Role of the Renin–Angiotensin–Aldosterone and Kinin–Kallikrein Systems in the Cardiovascular Complications of COVID-19 and Long COVID

Abstract

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the virus responsible for the COVID-19 pandemic. Patients may present as asymptomatic or demonstrate mild to severe and life-threatening symptoms. Although COVID-19 has a respiratory focus, there are major cardiovascular complications (CVCs) associated with infection. The reported CVCs include myocarditis, heart failure, arrhythmias, thromboembolism and blood pressure abnormalities. These occur, in part, because of dysregulation of the Renin–Angiotensin–Aldosterone System (RAAS) and Kinin–Kallikrein System (KKS). A major route by which SARS-CoV-2 gains cellular entry is via the docking of the viral spike (S) protein to the membrane-bound angiotensin converting enzyme 2 (ACE2). The roles of ACE2 within the cardiovascular and immune systems are vital to ensure homeostasis. The key routes for the development of CVCs and the recently described long COVID have been hypothesised as the direct consequences of the viral S protein/ACE2 axis, downregulation of ACE2 and the resulting damage inflicted by the immune response. Here, we review the impact of COVID-19 on the cardiovascular system, the mechanisms by which dysregulation of the RAAS and KKS can occur following virus infection and the future implications for pharmacological therapies.

Long COVID and long chain fatty acids (LCFAs): Psychoneuroimmunity implication of omega-3 LCFAs in delayed consequences of COVID-19

“…The development of long COVID is speculated to be directly linked to the viral S protein/ACE2 axis, the downregulation of ACE2, and the damage caused by the immune response ( Cooper et al, 2021 ). Interestingly, intervention with omega-3 PUFAs not only improve the formation of beneficial PGs, but also inhibit angiotensin-converting enzyme activity, reduce angiotensin II formation, activate endothelial nitric oxide synthase (eNOS) generation, suppress TGF-beta expression and enhance the parasympathetic nervous system ( Borghi and Cicero, 2006 , Darwesh et al, 2021 ).…”

“…NOS)Directly scavenge free radicals ( Anderson et al, 2014 ) ME/CFS, the symptoms of long COVID may also be due to redox imbalance, which in turn is associated with inflammation, a defective energy metabolism, and a hypometabolic state ( Paul et al, 2021 ) Imbalance of RAAS system Induces a downregulation of ACE2, from which follow the reduced ACE2 levels that are associated with decreased formation of Ang-(1-7) and the loss of its vasodilatory, anti-inflammatory and cardiovascular protective effects ( Yan et al, 2020 ). Improve the formation of beneficial prostaglandin, but also inhibit ACE activity, reduce angiotensin II formation, activate eNOS generation, suppress TGF-β expression and enhance the parasympathetic nervous system ( Borghi and Cicero, 2006 , Darwesh et al, 2021 ) Directly linked to the viral S protein/ACE2 axis, the downregulation of ACE2, and the damage caused by the immune response ( Cooper et al, 2021 ) Disordered Coagulopathy The consumption of coagulation factors, as marked by thrombocytopenia-extension of prothrombin time-prominent elevation of D-dimer and other fibrinogen degradation products (FDPs) ( Tang et al, 2020 ) Antithrombotic effects against platelet activating factors and other prothrombotic pathways, including thrombin, collagen, and adenosine diphosphate ( Lordan et al, 2020 ) Some of the most resistant amyloid deposits to fibrinolysis are present in large amounts in plasma samples from long COVID and are not readily lysed even by the two-step trypsin method ( Pretorius et al, 2021 ) EPA and DHA contribute significantly to the regulation of platelet function in hemostasis and thrombosis due to their ability to act on platelet membranes via COX-1 and 12-LOX to reduce platelet aggregation and TX release, and metabolize fatty acids in platelets into a beneficial group of oxylipins ( Lordan et al, 2020 , Park and Harris, 2002 ) Virus entry and replication for persistent viral infection Lipid raft modulation may be an option to reduce ACE2-mediated virus infection where ACE2 and TMPRSS2 are mainly expressed ( Goc et al, 2021 , Vivar-Sierra et al, 2021 ) EPA and DHA could bind to the S protein of SARS-CoV-2, locking its inactive conformation and preventing the interaction between S protein and ACE2, thus preventing SARS-CoV-2 infection ( …”

Angiotensin System Modulations in Spontaneously Hypertensive Rats and Consequences on Erythrocyte Properties; Action of MLN-4760 and Zofenopril

“…Benefits provided by Ang 1-7 are compromised in SARS-CoV-2 infection due to downregulation of tissue ACE2 receptors. This is considered to be one of the major factors responsible for cardiovascular complications in patients with COVID-19 [ 14 , 15 , 36 ]. In the present study, two RAS-modulating chemical compounds were administered to experimental animals—two enzyme inhibitors: MLN (ACE2 inhibitor) and zofenopril (ACE inhibitor).…”

Plasma Renin Concentration in Critically Ill COVID-19 Patients

“…However, their measurement is often not simple or easy to perform, or their accuracy is not entirely known, and many conditions can alter their values [6]. Furthermore, RAAS dysregulation in COVID-19 patients has a dangerous role in cardiovascular complications [7]. In eight patients, we observed a higher plasma renin concentration in patients with difficulty weaning and in non-survivors; only one patient with a low value of plasma renin died, due to a sudden cerebral disease one day before ICU discharge.…”