Abstract:The Coronavirus Disease 2019 (COVID-19) has already caused hundreds of thousands of deaths worldwide in a few months. Cardiovascular disease, hypertension, diabetes and chronic lung disease have been identified as the main COVID-19 comorbidities. Moreover, despite similar infection rates between men and women, the most severe course of the disease is higher in elderly and co-morbid male patients. Therefore, the occurrence of specific comorbidities associated with renin-angiotensin system (RAS) imbalance mediat… Show more
“…In addition, we have previously demonstrated that ACE2 ectodomain shedding takes place in human brains, and ADAM17-mediated ACE2 shedding is exacerbated in the brains of hypertensive patients [ 6 ]. Recent studies further highlight an important role for ACE2 as a viral receptor in the pathogenesis of severe acute respiratory syndrome corona virus 2 [ 13 , 14 ] and it has been suggested that the delicate balance between ACE2 and ADAM17 interactions could play a critical role in clinical outcome of corona virus disease 19 [ 15 ].…”
Angiotensin converting enzyme 2 (ACE2) is a critical component of the compensatory axis of the renin angiotensin system. Alterations in ACE2 gene and protein expression, and activity mediated by A Disintegrin And Metalloprotease 17 (ADAM17), a member of the “A Disintegrin And Metalloprotease” (ADAM) family are implicated in several cardiovascular and neurodegenerative diseases. We previously reported that activation of kinin B1 receptor (B1R) in the brain increases neuroinflammation, oxidative stress and sympathoexcitation, leading to the development of neurogenic hypertension. We also showed evidence for ADAM17-mediated ACE2 shedding in neurons. However, whether kinin B1 receptor (B1R) activation has any role in altering ADAM17 activity and its effect on ACE2 shedding in neurons is not known. In this study, we tested the hypothesis that activation of B1R upregulates ADAM17 and results in ACE2 shedding in neurons. To test this hypothesis, we stimulated wild-type and B1R gene-deleted mouse neonatal primary hypothalamic neuronal cultures with a B1R-specific agonist and measured the activities of ADAM17 and ACE2 in neurons. B1R stimulation significantly increased ADAM17 activity and decreased ACE2 activity in wild-type neurons, while pretreatment with a B1R-specific antagonist, R715, reversed these changes. Stimulation with specific B1R agonist Lys-Des-Arg9-Bradykinin (LDABK) did not show any effect on ADAM17 or ACE2 activities in neurons with B1R gene deletion. These data suggest that B1R activation results in ADAM17-mediated ACE2 shedding in primary hypothalamic neurons. In addition, stimulation with high concentration of glutamate significantly increased B1R gene and protein expression, along with increased ADAM17 and decreased ACE2 activities in wild-type neurons. Pretreatment with B1R-specific antagonist R715 reversed these glutamate-induced effects suggesting that indeed B1R is involved in glutamate-mediated upregulation of ADAM17 activity and ACE2 shedding.
“…In addition, we have previously demonstrated that ACE2 ectodomain shedding takes place in human brains, and ADAM17-mediated ACE2 shedding is exacerbated in the brains of hypertensive patients [ 6 ]. Recent studies further highlight an important role for ACE2 as a viral receptor in the pathogenesis of severe acute respiratory syndrome corona virus 2 [ 13 , 14 ] and it has been suggested that the delicate balance between ACE2 and ADAM17 interactions could play a critical role in clinical outcome of corona virus disease 19 [ 15 ].…”
Angiotensin converting enzyme 2 (ACE2) is a critical component of the compensatory axis of the renin angiotensin system. Alterations in ACE2 gene and protein expression, and activity mediated by A Disintegrin And Metalloprotease 17 (ADAM17), a member of the “A Disintegrin And Metalloprotease” (ADAM) family are implicated in several cardiovascular and neurodegenerative diseases. We previously reported that activation of kinin B1 receptor (B1R) in the brain increases neuroinflammation, oxidative stress and sympathoexcitation, leading to the development of neurogenic hypertension. We also showed evidence for ADAM17-mediated ACE2 shedding in neurons. However, whether kinin B1 receptor (B1R) activation has any role in altering ADAM17 activity and its effect on ACE2 shedding in neurons is not known. In this study, we tested the hypothesis that activation of B1R upregulates ADAM17 and results in ACE2 shedding in neurons. To test this hypothesis, we stimulated wild-type and B1R gene-deleted mouse neonatal primary hypothalamic neuronal cultures with a B1R-specific agonist and measured the activities of ADAM17 and ACE2 in neurons. B1R stimulation significantly increased ADAM17 activity and decreased ACE2 activity in wild-type neurons, while pretreatment with a B1R-specific antagonist, R715, reversed these changes. Stimulation with specific B1R agonist Lys-Des-Arg9-Bradykinin (LDABK) did not show any effect on ADAM17 or ACE2 activities in neurons with B1R gene deletion. These data suggest that B1R activation results in ADAM17-mediated ACE2 shedding in primary hypothalamic neurons. In addition, stimulation with high concentration of glutamate significantly increased B1R gene and protein expression, along with increased ADAM17 and decreased ACE2 activities in wild-type neurons. Pretreatment with B1R-specific antagonist R715 reversed these glutamate-induced effects suggesting that indeed B1R is involved in glutamate-mediated upregulation of ADAM17 activity and ACE2 shedding.
