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{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/7408073","sourcedb":"PMC","sourceid":"7408073","source_url":"https://www.ncbi.nlm.nih.gov/pmc/7408073","text":"(s)ACE2 or Ang (1–7) upregulation have been associated to some pathological conditions such as inflammation of the renal and gastrointestinal tract, cardiac dysfunction, human cirrhosis and lung injury/fibrosis. Tissue/organ specific effects of excessive pathway activation that in some case resemble those produced by excessive Ang II/AT1R pathway activation (see Figure 1). For example, systemic infusion of Ang (1–7) into mice had renal proinflammatory properties mediated by Mas receptor (MasR) activation [47]. Moreover, Ang (1–7) infusion was associated with increases in blood pressure, cardiac hypertrophy and fibrosis in rats with subtotal nephrectomy [48]. Similarly, elevated plasma sACE2 activity was associated both with greater severity of myocardial dysfunction and with an independent prediction of adverse clinical events [22,49]. Transgenic mice with increased cardiac ACE2 expression suffered from lethal ventricular arrhythmia (heart block, ventricular tachycardia and terminal ventricular fibrillation) consequent upon downregulation of connexins involved in gap junction formation [50]. In another model, ACE2 transgenic mice suffered from cardiac fibrosis with concomitant deficits in ejection fraction and fractional shortening [51]. Interestingly, in a rat model of myocardial infarction following coronary artery ligation, there is evidence that C16/MLN-4760 (a specific ACE2 inhibitor, see later) administration inhibits fibrosis and hypertrophy of non-infarcted myocardium and increases diastolic relaxation, raising the possibility that ACE2 activity may have some adverse effects on post-myocardial infarction heart [52]. The risk factors for cardiovascular disease include alterations in platelet function and coagulation with an increased risk of thrombosis. Ang II and hypercholesterolemia are known to participate in microvascular thrombosis and enhanced thrombus formation in the microvasculature may contribute to microinfarctions. To this end, in a rat model in which AT1R activation produce baseline thrombosis by platelet aggregation, Ang (1–9), known to bind AT2R [42], has been shown to enhance the thrombotic process [53]. Moreover, in a mouse model, AT2R activation (inhibited by AT2R antagonist, PD12319) mediated the onset of arteriolar microvascular thrombosis following chronic Ang II infusion [54], indicating both the recruitment of the AT2R pathway downstream of AT1R activation and its involvement in arteriolar thrombosis. Of interest, disseminated intravascular coagulation is associated with hypoproteinaemia and deficit of coagulation and anticoagulation proteins, which can originate by their renal loss (and consequent proteinuria) and/or by their increased (pathological) consumption and/or by their reduced hepatic synthesis. To this end, in healthy livers, ACE2 is limited to perivenular hepatocytes and endothelial cells; instead, in human hepatitis C cirrhosis, ACE2 protein expression is widespread in the hepatic parenchyma [55]. Notably, human hepatocytes cultured in hypoxic conditions upregulated ACE2 protein expression [55] and ACE2 mRNA, protein and activity were increased in response to hypoxia and by IL-1β [56]. In line with these observations, in peripheral blood human CD34+ cells, MasR expression and ACE2 expression, activity and shedding (of sACE2 catalytically active forms) were increased under hypoxia [57]. Moreover, under hypoxic conditions human pulmonary artery smooth muscle cells upregulated both (arms of the RAS) ACE and ACE2 mRNA and protein expression, and ACE2 was subsequently downregulated by (ACE-derived) Ang II through an AT1R-mediated process [58]. Similarly, both ACE and ACE2 expression were increased in vascular endothelium and smooth muscle of human left ventricle from patients with ischaemic (local hypoxia) heart disease [59]. Concomitant upregulation of both arms of the RAS that suggests a tight link between ACE and ACE2 under hypoxic conditions. Indeed, several reports have shown a complex interplay of regulation between the two arms of the RAS independently on hypoxia (see Box 2). Interestingly, chronic hypoxia induced activation of ACE2/Ang (1–7)/MasR axis and suppression of ACE/Ang II/AT1 receptor axis in lungs of pulmonary hypertensive Ren-2 transgenic rats (constructed by inserting the mouse Ren-2 renin gene) but not in normotensive transgene-negative control rats [60], suggesting that the baseline renin activity in hypertensive rats may be crucial to determine the differential response to hypoxia and that renin inhibition might be useful to inhibit the ACE to ACE2 pathway shift under hypoxic conditions. Of interest, hypoxia