Apelin-ACE2 axis fate in hypertension and macrophage syndrome as complications in COVID-19: focus on gender, age and comorbidities.

Age and cardio-metabolic risk factors are one of the main determinants of SARS-CoV2-induced disease severity and death. 30 to 40% of the patients present severe acute cardiovascular damages. Consequently, heart failure is a prominent cause of death in COVID-19 severely ill patients. Besides, it is also expected that patients recovering from COVID-19 may develop chronic cardiovascular diseases (CVD). Interestingly, the angiotensin-converting enzyme 2 (ACE2), a transmembrane protein, is the main target of the SARS-CoV2 to infect the host cells and represents a critical connection between immunity, inflammation, and cardiovascular disease. A puzzling and unsolved question relies on the effect of medications taken by a large number of CVD patients that interfere with the renin-angiotensin system (RAS). One of the crucial observations for ACE2 is that its levels can be increased by the use of anti-hypertensive drugs that consequently might increase the level of virus infection for treated patients. This issue is yet to be evaluated. Whether patients with COVID-19 and hypertension treatment present a higher risk and should modify their anti-hypertensive medications is unproven, and experimental evidence is required. Understanding the acute and chronic cardiac damages caused by the hijacking of ACE2 (as occurring with by SARS CoV-2) with or without anti-hypertensive treatment is of paramount to define therapeutic strategies for COVID-19 patients, to reduce the mortality.Therefore, in the first part, our objectives are to 1) quantify the tissue RAS agents such as ACE2 and receptors in related to age, sex and health status in rodent models with several physiological and pathophysiological heart alterations, and 2) investigate different therapeutic strategies in these models based on the modulation of ACE2 focusing in particular, on the Apelin-ACE2 axis. Activation of Apelin and its receptor Aplnr axis increase the expression of ACE2 and interfere with the RAS by decreasing angiotensin-converting enzyme (ACE) and angiotensin II (Ang-II) production, and angiotensin receptor 1 (AT1R).In addition, using global transcriptomic and system biology approach, we have identified APELIN-ACE2 axis as one of the important pathway altered during cardiac aging. Apelin-Aplnr axis regulates several transcription factors like SMAD2/3/4, PGC-1a, KLF2, and MEF2, and signalling pathways like PI3K/Akt, ERK1/2 and AMPK. Interestingly, 55 amino acid proapelin is cleaved to its active form of 13 amino acids by PCSK3/Furin, which is an essential protein involved in the processing of SARS-CoV2 spike protein. These findings suggest a possible role of Apelin-APLNR axis in SARS-CoV2 cellular entry. Therefore, in the second part, we aim at exploring whether 1) activation and 2) inhibition of apelin signalling pathway would regulate cellular proteins involved in SARS-CoV2 viral entry in rodents. In mild and severe Covid-19 patients, apelin levels will be correlated with various cardiac, kidney and lung function parameters.Severe Covid-19 patients exhibit features of systemic hyper-inflammation termed as macrophage activation syndrome or cytokine syndrome. Apelin signalling pathway plays a crucial role in macrophage physiological and pathological functions. However, its role in macrophage activation syndrome is not well studied. In addition, elevated ROS production has been critical for the phagocyte action and killing of the invading pathogen, making it an integral part of the innate immune response. Additionally, apelin signalling pathway also regulates ROS production. Based on our preliminary results, we have seen that infusion of AngII to p47 phox (an enzyme involved in ROS production) knockout mice results in macrophage activation syndrome, characterised by increased expression of several cytokines. Here, in the third part, we aim to 1) decipher the role of apelin signalling in macrophage activation syndrome and 2) assess the role of p47phox in macrophage activation syndrome-like condition and its effect on Apelin-Aplnr, ACE-2 axis.Overall the project will simultaneously address the disease mechanism and optimisation of therapy for COVID-19 patients. In particular, we expect to define the effect of anti-hypertensive treatment on ACE2 modulation related to conditions such as age, gender and macrophage activation syndrome. This will provide the necessary information concerning the beneficial or deleterious effect on this multi-drug therapy. The collaboration will expose both the institutes to their state-of-the-art facilities, leading to overall growth and advancement of the area. Knowledge gained from this proposed study will be very critical for future COVID-19 patient care and bears a very high clinical importance. The project paves the way to the next step on human interventional studies implementing the evidence-based results.