Sex differences in COVID-19: candidate pathways, genetics of ACE2, and sex hormones.

Biological sex is increasingly recognized as a critical determinant of health and disease, particularly relevant to the topical COVID-19 pandemic caused by the SARS-CoV-2 coronavirus. Epidemiological data and observational reports from both the original SARS epidemic and the most recent COVID-19 pandemic have a common feature: males are more likely to exhibit enhanced disease severity and mortality than females. Sex differences in cardiovascular disease and COVID-19 share mechanistic foundations, namely, the involvement of both the innate immune system and the canonical renin-angiotensin system (RAS). Immunological differences suggest that females mount a rapid and aggressive innate immune response, and the attenuated antiviral response in males may confer enhanced susceptibility to severe disease. Furthermore, the angiotensin-converting enzyme 2 (ACE2) is involved in disease pathogenesis in cardiovascular disease and COVID-19, either to serve as a protective mechanism by deactivating the RAS or as the receptor for viral entry, respectively. Loss of membrane ACE2 and a corresponding increase in plasma ACE2 are associated with worsened cardiovascular disease outcomes, a mechanism attributed to a disintegrin and metalloproteinase (ADAM17). SARS-CoV-2 infection also leads to ADAM17 activation, a positive feedback cycle that exacerbates ACE2 loss. Therefore, the relationship between cardiovascular disease and COVID-19 is critically dependent on the loss of membrane ACE2 by ADAM17-mediated proteolytic cleavage. This article explores potential mechanisms involved in COVID-19 that may contribute to sex-specific susceptibility focusing on the innate immune system and the RAS, namely, genetics and sex hormones. Finally, we highlight here the added challenges of gender in the COVID-19 pandemic.

Urinary angiotensin-converting enzyme 2 and metabolomics in COVID-19-mediated kidney injury.

Background: Angiotensin-converting enzyme 2 (ACE2), the receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is highly expressed in the kidneys. Beyond serving as a crucial endogenous regulator of the renin-angiotensin system, ACE2 also possess a unique function to facilitate amino acid absorption. Our observational study sought to explore the relationship between urine ACE2 (uACE2) and renal outcomes in coronavirus disease 2019 (COVID-19). Methods: In a cohort of 104 patients with COVID-19 without acute kidney injury (AKI), 43 patients with COVID-19-mediated AKI and 36 non-COVID-19 controls, we measured uACE2, urine tumour necrosis factor receptors I and II (uTNF-RI and uTNF-RII) and neutrophil gelatinase-associated lipocalin (uNGAL). We also assessed ACE2 staining in autopsy kidney samples and generated a propensity score-matched subgroup of patients to perform a targeted urine metabolomic study to describe the characteristic signature of COVID-19. Results: uACE2 is increased in patients with COVID-19 and further increased in those that developed AKI. After adjusting uACE2 levels for age, sex and previous comorbidities, increased uACE2 was independently associated with a >3-fold higher risk of developing AKI [odds ratio 3.05 (95% confidence interval 1.23‒7.58), P = .017]. Increased uACE2 corresponded to a tubular loss of ACE2 in kidney sections and strongly correlated with uTNF-RI and uTNF-RII. Urine quantitative metabolome analysis revealed an increased excretion of essential amino acids in patients with COVID-19, including leucine, isoleucine, tryptophan and phenylalanine. Additionally, a strong correlation was observed between urine amino acids and uACE2. Conclusions: Elevated uACE2 is related to AKI in patients with COVID-19. The loss of tubular ACE2 during SARS-CoV-2 infection demonstrates a potential link between aminoaciduria and proximal tubular injury.

ADAM15 is required for optimal collagen cross-linking and scar formation following myocardial infarction.

Collagen cross-linking is an important step in optimal scar formation. Myocardial infarction (MI) results in loss of cardiomyocytes that are replaced with a scar (infarct) tissue. Disintegrin and metalloproteinases (ADAMs) are membrane-bound proteases that can interact with molecules intra- and extra-cellularly to mediate various cellular functions. ADAM15 is expressed in the myocardium, however its function in heart disease has been poorly explored. We utilized mice lacking ADAM15 (Adam15-/-) and wildtype (WT) mice. MI, induced by ligation of the left anterior descending artery, resulted in a transient but significant rise in ADAM15 protein in the WT myocardium at 3-days. Following MI, Adam15-/- mice exhibited markedly higher rate of left ventricular (LV) rupture compared to WT mice (66% vs. 15%, p<0.05). Echocardiography and strain analyses showed worsened LV dysfunction in Adam15-/- mice at 3days, prior to the onset of LV rupture. Second harmonic generation imaging revealed significant disarray and reduction in fibrillar collagen density in Adam15-/- compared to WT hearts. This was associated with lower insoluble and higher soluble collagen fractions, reduced cross-linking enzyme, lysyl oxidase-1 (LOX-1), and fibronectin which is required for LOX-1 function, in Adam15-/--MI hearts. Post-MI myocardial inflammation was comparable between the genotypes. In vitro, primary adult cardiac fibroblasts from Adam15-/- mice showed suppressed activation in response to ischemia (hypoxia+nutrient depletion) compared to WT fibroblasts. Adam15-deficiency was associated with reduced PAK1(p21-activated kinase-1) levels, a regulator of fibronectin and LOX-1 expression. In female mice, the rate of post-MI LV rupture, PAK1 signaling, LOX-1 and fibronectin protein levels were comparable between Adam15-/- and WT, indicating less impact of ADAM15 loss in females post- MI. This study reports a novel function for ADAM15 in collagen cross-linking and optimal scar formation post-MI which may also apply to scar formation in other tissues.