The potential actions of angiotensin‐converting enzyme II (ACE2) activator diminazene aceturate (DIZE) in various diseases

Abstract

The renin angiotensin system (RAS) regulates fluid balance, blood pressure and maintains vascular tone. The potent vasoconstrictor angiotensin II (Ang II) produced by angiotensin‐converting enzyme (ACE) comprises the classical RAS. The non‐classical RAS involves the conversion of Ang II via ACE2 into the vasodilator Ang (1‐7) to counterbalance the effects of Ang II. Furthermore, ACE2 converts AngA into another vasodilator named alamandine. The over activation of the classical RAS (increased vasoconstriction) and depletion of the non‐classical RAS (decreased vasodilation) results in vascular dysfunction. Vascular dysfunction is the leading cause of atherosclerosis and cardiovascular disease (CVD). Additionally, local RAS is expressed in various tissues and regulates cellular functions. RAS dysregulation is involved in other several diseases such as inflammation, renal dysfunction and even cancer growth. An approach in restoring vascular dysfunction and other pathological diseases is to either increase the activity of ACE2 or reduce the effect of the classical RAS by counterbalancing Ang II effects. The antitrypanosomal agent, diminazene aceturate (DIZE), is one approach in activating ACE2. DIZE has been shown to exert beneficial effects in CVD experimental models of hypertension, myocardial infarction, type 1 diabetes and atherosclerosis. Thus, this review focuses on DIZE and its effect in several tissues such as blood vessels, cardiac, renal, immune and cancer cells.

Assessing ACE2 expression patterns in lung tissues in the pathogenesis of COVID-19

“…In view of the role of the ACE2 receptor in the ability of SARS-CoV-2 to enter host cells [20], the question arises as to the effect of ACE inhibitors and angiotensin-receptor blockers (ARBs) in the pathogenesis of COVID-19. This turns out to be a very complex relationship and is currently still very controversial.…”

The Anti-Inflammatory Effect of Taurine on Cardiovascular Disease

“…The RAS is usually pharmacologically targeted for the management of heart failure [34][35][36][37], diabetes [38,39], and hypertension/blood pressure control [40][41][42]. The main effector of RAS is angiotensin II (AngII), which is produced by angiotensin-converting enzyme (ACE) within the circulation or in ACE-expressed cells [43][44][45]. AngII stimulates the AngII type 1 receptor (AT1R) and AngII type 2 receptor (AT2R) on blood vessels to cause vasoconstriction and vasodilation, respectively [44][45][46].…”

“…The main effector of RAS is angiotensin II (AngII), which is produced by angiotensin-converting enzyme (ACE) within the circulation or in ACE-expressed cells [43][44][45]. AngII stimulates the AngII type 1 receptor (AT1R) and AngII type 2 receptor (AT2R) on blood vessels to cause vasoconstriction and vasodilation, respectively [44][45][46]. Another enzyme of RAS is angiotensin-converting enzyme II (ACE2), which is important for producing the other components of RAS, such as angiotensin (1-7) (Ang 1-7) and alamandine, both of which stimulate the oncogene receptors, Mas R and Mas-related G-coupled protein receptor member D (MrgD R) [46].…”

Could DIZE be the answer to COVID-19?

“…Patients with SARS-CoV-2 virus infection develop pulmonary edema and acute respiratory distress syndrome. ACE2 is expressed in the lungs, heart, kidneys and testes [2][3][4], and converts angiotensin II to angiotensin (1-7) or alamandine [5][6][7], thus, removing the pathogenic angiotensin II from the cellular milieu [8][9][10][11]. The role of ACE2 in normal pulmonary and myocardial physiology is well established, considering ACE2 reduction leads to myocardial [12,13] and pulmonary disease [14,15].…”

“…We published a paper on DIZE [8] showing its effect at increasing ACE2 activity. We have also noted that DIZE increases ACE2 protein in blood vessels (manuscript submitted) but whether or not DIZE can directly bind to ACE2 is currently unknown.…”