Plasma levels of soluble ACE2are associated with sex, Metabolic Syndrome, and its biomarkers in a large cohort, pointing to a possible mechanism for increased severity in COVID-19

Abstract

To the Editor: Patients at high risk for mortality from COVID-19, the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are more likely to be older and male and have chronic diseases such as hypertension, diabetes, cardiovascular, and chronic lung disease [1, 2]. Although the mechanisms behind these associations are poorly understood, this increased risk could be partly associated with increased expression of the cellular receptor of SARS-CoV-2, angiotensin-converting enzyme-2, found at elevated levels in older individuals, men, and in cardiovascular and inflammatory conditions [3, 4]. It maintains homeostasis of the renin-angiotensin system and converts angiotensin II to angiotensin 1-7, which has vasodilatory and anti-inflammatory properties. The membrane-bound form (mACE2) is highly expressed in the heart, airways, kidney, and liver tissue, and the enzymatically active soluble form (sACE2) is generated in response to inflammatory signals and disease via mACE2 shedding. We interrogated the associations between plasma concentrations of sACE2 and biomarkers of metabolic syndrome (body mass index, BMI; blood pressure; glycemic markers; and lipid levels), adiposity (plasma leptin and serum adiponectin), inflammation (high-sensitivity Creactive protein, hsCRP, white blood cell count, and interleukin-8), and liver damage (alanine aminotransferase, aspartate transaminase, and gamma-glutamyltransferase, GGT) in a large cohort of participants in a commercial wellness program who had undergone comprehensive multi-omic profiling (N = 2051; 1238 women and 813 men, aged 22 to 87 years, M = 47.3, SD = 11.71) (see [5] for details). Clinical laboratory tests were performed in CLIA-certified laboratories by Quest Diagnostics or LabCorp. Plasma sACE2 and leptin levels were measured via proximity extension immunoassaying using Olink® Cardiovascular II proteomics panel. Analyses were performed using transformed and scaled biomarker values in a robust linear regression framework controlling for age, sex (where appropriate), 8 genetic principal components, smoking, vendor, season, use of diabetes, cholesterol-lowering, and ACE-inhibitor medications. Confirming results from recent studies [3, 4], we found higher plasma sACE2 levels in men compared to women (P = 2 × 10 −16), and in older individuals (P = 8.6 × 10 −11), with the age association more pronounced in women (for the interaction, P int = 0.02). We found higher levels of sACE2 in post-menopausal women, compared to premenopausal women (P = 0.02; see Fig. 1).

COVID-19: angiotensin-converting enzyme 2 (ACE2) expression and tissue susceptibility to SARS-CoV-2 infection

“…In line with these findings, higher levels of plasma sACE2 were found in men when compared to women and in older individuals, with the age association more pronounced in women [ 105 ]. In addition, higher levels of sACE2 were detected in post-menopausal women, compared to pre-menopausal women.…”

“…When tissues are damaged, ACE2 is released from cytoplasmic membrane to plasma and, therefore, can be used as a surrogate marker of mortality. Thus, plasmatic ACE2 is increased in individuals with coronary artery disease [ 56 , 100 ], myocardial infarction [ 56 ], heart failure [ 101 ], atrial fibrillation [ 56 , 102 ], and aortic stenosis [ 103 – 105 ]…”

“…In addition, higher levels of sACE2 were detected in post-menopausal women, compared to pre-menopausal women. In other diseases, such as metabolic syndrome (effect stronger in men) and its components, such as obesity, hypertension, insulin resistance, and dyslipidaemia displayed elevated plasma sACE2 levels when compared to controls [ 105 ]. Importantly, the impact of sex on the immune response may provide a broader explanation of the differences in COVID-19-related mortality in men [ 104 ].…”

ACE2: The Major Cell Entry Receptor for SARS-CoV-2

“…Some researchers think that elevated levels of sACE2 may be protective because they are capable of inhibiting the binding of SARS-CoV-2 to membrane-bound ACE2 [4] and would explain why women and children are less susceptible [57]. Conversely, recent studies have shown that high levels of sACE2 could be evidence of increased ACE2 expression, elevated ADAM17 activity or both and, therefore, greater susceptibility to SARS-CoV-2 infection [58,59].…”

Renin–Angiotensin System: An Important Player in the Pathogenesis of Acute Respiratory Distress Syndrome

“…ADAM17-dependent ACE2 shedding can be induced by Ang II via AT1R as well as by elevated glucose levels or by several members of the Coronavirus family, including SARS-CoV and SARS-CoV-2 [52][53][54][55][56][57]. Higher sACE2 plasma levels were observed in men compared to women, the older population, post-menopausal women and in patients with metabolic syndrome or heart failure [58][59][60]. The role of ACE2 shedding under physiological and pathological conditions remains, however, insufficiently understood.…”