Angiotensin-Converting-Enzyme (ACE) One Receptor, Two Diseases COVID and Infrarenal Aortic Aneurysm: A Mini- Review

The high morbidity and mortality caused by coronavirus disease 2019 (COVID-19) includes cardiovascular functional impairment. Evidence suggests that COVID infection causes symptomatic cardiac sufficiency in patients with preexisting cardiac disease and troponin elevation in critically ill patients [1-5]. The S1 subunit of the COVID virus S-glycoprotein functions as the Receptor-Binding Domain (RBD) for host cell entry [6]. The S2 subunit regulates both receptor recognition and fusion of viral and cellular membranes [7]. Angiotensin-Converting Enzyme 2 (ACE2) functions as a receptor for SARS-CoV-2. This results in the simultaneous binding of two S-glycoprotein trimers to an ACE2 dimer [8,9]. The cleavage of S2 subunit induced after binding itself leads to activation and uncaptured irreversible conformational change of gylcoprotein, facilitating membrane fusion [10]. Host proteases activated by SARS-CoV-2, such as cathepsin B, factor X, elastase, TMPRSS2 (Transmembrane Protease Serine 2), furin, etc., enhance S-glycoprotein priming and thus cell entry [11,12], which is inhibited by a serine protease inhibitor, mesylate combined with E-64d, an athepsin L/B inhibitor [13]. Binding of SARS-CoV-2 to the extracellular domains of transmembrane ACE2 proteins leads to downregulation of ACE2 expression [14,15]. From this, threapeutic approaches have already been developed by blocking the binding of SARSCoV- 2 to ACE2 receptors via inhibition of the Receptor Binding Domain (RBD) of the viral S protein [16-18]. In myocardial biopsies from patients after fatal COVID infection, in addition to myocardial fibrosis, a reduction in myocardial ACE2 expression was detected [19]. Expression of the ACE2 receptor in the heart, lung, gastrointestinal tract, and kidney, in conjunction with dysregulation of the renin-angiotensin system caused by binding of SARS co-virus to this receptor, explains the multiorgan attack, which can be lethal in the presence of comorbidities such as coronary artery disease, COPD, and diabetes [20-28].

The expression of ACE2 at the endothelium of the entire gastrointestinal tract forms the basis for enteric SARS-CoV-2 infection, the severity of which is directly related to the expression of ACE-II receptor [29,30].

It is not uncommon for gastrointestinal symptoms to appear earlier than respiratory manifestations [31-34]. The loss of ACE2 associated with hyperactivation of the ACE/Ang II/AT1R (angiotensin II type 1 receptor) axis not infrequently leads to disruptions in the integrity of the gastrointestinal-blood barrier, which may promote septic courses [30-34]. Recent studies suggest that it is the gastrointestinal tract of SARS-CoV-2 patients that acts as a starting point for recurrent infections [35,36]. Apart from direct effects of SARS-CoV-2 infection on the gut, preexisting and exacerbating lung disease indirectly affects the gut microbiome [37-40].

In addition, increased intestinal wall pathology as a consequence of Ang II-dependent hypertension has been demonstrated in both animal and human studies [41-43]. Similar pathologic gut wall changes have been noted in pulmonary diseases such as COPD and bronchial asthma [44-46]. Moreover, ACE-II deficiency may exacerbate intestinal wall pathology induced by diabetes mellitus in terms of dysbiosis associated with decreased levels of circulating angiogenic cells, hematopoietic cells with loss of reparative function, at least in animal models [47]. Thus, decreased enteric ACE2 expression induced by SARS-CoV-2 infection could similarly reduce circulating angiogenic cells and initiate the dysbiosis [47]. In the proteolysis and ectodomain shedding of ACE2, the membranebound protease TACE (TNF-α-converting enzyme), also known as ADAM-17 (A disintegrin and metalloproteinase 17), is of major importance [48-50].

