Exploration of multifaceted molecular mechanism of angiotensin-converting enzyme 2 (ACE2) in pathogenesis of various diseases

Abstract

Angiotensin converting enzyme 2 (ACE2) is a homolog of ACE (a transmembrane bound dipeptidyl peptidase enzyme). ACE2 converts angiotensinogen to the heptapeptide angiotensin-(1-7). ACE2 and its product, angiotensin-(1-7), have counteracting effects against the adverse actions of other members of renin-angiotensin system (RAS). ACE2 and its principal product, angiotensin-(1-7), were considered an under recognized arm of the RAS. The COVID-19 pandemic brought to light this arm of RAS with special focus on ACE2. Membrane bound ACE2 serves as a receptor for SARS-CoV-2 viral entry through spike proteins. Apart from that, ACE2 is also involved in the pathogenesis of various other diseases like cardiovascular disease, cancer, respiratory diseases, neurodegenerative diseases and infertility. The present review focuses on the molecular mechanism of ACE2 in neurodegenerative diseases, cancer, cardiovascular disease, infertility and respiratory diseases, including SARS-CoV-2. This review summarizes unveiled roles of ACE2 in the pathogenesis of various diseases which further provides intriguing possibilities for the use of ACE2 activators and RAS modulating agents for various diseases.

Keywords: Angiotensin II; Angiotensin-converting enzyme 2; Cancer; Neurodegenerative diseases; Renin-angiotensin system; SARS-CoV-2.

Graphical abstract

Fig. 1

Renin-angiotensin system (RAS) targeting SARS-CoV-2 viral entry mechanism. (The process of SARS-CoV-2 entering host cells in the lungs is represented here. SARS-CoV-2 enters the lungs via spike glycoprotein of the virus. Spike protein binds to ACE2 on cells and allows viral entry. Transmembrane protease serine 2 (TMPRSS2) also participates in this process. Viral entry to the host cell further produces mature virion which causes immunological reactions and inflammatory responses. ANG II contributes to the key events of the inflammatory response. It also plays a role in the recruitment of infiltrating inflammatory cells into tissues, either directly activating them or by controlling the expression of adhesion molecules and chemokines by resident cells. Other pro-inflammatory effects of ANG II are also possible. ANG II stimulates MCP-1 (Monocyte chemoattractant protein-1), a crucial component of the inflammatory process. Nuclear factor Kappa B (NF-ĸB) is activated as a result of AT1R activation, and this in turn triggers the production of a number of cytokines and adhesion molecules, including TNF-α, IL-6, IL-8, MCP-1, and transforming growth factor (TGF)-β. In addition, ROS and cytokines like TNF-β may activate NF-ĸB, which increases cytokine production, the creation of a positive feedback loop, and thereafter amplification of the inflammatory process leading to lung injury.).

Fig. 2

Role of members of the RAS system in Cancer. (ANG II, a member of the RAS system acts as a potent mitogen. ANG II is involved in cell proliferation, inflammation, migration and angiogenesis process. ANG II increases ROS production which further induces VEGF production and causes cancer. Effect of ACE2 enzyme in cancer is complicated. It may have both positive and negative roles in cancer therapies. It can decrease cancer cell growth, invasion and angiogenesis in breast cancer, lung cancer, colon cancer and pancreatic cancer but it promotes the migration and invasion of human renal cell carcinoma cells.)

Fig. 3

Role of RAS in various neurodegenerative diseases. (A decreased level of ACE2 is responsible for several neurodegenerative diseases. A decrease in ACE2/ANG-(1–7)/MasR causes an increase in neuroinflammation, oxidative stress, cognitive impairment, β–peptide formation and tau phosphorylation. Therefore, ACE2/ANG-(1–7)/MasR axis components lead to neuroprotection in CNS disorders like AD, PD and HD.).