In a recent study discussing the effects of the coronavirus disease 2019 (COVID-19) on blood pressure regulating biomarkers, scientists suggest that this disease may alter the expression of several molecules involved in the homeostasis of blood pressure.
Study: Expression of ACE2, Soluble ACE2, Angiotensin I, Angiotensin II and Angiotensin-(1-7) Is Modulated in COVID-19 Patients. Image Credit: Andrii Vodolazhskyi / Shutterstock.com
SARS-CoV-2 and ACE2
The virus that is responsible for COVID-19 is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is primarily a pulmonary-tropic coronavirus. The infection of alveolar pneumocytes by SARS-CoV-2 requires the binding of the virus to the angiotensin I converting enzyme 2 (ACE2) receptor.
ACE2 is known to be a regulator of blood pressure homeostasis and is present on the surface of many cell types. ACE2 catalyzes the proteolysis of Angiotensin II (Ang II) into Angiotensin-(1-7). A new study recently published in the scientific journal Frontiers of Immunology has shown that SARS-CoV-2 may affect the expression of blood pressure regulators with potentially harmful consequences for COVID-19 patients.
In up to one-third of COVID-19 patients, venous thromboembolism is observed as a common side effect of SARS-CoV-2 infection. It is characterized by acute pulmonary embolism or intravascular coagulopathy that makes the patients vulnerable to thrombotic events. More research is needed on the ACE2 viral receptor and its function to fully understand the physiopathology of COVID-19.
Can reduced ACE2 expression affect COVID-19 outcomes?
The scientists of the current study hypothesized that a decrease in ACE2 expression caused by SARS-CoV-2 and/or inhibition of ACE2 peptidase function could result in an increased production of Ang II, which could enhance the severity of COVID-19.
To this end, the expression of ACE2 messenger ribonucleic acid (mRNA), ACE2 cell-surface protein, as well as the plasma concentrations of soluble ACE2 (sACE2), Ang I, Ang II, and Ang-(1-7) was studied in the plasma of 44 COVID-19 positive patients. Of these 44 patients, 30 were prolonged SARS-CoV-2 shedders, whereas the remaining 14 individuals were short viral shedders. These samples were then compared to the plasma of 15 healthy volunteers.
The researchers used the quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) experiment to compare the ACE2 mRNA expression levels in circulating cells between the treatment and control groups. This was done to assess the effect of SARS-CoV-2 on the ACE2 gene expression in patients with COVID-19.
A lower expression of ACE2 mRNA was observed in the prolonged viral shedders (0.722 x 10-3) as compared to the control group (1.433 x 10-3), though this result did not appear to be statistically significant. This same phenomenon was also observed in the short viral shedders. A significantly lower expression of ACE2 mRNA was observed in the monocytic cells of prolonged viral shedders (n=6; p=0.0043) and short viral shedders (n=6; p=0.0087), in contrast to healthy volunteers (n=6).
An enzyme-linked immunosorbent assay (ELISA) assay was used to analyze the release of sACE2 in the plasma. The expression of sACE2 was heterogeneous in both the control group and among the high viral shedders, whereas the results among the short viral shedders were more homogenous.
Despite these variations, the concentration of sACE2 in the plasma was found to be significantly lower in the prolonged viral shedders when compared to the control group at 19,396 picograms (pg)/ milliliter (mL) and 22,600 pg/m, respectively. The short viral shedders had a plasma concentration of sACE2 of 22,141 pg/mL.
A higher plasma concentration of Ang I and Ang II was observed in COVID-19 patients. Since ACE2 mRNA expression was found to be lower in COVID-19 patients, scientists were interested to study whether this affected the plasma concentrations of these Ang metabolites.
A significantly higher amount of Ang I was observed in prolonged viral shedders (median= 2,979 pg/mL) and short viral shedders (median= 3,603 pg/mL) as compared to that which was identified in the healthy group of individuals (median= 1,496 pg/mL). Ang II concentration was also observed to be higher in the prolonged viral shedders (median= 921 pg/mL) and short viral shedders (median= 1,038 pg/mL), than in the healthy volunteers (median= 746 pg/mL).
The findings of the current study prompted researchers to study the plasma concentrations of Ang-(1-7). They found slightly higher plasma concentrations of Ang-(1-7) in the prolonged viral shedders as compared to those which were detected in the short viral shedders. However, as compared to the healthy volunteers; these differences were not statistically significant.
The concentrations of the Ang metabolites were significantly different between the two groups of patients and the control group. This was confirmed using a Mann Whitney U test, a principal component analysis, and a hierarchical clustering heat map.
The current study provides evidence that ACE2 mRNA, ACE2 protein expression, as well as sACE2, Ang I, Ang II, and Ang-(1-7) plasma concentrations are altered during COVID-19. Some limitations of this study include the small sample size and limited representativeness of the sample.