alone or combined with hypercapnia has been shown to significantly increase both plasma renin expression or activity and plasma Ang II expression [61,62]. Moreover, hypercapnic acidosis (pH 6.8/6.9, a condition that could occur in SARS) induced in isolated rat lungs has been shown to induce a (compensatory) venular dilatation mediated by cyclooxygenase activation (inhibited by indomethacin) [63], an enzyme that has been shown to be induced downstream of Ang (1–7)/MasR pathway in isolated rat hearts (again inhibited by indomethacin) [64], suggesting the involvement of ACE2/Ang (1–7) pathway in mediating CO2-dependent lung venular vasodilation. Altogether these observations indicate that there is a high probability that hypoxia/hypercapnia, a condition that occurs in SARS patients, might upregulate the activity of both arms of the RAS by suppling high amounts of renin product, Ang I, to ACE and ACE2, which, together, can produce high amounts of Ang II, Ang (1–9), Ang (1–7) and its (ACE-produced) metabolite, Ang (1–5) (see Figure 1). Similarly to both Ang (1–7)/MasR and Ang (1–9)/AT2R pathways, Ang (1–5) has been shown to induce the secretion of atrial natriuretic peptide via MasR/NOS pathway in isolated perfused rat atria [65], indicating that Ang (1–5) is a heart active peptide (at least in Sprague-Dawley rats). Interestingly, in the plasma of patients with inflammatory bowel disease, Ang (1–7) concentrations and (s)ACE2 activity were higher compared to healthy subjects [66]. Moreover, Ang (1–7) alone can either activate the Bax/Caspase–dependent apoptotic pathway or upregulate NF-kB signaling in lung fibroblast cultures [67]. Moreover, in vivo administration of Ang (1–7) alone (in Wistar rats) promoted morphological lung alterations, extracellular matrix accumulation and inflammatory cytokine production (including TNF-α and IL-6), characteristics of lung inflammation in pulmonary fibrosis [67]. Thereby, a condition that deteriorates respiratory compliance, could lead to hypoxia/hypercapnia. Hypoxia, in turn, will induce ACE2 upregulation which possibly increases cardiac/lung detrimental effects mediated by Ang (1–7)/MasR pathway activation finally leading to further ACE2 cell membrane upregulation. A condition that in COVID-19 can increase the probability of both SARS-CoV-2 entry and ACE2 shedding/systemic activity, finally generating positive feedback loops that might sustain SARS independently of viral infection (see Figure 2). This hypothesis is supported by the observations that, in lung aspirates of acid- and/or spike-treated mice, Ang II and ACE2 are synergistically upregulated and cell surface downregulated (shed), respectively, suggesting their involvement in the increased lung microvascular permeability and pulmonary oedema [14,15]. Indeed, this condition might subsequently favour the diffusion, in neighbouring lung tissues and systemic circulation, of both (s)ACE2, Ang II and Ang (1–7), the Ang II-derived product of (s)ACE2 processing. As already proposed, enhanced ACE2 shedding may locally reduce ACE2 activity in lung, however, it likely increases ACE2 systemic activity and subsequent production of circulating Ang (1–7). Interestingly, Ang (1–7) has been also reported to promote eosinophil apoptosis in lungs and in bronco-alveolar lavage fluid (BALF) [40]. Moreover, Ang (1–7)/MasR axis inhibits allergic airway inflammation and eosinophil cell counts in the BALF of a murine model of asthma, indicating both that an impairment of ACE2 pathway may favour asthma and that ACE2 pathway activation can reduces asthma symptoms [68]. Moreover, a compound that mimics the Ang (1–7) actions has been shown to induce IL-10 upregulation via a MasR-dependent pathway in BALF [69] and IL-10 is thought to mediate anti-inflammatory effects of MasR pathway activation [70]. IL-10 secretion in mouse plasma was also induced by an AT2 receptor agonist and downstream nitric oxide signalling [71]. Increased IL-10 production (e.g., by T regulatory cells) is often associated with immune tolerance, which is the consequence of reduced number and function of specific immune compartments [72]. Indeed, IL-10 has been shown not only to suppress antigen-specific Th2-mediated immune responses including eosinophil expansion in allergic inflammation [72], but also to augment airway reactivity, suggesting that despite its potent anti-inflammatory activity, an excess of IL-10, as well as Ang (1–7), may contribute to the decline in pulmonary function [73]. Of note, IL-10 is one of the cytokines downstream ACE2 pathway [25] and is significantly upregulated in the most severe forms of COVID-19 [2,8,9], indicating an important correlation between ACE2/Ang (1–7) axis activation and IL-10 upregulation which might lead to eosinopaenia/lymphopaenia in COVID-19 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