Both, the new SARS-CoV-2 and SARS-CoV-1 invade host cells via angiotensin-converting enzyme 2 (ACE2) receptors.

ACE2 receptors are found to be overexpressed in lung alveolar epithelial cells, small intestinal enterocytes, and arterial and venous endothelial cells. Previous research has linked high levels of plasma ACE2 to an increased risk of severe disease from SARS-CoV-2 infection, which can lead to COVID-19.

Because ACE2 plays an important role in viral pathogenesis and is abundant in tissues, scientists wondered if ACE inhibitors and/or angiotensin receptor blockers (ARB) could alter ACE2 tissue abundance and thus change host susceptibility to SARS-CoV-2 infection or the progression, severity, and tissue-specific pathology of COVID-19.

This new study, published in the preprint server bioRxiv, sought to determine whether ACE2 targeted drugs alter ACE2 tissue levels in healthy mice by investigating the function of ACE1 inhibitors (e.g., lisinopril) or angiotensin receptor blockers (e.g., losartan), either alone or in combination, in altering ACE2 tissue expression.

The researchers conducted a tissue-specific (lung, small intestines, kidney, and brain) analysis, as well as variations in tissue ACE2 levels between male and female mice, plasma ACE2 association with tissue ACE2, and tissue ACE2 correlation with plasma ACE2.

They discovered that oral lisinopril elevated ACE1 in tissue linked to SARS-CoV-2 transmission and COVID-19 development. This was not seen when lisinopril was given in conjunction with oral losartan.

The authors investigated tissue-specific changes in ACE2 abundance in mice after treatment with an ACE inhibitor (lisinopril), an ARB (losartan), or the combination of both, relative to the vehicle.

Each drug treatment group consisted of five female and five male eight-week-old C57Bl/6J mice: lisinopril, losartan, lisinopril and losartan combined, or vehicle control. The mice were given the medicines in their drinking water for 21 days. The vehicle control consisted solely of regular drinking water. The researchers first evaluated the mice’s average daily drinking water intake to achieve a 10mg/kg/day medication dosage in the daily drinking water. They changed the drug concentration weekly based on this to ensure consistent dosage throughout the study.

While half of the mice were used for plasma and tissue collection, the other half were switched to drinking water for another 21 days to see if the drug-induced alterations in ACE2 resolved when the treatment was stopped.

The total protein concentration in the flash-frozen tissue samples was determined using the BCA assay, and the ACE2 tissue abundance was determined using an ELISA. The ACE2 protein index was computed by dividing the ELISA-measured quantity by the total protein concentration of each specimen.

The researchers discovered that lisinopril medication increased the ACE2 protein index in tissues. However, the combination of lisinopril and losartan did not increase ACE2 tissue levels. The researchers discovered that ACE2 abundance was highest in the small intestine, followed by the kidney, lung, and brain in tissue-specific profiling.

The researchers looked at gene expression in the small intestine, which had the highest ACE2 protein index. Only the lisinopril/losartan combo medication decreased ACE2 gene expression in the small intestine, according to the researchers. Monotherapy with lisinopril or losartan had no effect on ACE2 expression.

Concerns about fecal-oral transmission suggest that the intestinal system may be a location of viral transmission; this has to be examined further in patients taking ACE inhibitors, as increases in small intestine ACE2 may increase the risk of SARS-CoV-2 viral infection.

The medication-induced rise of the ACE2 protein index maintained even after the treatment was discontinued for up to 21 days, according to the researchers. In order to determine whether plasma ACE2 could be used as a biomarker for tissue ACE2, the researchers discovered that plasma ACE2 was not related with ACE2 in any tissue. Despite the fact that increased plasma ACE2 has been linked to severe COVID-19 in clinical investigations, the findings here suggest that plasma ACE2 is not a useful biomarker for tissue ACE2 in any tissue.

The researchers discovered that ACE2 levels were higher in male kidneys than female kidneys in a gender-specific investigation of ACE2 levels. Previous research has found similar results in mice that were not given any drugs, as well as in kidney tissue from human donors. This is the first time that sex variations in kidney ACE2 have been reported in mice treated with an ACE inhibitor plus an ARB.

Limitations of the study:

Aside from the ACE inhibitors or ARBs employed in this study, other ACE inhibitors or ARBs may have distinct effects on ACE2 abundance.

Because hypertension and cardiovascular illness might affect ACE2, the results observed in this study’s healthy mice may differ in cardiovascular diseases.

While the findings in this study are identical with those in rats, the impact in people may be different. As a result, a similar controlled investigation in humans is required.

While lisinopril alone raised ACE2 protein expression in critical tissues affected by SARS-CoV-2, combining lisinopril with losartan inhibited the rise in ACE2 expression. This significant work shows that ACE inhibition and angiotensin receptor blockade interact to determine ACE2 tissue levels, concluded the study.

Important Note: bioRxiv provides preliminary scientific studies that have not been peer-reviewed and so should not be considered conclusive, guide clinical practice/health-related behaviour, or be treated as established information.

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