Association of ACE inhibitors and angiotensin type II blockers with ACE2 overexpression in COVID-19 comorbidities: A pathway-based analytical study

Abstract

Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) outbreak is a major public health concern, which has accounted for >1.7 million deaths across the world. A surge in the case fatality ratio as compared with the infection ratio has been observed in most of the countries. The novel Coronavirus SARS-CoV-2 shares the most common sequence with SARS-CoV, but it has a higher rate of transmission. The SARS-CoV-2 pathogenesis is initiated by the binding of viral spike protein with the target receptor Angiotensin-Converting Enzyme 2 (ACE2) facilitating virus internalization within host cells. SARS-CoV-2 mainly causes alveolar damage ranging from mild to severe clinical respiratory manifestations. Most of the cases have revealed the association of Coronavirus disease with patients having earlier comorbidities like Hypertension, Diabetes mellitus, and Cerebrovascular diseases. Pharmacological investigation of the SARS-Cov-2 patients has revealed the frequent use of drugs belongs to Angiotensin-converting enzyme inhibitors (ACEi) and/or Angiotensin II type I receptor blockers (ARBs). Interestingly, a significant increase in ACE2 expression was noticed in patients routinely treated with the above group of drugs were also reported. To date, the association of ACEi and/or ARBs with the up-regulation of ACE2 expression has not been defined distinctively. The proposed review will focus on the pathways which are responsible for the upregulation of ACE2 and its impact on gravity of SARS-CoV-2 disease.

Keywords: ACE2; ACEi; ARB; COVID-19; Comorbidities; Pathways.

Fig. 1

Diagrammatic portrayal of the Renin-angiotensin system. (AP-A: Glutamyl aminopeptidase, AP-N: Alanyl aminopeptidase, PREP: Prolyl endopeptidase, IRAP: Leucyl and cystinyl aminopeptidase).

Fig. 2

Schematic representation of RAAS associated AT1 and AT2/Mas receptor activity. ACEi inhibits the function of ACE I and ARBs inhibit the downstream signaling of AT1 receptor. AMPK/SIRT1 induces ACE2 regulation. Cytokines and Interferon's upregulating ACE2 expression through JAK/STAT signaling. IL-6 mediated STAT3 signaling upregulates ACE2. In comparison with the ACEi and ARBs, insulin, Non-steroidal anti-inflammatory drugs, dipeptidyl peptidase-4 inhibitor, glucagon-like peptide 1 receptor agonists in association with crucial molecular pathways regulate the ACE2 expression.