (ADAM17) protein (which is required for cleavage of ACE-2 ectodomain resulting in increased ACE2 shedding), and TMPRSS2 (which is required for spike glycoprotein priming). To date, ACE inhibitors and Angiotensin II Receptor Blockers (ARBs) treatment interruption in patients with chronic comorbidities appears unjustified. The rollout of COVID-19 vaccines provides opportunities to study the effects of different COVID-19 vaccines on ACE2 in patients on treatment with ACEi/ARB. strong class=”kwd-title” Keywords: cardiovascular system, ACE2, RAS, COVID-19, SARS- CoV-2, TMPRSS2, ADAM17, pandemic, vaccines 1. Introduction Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first identified as a novel human pathogen in December 2019 and since has caused a worldwide pandemic [1]. As of 8 February 2021, there have been over 105 million Coronavirus Disease-2019 (COVID-19) cases including 2.3 million deaths reported by the World Health Organization (WHO) [2]. Epidemiologic studies highlight that age, gender and Rabbit polyclonal to PCSK5 comorbidities (hypertension, renal insufficiency, diabetes and ischemic heart disease) are frequently associated with greater mortality risk after SARS-CoV-2 infection [3,4]. The pathogenesis of COVID-19 has two stages [5,6,7]: the first one, where SARS-CoV-2 replicates and patients manifest a range of non-specific symptoms (e.g., fever, muscle aches, shortness of breath, headache, sore throat and gastrointestinal discomfort) [3,6]. The second stage is characterized by an adaptive immune response with humoral, cellular and cytokine responses manifesting in a large range of clinical presentations [6]. Some patients develop the most severe forms of COVID-19, leading to fatal complications such are acute respiratory distress syndrome (ARDS), acute kidney injury and thromboembolism [3,6]. Angiotensin-converting enzyme 2 (ACE2) is the entry receptor for SARS-CoV-2, which is the cause of COVID-19 in humans. ACE2 is a type I transmembrane metallocarboxypeptidase expressed in endothelial cells, alveolar type 2 lung epithelial cells, renal tubular epithelium, Leydig cells in the testes, and Peptide M gastrointestinal tract [7]. ACE2 mediates the interaction between host cells and SARS-CoV-2 spike (S) protein [8]. However, ACE2 is not only a SARS-CoV-2 receptor. Indeed, it also has an important homeostatic function regulating renin-angiotensin system (RAS), which is pivotal for both the Peptide M cardiovascular and immune systems [9]. Therefore, ACE2 appears to be the key link between SARS-CoV-2 infection, cardiovascular diseases (CVDs) and immune response [8,10,11]. RAS pathway has a fundamental role in human body homeostasis and its imbalance is associated with inflammation and cardiovascular alterations [12,13]. SARS-CoV-2 binds to human cells through ACE2, and it appears that pre-existing alterations in ACE2 expression and activity could determine susceptibility to SARS-CoV-2 infections [4,14]. The aim of this review is to summarize the state of the art in ACE2-SARS-CoV-2 interactions in the context of the cardiovascular system and to discuss the implications and impact of the use of ACE inhibitors (ACEi) and angiotensin receptor blockers (ARB) in patients with SARS-CoV-2 infection. We also discuss the rollout of COVID-19 vaccines and the opportunities this provides to study the effects of different COVID-19 vaccines on ACE2 in patients on treatment with ACEi/ARB. 2. Peptide M ACE2 Physiological Role The ACE2 gene, located on chromosome Xp22, consists of 18 exons and 20 introns [15] and encodes a type I transmembrane glycoprotein of 805 amino acids [16,17]. The N-terminal catalytically active domain is located in the extracellular space while the intracellular C-terminal consists of a collectin and an insulin-like domain [16,17]. In RAS, Renin produces Angiotensin I (Ang I) starting from Angiotensinogen, then angiotensin-converting enzyme (ACE) removes two amino acids from Ang I generating the.