Classical and Counter-regulatory Renin-angiotensin System: potential key roles in COVID-19 pathophysiology.

In the current coronavirus disease 2019 (COVID-19) pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses angiotensin-converting enzyme-2 (ACE-2) receptor for cell entry leading to ACE-2 dysfunction and downregulation which disturbs the balance between classical and counter-regulatory renin-angiotensin system (RAS) in favor of classical RAS. RAS dysregulation is one of the major characteristics of several cardiovascular diseases, thus adjustment of this system is the main therapeutic target. RAS inhibitors - particularly angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II type 1 receptor blockers (ARBs) - are commonly used for treatment of hypertension and cardiovascular disease. Patients with cardiovascular diseases are the group most commonly seen amongst those with COVID-19 comorbidity. At the beginning of this pandemic, a dilemma occurred regarding the use of ACEIs and ARBs potentially aggravating cardiovascular and pulmonary dysfunction in COVID-19 patients. Urgent clinical trials from different countries and hospitals reported that there is no association between RAS inhibitor treatment and COVID-19 infection or comorbidity complication. Nevertheless, the disturbance of the RAS system that is associated with COVID-19 infection and the potential treatment targeting this area has yet to be resolved. In this review, the link between the dysregulation of classical RAS and counter-regulatory RAS activities in COVID-19 patients with cardiovascular metabolic diseases is investigated. In addition, the latest findings based on ACEIs and ARBs administration and ACE-2 availability in relation to COVID-19 which may provide a better understanding of RAS contribution to COVID-19 pathology is discussed as it is of the utmost importance amid the current pandemic.