The family of RAS consists of angiotensin-1-7(ANG (1- 7), angiotensin-2-8 (ANG III), angiotensin-3-8 (ANG IV), and angiotensin-1-12 (ANG (1-12)). ANG (1-7), produced by the catalytic action of ACE2 on ANG II, abolishes the vasodilation induced by ANG II-AT1R. RAS angiotenins are of major importance insofar as ANG (1-9) arises from ANG-I through various carboxypeptidase enzymes such as carboxypeptidase A, cathepsin A, and ACE2. However, ANG represents a competitive inhibitor of ACE [51-60]. An important substrate for ADAM17 is Angiotensin-Converting Enzyme 2 (ACE2), cleavage of which by ADAM17 inactivates ACE2 itself, leading to reduced Ang (1-7) expression and increased angiotensin II retention [61-64]. This not only contributes to arterial hypertension but is involved in cardiovascular remodeling and other vascular diseases [65,66].

Angiotensin 1-7, through its protective effect by reducing oxidative stress and apoptosis, was able to reduce not only infarct size and neurological deficit after induced ischemia but also the risk of rupture of cerebral aneurysms in animal studies [67-78]. Because several studies have excluded a reduction in systolic arterial hypertension by Ang-1-7, the protective effect of Ang 1-7 cannot be related to the level of blood pressure [79-82]. Great importance is attached in the development of aneurysms not to the level of ACE-II expression but to the relative balance of AngII/Ang- (1-7) [83-86].

Deficiency of ACE2 promotes AngII-induced AAAs formation, which results from the reduction of Ang-(1-7) and consequently its protective effect [87,89]. Angiotensin type 1a receptors (AT1aR) are important for AngII-induced AAAs. Nevertheless, animal studies have demonstrated that AT1aR deficiency on endothelial cells and smooth muscle cells does not affect AngII-induced AAAs [89]. Future research will target cells that express ACE2 and control local angiotensin peptide concentrations [90]. Different mutations lead to increased plasma and tissue AngII levels via alterations in the expression level of ACE2 protein, resulting in cardiovascular disease [91-93]. The protective effect of Ang (1-7) on inflammation is achieved through inhibition of the resistin/Toll-like receptor 4 (TLR4)/MAPK/NF-kB signaling pathway. Indirectly, high variability of the TLR4 gene leads to the reduction of this protective effect [94- 97].

Previous studies have found differential expression of ACE and ACE2 messengers in patients with thoracic aortic dissection and thoracic aneurysms, but a significant correlation to ACE I/D and ACE2 (A8790G) polymorphisms has not been demonstrated [98- 101]. Thereby, the reports are very contradictory especially for ACE I/D polymorphism [101-105]. In abdominal aneurysms, a significant difference in genotype distribution and allele frequency was found only for ACE but not for AT1R and TGFBR1 polymorphisms. In this regard, the ACE DD genotype increased susceptibility to AAA, which was more significant when the ACE DD genotype and TGFBR1 6A allele were concurrent [106]. The influence of ACE DD genotype on the development of abdominal aortic anuerysms varies depending on ethnic origin. The association with CE I/D polymorphism occurred much more consistently [107-117].

A large study retrospectively examined the influence of 61 gene polymorphisms on BAA development. strong evidence was found for DAB2IP and LRP1, 9p21/CDKN2BAS, IL6R, LPA, LDLR, MMP3, and AGTR1 polymorphisms, and SORT1 [118-125]. Of course, a number of other polymorphisms and gene variants, such as the Marfan FBN1 gene on chromosome 15, transforming growth factor (TGF) β-signaling, play an important role in the development of the disease, TGFBR2, myosin heavy chain-11 (MYH11), and α-smooth muscle actin-2 (ACTA2) play a major role but are not the subject of this paper [126-130].

In summary, the role of ACE-II receptor as well as the RAS system goes far beyond blood pressure regulation. Its imbalance contributes to the pathophysiology and severity of cardiovascular disease. This role of the ACE-II receptor is either direct or indirect via ANg 1-7. Future research with RAS components based on nanotechnology opens new perspectives for the treatment of severe cardiovascular diseases.

I hereby declare that there were no financial or other interests in the execution and evaluation of this work.

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