Gender Differences in Stroke With COVID-19: Epigenetic and Biochemical Study of ACE2 Receptor and Relationship With Rehabilitative Outcome

Detailed Summary

The new coronavirus SARS-CoV-2, causes the COVID-19 infection, which showed a form of neurovirulence involving the Central and peripheral Nervous Systems \[Baig et al, 2020\]. In a mouse model for human ACE2 expression, the virus entered the brain mainly through the olfactory bulb pathway \[Netland et al, 2008\], with an encephalic invasion uniformly lethal even with low viral doses and without lung involvement. The death of the animal was reasonably related to neuronal dysfunction/death in cardiorespiratory bone marrow centers, while the absence of ACE2 prevented severe encephalopathy. Men has a highly frequency of severe and lethal COVID-19, and the observed gender difference could be related to the regulation of ACE2 receptor expression. The ACE2 gene is encoded by a region of the X chromosome that escapes inactivation, so that women have an increased expression of this protein. The process of inactivation of the X chromosome includes DNA methylation with a decrease in the expression of genes that are affected by methylation. In This way an epigenetic mechanism could modulate the expression of ACE2 in a gender-specific way determining its levels and consequently its protective role. Also in this regulatory context of ACE2 expression the role of microRNA (miRNA) could be very important. In fact, the untranslated 3' region (UTR) of ACE2 presents a binding sequence for miRNA miR-200c-3p that has been found at high levels of expression in cellular models infected with H5N1 influenza virus \[Liu et al, 2017\]. In addition, high plasma levels of miR-200c-3p were found in patients with severe pneumonia while ACE2 was reduced suggesting a regulatory role of this miRNA in ACE2 receptor expression \[Liu et al, 2017\]. Deficiency of 25 (OH)D is common among elderly and obese men (during winter and spring), highlighting the sex-specific difference observed in COVID-19 infection \[La Vignera et al, 2020\]. This vitamin, envolved in physical recovery \[Siotto et al, 2019\], and in the pathway of the renin angiotensin system, seems important to be assessed in ex-COVID-19 patients with stroke outcomes in admission and at the end of the rehabilitation process. The study will consist in: * Epigenetic study: evaluation of methylation of ACE2 promoter and miR-200c-3p levels. * Biochemical analysis: the evaluation of levels of angiotensin II, ACE2 and Vitamin D. * Correlation between rehabilitative outcome and biological markers

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