Combination of Angiotensin (1-7) Agonists and Convalescent Plasma as a New Strategy to Overcome Angiotensin Converting Enzyme 2 (ACE2) Inhibition for the Treatment of COVID-19

Abstract

Coronavirus disease-2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently the most concerning health problem worldwide. SARS-CoV-2 infects cells by binding to angiotensin-converting enzyme 2 (ACE2). It is believed that the differential response to SARS-CoV-2 is correlated with the differential expression of ACE2. Several reports proposed the use of ACE2 pharmacological inhibitors and ACE2 antibodies to block viral entry. However, ACE2 inhibition is associated with lung and cardiovascular pathology and would probably increase the pathogenesis of COVID-19. Therefore, utilizing ACE2 soluble analogs to block viral entry while rescuing ACE2 activity has been proposed. Despite their protective effects, such analogs can form a circulating reservoir of the virus, thus accelerating its spread in the body. Levels of ACE2 are reduced following viral infection, possibly due to increased viral entry and lysis of ACE2 positive cells. Downregulation of ACE2/Ang (1-7) axis is associated with Ang II upregulation. Of note, while Ang (1-7) exerts protective effects on the lung and cardiovasculature, Ang II elicits pro-inflammatory and pro-fibrotic detrimental effects by binding to the angiotensin type 1 receptor (AT1R). Indeed, AT1R blockers (ARBs) can alleviate the harmful effects associated with Ang II upregulation while increasing ACE2 expression and thus the risk of viral infection. Therefore, Ang (1-7) agonists seem to be a better treatment option. Another approach is the transfusion of convalescent plasma from recovered patients with deteriorated symptoms. Indeed, this appears to be promising due to the neutralizing capacity of anti-COVID-19 antibodies. In light of these considerations, we encourage the adoption of Ang (1-7) agonists and convalescent plasma conjugated therapy for the treatment of COVID-19 patients. This therapeutic regimen is expected to be a safer choice since it possesses the proven ability to neutralize the virus while ensuring lung and cardiovascular protection through modulation of the inflammatory response.

Keywords: ACE2; Angiotensin 1-7 (Ang1-7); COVID-19; SARS-CoV-2; cardiovascular pathology; combination therapy; convalescent plasma (CP); lung pathology.

Figure 1

Simplified view of the extended RAS. In the classically described RAS, the inactive zymogen angiotensinogen secreted mainly by the liver, is converted into Ang I by the action of the renal aspartyl protease, renin. Ang I is then cleaved by ACE to generate the Ang II octapeptide. Ang II is a multifunctional hormone that regulates blood pressure and fluid homeostasis. This peptide exerts its actions through binding to two main receptors, AT1R and AT2R, which are typical seven transmembrane GPCRs. More specifically, Ang II mediates its vasoconstrictor effects by stimulating AT1Rs while AT2Rs are known to balance the actions of AT1Rs via activation of vasodilatory pathways. Dysregulation of the RAS in favor of the ACE/Ang II/AT1R axis leads to the pathogenesis of hypertension as well as tissue injury and multi-organ damage through activation of oxidative stress, proliferation, inflammation, fibrosis, edema, and apoptosis. Ang II can either bind to its receptors or is further cleaved to yield degradation products such as Ang (1-7). This bioactive peptide is produced mainly by means of ACE2. Ang (1-7) is obtained directly by the action of ACE2 on Ang II or indirectly by generating Ang (1-9) as an intermediate product. Ang (1-7) exerts its protective effects through activation of the AT2R and MasR and opposes the described detrimental effects of the ACE/Ang II/AT1R axis.

Figure 2

ACE2 in the pathology of COVID-19. The novel SARS-CoV-2 infects the cells through binding to its main receptor ACE2. The latter recognizes the RBD of the S1 subunit and allows the endocytosis of the virus (1). Once exposed to the action of proteases, such as the cellular TMPRSS2, the S1 subunit is cleaved away to ensure S protein priming (2). The fusion peptide (FP) of the S2 subunit is thus exposed to the cellular membrane. The FP initiates the fusion of the viral coat to the endosomal membrane enabling the uncoating of the virus (3). Released into the cytoplasm of the host cell, the viral RNA hijacks the cellular machinery to produce novel viral particles (4). Massive viral replication is thought to be linked with pyroptosis (5), an inflammatory form of apoptosis associated with the release of inflammatory mediators that activate various immune cells in order to create a cytokine storm (6) contributing to the pathogenesis of COVID-19. Viral entry and cellular apoptosis lead to ACE2 downregulation (7), thus stimulating the harmful effects of the ACE/Ang II/AT1R axis. Altogether, these processes are translated into tissue injury and multi-organ damage (8) that can evolve into respiratory, cardiac, hepatic, and/or renal failure (9), causing death (10).

Figure 3

Possible treatment strategies for COVID-19. ACE2 is believed to be the main entry door for the SARS-CoV-2. ACE2 interaction with the RBD of the S1 subunit mediates viral entry into the host cell. To inhibit viral entry, researchers suggest the use of several drugs, including ACE2 inhibitors, soluble ACE2 analogs, S protein inhibitors, and transfusion of convalescent plasma from recovered patients. First, ACE2 inhibitors (pharmacological inhibitors and Abs) are more harmful than protective since ACE2 is known to be the primary source of the anti-inflammatory Ang (1-7) peptide. ACE2 inhibition and upregulation of Ang II expression stimulate the pathogenesis of many diseases through activation of AT1R. The latter stimulates oxidative stress, proliferation, inflammation, fibrosis, edema, and apoptosis, thus leading to tissue injury and multi-organ damage. Of note, Ang (1-7) counteract the ACE/Ang II/AT1R axis by activating the MasR and the AT2R. Second, soluble ACE2 analogs act as a trap competitively binding the virus to prevent cellular entry while rescuing ACE2 activity. Despite their beneficial effects, they can form a circulating reservoir of the virus. Third, spike protein inhibitors appear to be more promising to reduce disease severity. Fourth, another effective plan is based on the use of COVID-19 Abs from CP of recovered patients to neutralize the virus. This alternative has been proved to be safe and efficient in critically ill patients. Fifth, other therapeutic approaches encourage targeting S protein priming by means of protease inhibitors such as TMPRSS2 inhibitors to prevent the release of viral RNA into the cytoplasm of host cells, thus blocking subsequent viral replication and inflammation. In fact, virus entry and apoptosis are associated with ACE2 downregulation and consequently Ang II overproduction. Sixth, recent reports propose the use of Ang (1-7) analogs to block excessive inflammation through stimulation of the protective arm of the RAS. Importantly, Ang (1-7) drug formulation is useful in the management of several diseases, including cancer. Seventh, others suggest that ARBs and ACEIs might be useful in blunting the detrimental effects of ACE/Ang II/AT1R axis. Of note, these could also upregulate the expression of ACE2 and thus the risk of viral entry. Based on the above, we encourage the adoption of CP and Ang (1-7) conjugated therapy to neutralize the virus while controlling the inflammatory process to ensure organ protection.