There has been suggestion that vitamin D may play a role in protection against severe infection with COVID-19. In this article a potential mechanism involving angiotensin-converting enzyme 2 (ACE2) is proposed.
Introduction
Retrospective studies revealed that vitamin D may protect against severe COVID-19 disease,1,2 and some pilot studies suggest that it even improves prognosis.3,4 The two most widely accepted theories are the vitamin D modulation of immunity and the renin–angiotensin system.5,6 So far, the mechanism of the benefit of vitamin D in COVID-19 remains unknown.
Role of ACE2
Angiotensin-converting enzyme 2 (ACE2) converts angiotensin (Ang) II to Ang(1–7) and Ang I to Ang(1–9) (figure 1).7 Ang(1–7) has a very short half-life (<9 seconds), and the release of a soluble catalytic ectodomain of ACE2 (ceACE2) from the vascular endothelium may serve to alter systemic Ang(1–7) concentrations and the relative peripheral balance of ACE2/ACE.8 Ang(1–7) acts on the Mas receptor to provide beneficial cardiovascular effects. Thus, the ACE2/Ang(1–7)/Mas axis exerts cardiovascular protection by providing antifibrotic, antihypertrophic, antithrombotic, and vasodilator effects. In contrast, the ACE/Ang II/Ang II receptor axis exerts the opposite effects.9 Many studies revealed that high levels of soluble ceACE2 plasma activity is a predictor of adverse cardiovascular events, cardiovascular mortality, and all-cause mortality,10,11 and also could be a potential biomarker of cardiac remodelling.11
Role of vitamin D
ACE2 can be present in two forms: the first as a transmembrane cell-associated form of ACE2, with mRNA cell expression present in the cardiovascular system, kidney, intestine, and alveolar type II cells,7,12 and the second as a soluble ceACE2 that is present in plasma and other body fluids.11,13 The catalytic active ectodomain of ACE2 is located in the extracellular region and undergoes shedding that results in a soluble ceACE2 form;11,13 this process is via a disintegrin and metalloproteinase domain-containing protein 17 (ADAM17),14 which is a protease up-regulated in heart failure (HF).8 In addition, the calcium signalling pathway is involved in the ceACE2 shedding process regulated by calmodulin (CaM),13 which is a ubiquitous calcium-binding protein. Basic science studies show that 1,25(OH)2D (vitamin D) enhances CaM function by increasing the ability of the vesicles to accumulate calcium.15 Moreover, a preclinical study proved that vitamin D produced slight increases in levels of soluble ceACE2 plasma activity.16
Implications for COVID-19
Many studies have proved that the administration of transgenic forms of soluble ceACE2 exerts an effect on the ACE2/Ang(1–7) axis modulation in HF, cardiovascular disease, and lung injury.9,17,18 Given that the catalytic ectodomain of ACE2 is an essential entry receptor for SARS-CoV2 infection, in vitro studies demonstrated that the administration of transgenic forms of soluble ceACE2 inhibits cell entry and replication of SARS-COV-2.19,20 Therefore, the administration of transgenic forms of soluble ceACE2, or enhancing the shedding of soluble ceACE2 with vitamin D, could be a potential therapy for inhibiting cell entry and replication of SARS-COV-2. Furthermore, vitamin D receptor is highly expressed in the cuboidal alveolar type II cells of the lung and preclinical studies revealed that overexpression of vitamin D receptor exerts anti-inflammatory effects in the lung, which decreases the storm of cytokines and chemokines.21 In this regard, meta-analysis (n=75541) reported that vitamin D supplementation was safe and had a small risk reduction of acute respiratory infections compared with placebo, protection was associated with administration of daily doses of 400–1000 IU for up 12 months and patients with severe vitamin D deficiency may experience the greatest benefit.22 Of note, to correct vitamin D deficiency in severely sick patients requires higher doses than usual, probably related to impaired hepatic conversion of vitamin D into 25-dihydroxyvitamin D.23 Thus, calcifediol may have some advantages over the native vitamin D, as it has a more reliable intestinal absorption (close to 100%) and can rapidly restore serum concentrations of 25-dihydroxyvitamin D, as it does not require hepatic 25-hydroxylation. Moreover, impaired hepatic 25-hydroxylation due to affected CYP2R1 expression has been demonstrated in preclinical models of obesity, diabetes and glucocorticoid excess.23 In this regard, some studies have showed that the administration of calcifediol (25-hydroxyvitamin D3) helps in the speedy recovery from early-stage mild to moderate symptoms of COVID-19,24 as well as reduced need for ICU treatment of patients requiring hospitalisation due to proven COVID-19.25 In addition, the studies demonstrated that the administration of calcifediol at high doses (0.532 mg on day 1, 0.266 mg on day 3 and 7, and then weekly until discharge) was well tolerated and without significant adverse effects.25
Hence, vitamin D replacement is a feasible and harmless adjuvant treatment for COVID-19, especially in those with vitamin D deficiency. Nevertheless, more clinical trials are required to confirm the therapeutic role of vitamin D in COVID-19.
Key messages
- Retrospective studies suggest that vitamin D may protect against severe COVID-19 disease
- The catalytic ectodomain (ce) of angiotensin-converting enzyme 2 (ACE2) is an essential entry receptor for SARS-CoV2 infection
- ACE2 can be present in two forms: a transmembrane cell-associated form of ACE2 and as a soluble ceACE2 that is present in plasma and other body fluids
- Vitamin D can enhance the shedding of soluble ceACE2 via the calmodulin calcium-signalling pathway
- Vitamin D could be a potential therapy for inhibiting cell entry and replication of SARS-COV-2
Conflicts of interest
None declared.
Funding
None.
References
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