The ACE-2 in COVID-19: Foe or Friend?

Abstract

COVID-19 is a rapidly spreading outbreak globally. Emerging evidence demonstrates that older individuals and people with underlying metabolic conditions of diabetes mellitus, hypertension, and hyperlipidemia are at higher risk of morbidity and mortality. The SARS-CoV-2 infects humans through the angiotensin converting enzyme (ACE-2) receptor. The ACE-2 receptor is a part of the dual system renin-angiotensin-system (RAS) consisting of ACE-Ang-II-AT₁R axis and ACE-2-Ang-(1-7)-Mas axis. In metabolic disorders and with increased age, it is known that there is an upregulation of ACE-Ang-II-AT₁R axis with a downregulation of ACE-2-Ang-(1-7)-Mas axis. The activated ACE-Ang-II-AT1R axis leads to pro-inflammatory and pro-fibrotic effects in respiratory system, vascular dysfunction, myocardial fibrosis, nephropathy, and insulin secretory defects with increased insulin resistance. On the other hand, the ACE-2-Ang-(1-7)-Mas axis has anti-inflammatory and antifibrotic effects on the respiratory system and anti-inflammatory, antioxidative stress, and protective effects on vascular function, protects against myocardial fibrosis, nephropathy, pancreatitis, and insulin resistance. In effect, the balance between these two axes may determine the prognosis. The already strained ACE-2-Ang-(1-7)-Mas in metabolic disorders is further stressed due to the use of the ACE-2 by the virus for entry, which affects the prognosis in terms of respiratory compromise. Further evidence needs to be gathered on whether modulation of the renin angiotensin system would be advantageous due to upregulation of Mas activation or harmful due to the concomitant ACE-2 receptor upregulation in the acute management of COVID-19.

Fig. 1

Schematic Representation to show the renin angiotensin system in diabetes and the interaction of the SARS-CoV 2 with the ACE-2. 1. The SARS-CoV 2 interacts with the ACE-2 through the spike proteins after priming by tissue serene proteases. It uses the ACE-2 protein to enter the alveolar cells in the lungs. 2. The renin angiotensin system consists of renin which catalyzes the conversion of angiotensinogen to angiotensin 1 (Ang 1). The subsequent axis depends on the balance between the Angiotensin converting enzyme (ACE) and ACE-2. ACE converts Ang 1 to Ang II and this acts in the angiotensin receptor (AT ₁ R), whereas ACE-2 converts it to Ang-(1–7), which acts on the Mas receptor. 3. In the respiratory system activation of ACE leads to a proinflammatory, pro-fibrotic , pro-hyperresponsiveness response in the respiratory system, whereas ACE-2-Ang-(1–7)-Mas induces a protective mechanism of anti-inflammatory, anti-fibrotic and anti-hyperresponsiveness. A lower ACE-2 will put these individuals at higher risk of respiratory distress. 4. In hypertension, diabetes, and CVD, the ACE related pathway is activated with downregulation of the ACE-2 pathway. These results in the multi-organ complications seen in metabolic diseases with endothelial dysfunction promoting atherosclerosis, increased cardiac fibrosis and LV remodeling, diabetic nephropathy, hyperactivity of adrenal gland, and it decreases insulin release and increases insulin resistance. 5. Infection with COVID-19 may exacerbate the ACE-2 deficiency in these patients in all organs and maybe responsible for the multiorgan failure.