Altered COVID-19 receptor ACE2 expression in a higher risk group for cerebrovascular disease and ischemic stroke

Abstract

Coronavirus disease 2019 (COVID-19) is a worldwide pandemic. It has a high transmission rate among humans, and is a threat to global public health. However, there are no effective prophylactics or therapeutics available. It is necessary to identify vulnerable and susceptible groups for adequate protection and care against this disease. Recent studies have reported that COVID-19 has angiotensin-converting enzyme 2 (ACE2) as a functional receptor, which may lead to the development of severe cerebrovascular diseases (CVD), including strokes, in patients with risk factors for CVD such as diabetes and smoking. Thus, the World Health Organization (WHO) advised caution against COVID-19 for smokers and patients with underlying clinical symptoms, including cardiovascular diseases. Here, we observed ACE2 expression in the brain of rat middle cerebral artery occlusion (MCAO) model and evaluated the effects of cigarette smoke extract (CSE) and diabetes on ACE2 expression in vessels. We showed that the levels of ACE2 expression was increased in the cortex penumbra after ischemic injuries. CSE treatment significantly elevated ACE2 expression in human brain vessels. We found that ACE2 expression was upregulated in primary cultured human blood vessels with diabetes compared to healthy controls. This study demonstrates that ACE2 expression is increased in ischemic brains and vessels exposed to diabetes or smoking, makes them vulnerable to COVID-19 infection.

Comparison of antiviral effect for mild-to-moderate COVID-19 cases between lopinavir/ritonavir versus hydroxychloroquine: A nationwide propensity score-matched cohort study

“…Since ACE2, the SARS-CoV-2 binding receptors, is widely expressed in the various organ including the lungs, heart, and vessels, it is possible that greater number of ACE2 receptors—along with blunted host response encountered in many comorbid conditions—might promote viral replication, resulting in prolonged viral shedding. Recent studies suggested that the negative outcomes in patients with underlying cerebrovascular disease might be due to elevated expression of ACE2 ( Choi et al, 2020a ). Besides prolonged viral shedding, pre-existing cardiovascular diseases were associated with worse outcomes of COVID-19 ( Fu et al, 2020 ).…”

Microvascular injury and hypoxic damage: emerging neuropathological signatures in COVID-19

“…It is striking that ACE2 expression is increased in ischaemic brains and also in blood vessels in patients with diabetes [2], given that ACE2 represents the receptor by which SARS-CoV-2 enters host cells. Similarly, certain treatment regimens, such as ECMO, may increase the risk of neurological complications [4].…”

SARS-CoV-2 Infection Reaches the Human Nervous System: How?

“…These observations were used to support a hypothesis that SARS-CoV-2 is potentially a neuroinvasive virus since it can turn on the machinery to enable the migration of infected immune cells into the brain parenchyma [151]. In blood vessels, the increase of VCAM1 and ICAM1 in response to the pro-inflammatory cytokines plays a crucial role in the adhesion of leukocytes, including macrophages and neutrophils, with the end result being disruption of the BBB and inflammation of the brain [97]. Viral gene products can also contribute to the BBB breakdown through up-regulation of many biomarkers [152].…”

“…Furthermore, it was found that ACE2 expression is increased in vessels exposed to diabetes or smoking and in ischemic brains , which leads to them being more susceptible to infection. Also, ACE2 expression was upregulated in primary cultured human blood vessels with diabetes when compared to healthy vessels [97]. Therefore, the regulation of ACE2 expression by cigarette smoke in the brain likely has a significant effect on SARS-CoV-2 susceptibility, and might facilitate viral dissemination [93].…”

“…Therefore, the regulation of ACE2 expression by cigarette smoke in the brain likely has a significant effect on SARS-CoV-2 susceptibility, and might facilitate viral dissemination [93]. The harmful effects of CSE on the BBB can upregulate several genes related to inflammation, such as VCAM1 and ICAM1, which also have destructive effects on the BBB [97].…”