“…In both situations, cell infection requires binding of the viral spike protein to the angiotensin converting enzyme 2 (ACE2) receptors on target cells ( Fig.1 ). This results in activating the transmembrane cell membrane TMPRSS2 and in some cases the metalloproteinase ADAM17, to cause access to the cell’s cytoplasm, after which the viral replication program begins [ 6 ]. New virus is assembled and released and the infected cell dies.…”
Section: The Variable Consequences Of Covid-19 Infectionmentioning
confidence: 99%
“…Newly formed virus is expelled by coughing and can infect other persons, but also disseminates to other parts of the respiratory tract and in addition can spread to infect ACE2 positive cells in extrapulmonary tissues [ 7 ]. These include adipose tissue, the kidneys, the myocardium, the liver, the gastro-intestinal tract and occasionally the brain [ 6 , 7 ]. Fig.…”
Section: The Variable Consequences Of Covid-19 Infectionmentioning
Section: The Variable Consequences Of Covid-19 Infectionmentioning
confidence: 99%
“…Damage to several extrapulmonary organs, which can be chronic, is not uncommon, especially in those that suffer severe clinical signs. The organs involved include the heart and other cardiovascular components, skeletal muscle, the brain and kidney, as well as the pancreas and gastrointestinal tissues [ 6 ]. The cause of the damage is still not clear, but many of these organs contain ACE2 positive cells so could be infected and damaged by virus.…”
Section: Metabolic Events During Severe Disease and Chronic Sequelaementioning
Cardiovascular (CV) engagement in coronavirus disease 2019 (COVID‐19) is a huge determinant of prognosis during the acute phase of the disease. However, little is known about the potential chronic implications of the late phase of COVID‐19 and about the appropriate approach to these patients. Heart failure, type 1 and type 2 myocardial infarction, arrhythmias, myocarditis, pulmonary fibrosis, and thrombosis have been shown to be related to severe acute respiratory syndrome coronavirus 2 infection, and a ‘long COVID‐19’ illness has been recognized with fatigue, chest pain, and dyspnoea among the most frequent symptoms reported after discharge from hospital. This paper focuses on some open questions that cardiologists are going to face during the next months in a general cardiology outpatient clinic, in particular how to evaluate a ‘post‐COVID’ patient during follow‐up of CV complications of the acute phase and how to manage new CV symptoms that could be the consequence, at least in part, of heart/vessels and/or lung involvement of the previous virus infection. Present symptoms and signs, history of previous CV disease (both preceding COVID‐19 and occurring during viral infection), and specific laboratory and imaging measurements during the acute phase may be of interest in focusing on how to approach the clinical evaluation of a post‐COVID patient and how to integrate in our standard of care the new information on COVID‐19, possibly in a multidisciplinary view. Dealing with the increased COVID‐associated CV risk burden and becoming acquainted with potential new e‐cardiology approaches aimed at integrating the cardiology practice are relevant new challenges brought by severe acute respiratory syndrome coronavirus 2 infection and its sequelae.
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