ACE2
Angiotensin-converting enzyme 2 precursor (EC 3.4.17.23) (Angiotensin-converting enzyme homolog) (ACEH) (Angiotensin-converting enzyme-related carboxypeptidase) (EC 3.4.17.-) (ACE-related carboxypeptidase) (Metalloprotease MPROT15) [Contains: Processed angiotensin-converting enzyme 2] [UNQ868/PRO1885]
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Interstitial pneumonia was the first manifestation to be recognized as caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); however, in just a few weeks, it became clear that the coronavirus disease-2019 (COVID-19) overrun tissues and more body organs than just the lungs, so much so that it could be considered a systemic pathology. Several studies reported the involvement of the conjunctiva, the gut, the heart and its pace, and vascular injuries such as thromboembolic complications and Kawasaki disease in children and toddlers were also described. More recently, it was reported that in a sample of 214 SARS-CoV-2 positive patients, 36.4% complained of neurological symptoms ranging from non-specific manifestations (dizziness, headache, and seizures), to more specific symptoms such hyposmia or hypogeusia, and stroke. Older individuals, especially males with comorbidities, appear to be at the highest risk of developing such severe complications related to the Central Nervous System (CNS) involvement. Neuropsychiatric manifestations in COVID-19 appear to develop in patients with and without pre-existing neurological disorders. Growing evidence suggests that SARS-CoV-2 binds to the human Angiotensin-Converting Enzyme 2 (ACE2) for the attachment and entrance inside host cells. By describing ACE2 and the whole Renin Angiotensin Aldosterone System (RAAS) we may better understand whether specific cell types may be affected by SARS-CoV-2 and whether their functioning can be disrupted in case of an infection. Since clear evidences of neurological interest have already been shown, by clarifying the topographical distribution and density of ACE2, we will be able to speculate how SARS-CoV-2 may affect the CNS and what is the pathogenetic mechanism by which it contributes to the specific clinical manifestations of the disease. Based on such evidences, we finally hypothesize the process of SARS-CoV-2 invasion of the CNS and provide a possible explanation for the onset or the exacerbation of some common neuropsychiatric disorders in the elderly including cognitive impairment and Alzheimer disease.
Keywords
- ACE2
- Alzheimer disease
- Ang(1-7)/Mas
- COVID-19
- RAAS
- SARS-CoV
- brain aging
- neurodegenerative and psychiatric disorders abstract
Aging increases risk for ischemic vascular diseases. Bone marrow-derived hematopoietic stem/progenitor cells (HSPCs) are known to stimulate vascular regeneration. Activation of either the Mas receptor (MasR) by angiotensin-(1-7) (Ang-(1-7)) or angiotensin-converting enzyme-2 (ACE2) stimulates vasoreparative functions in HSPCs. This study tested if aging is associated with decreased ACE2 expression in HSPCs and if Ang-(1-7) restores vasoreparative functions. Flow cytometric enumeration of Lin CD45 CD34 cells was carried out in peripheral blood of male or female individuals (22-83 years of age). Activity of ACE2 or the classical angiotensin-converting enzyme (ACE) was determined in lysates of HSPCs. Lin Sca-1 cKit (LSK) cells were isolated from young (3-5 months) or old (20-22 months) mice, and migration and proliferation were evaluated. Old mice were treated with Ang-(1-7), and mobilization of HSPCs was determined following ischemia induced by femoral ligation. A laser Doppler blood flow meter was used to determine blood flow. Aging was associated with decreased number (Spearman r = - 0.598, P < 0.0001, n = 56), decreased ACE2 (r = - 0.677, P < 0.0004), and increased ACE activity (r = 0.872, P < 0.0001) (n = 23) in HSPCs. Migration or proliferation of LSK cells in basal or in response to stromal-derived factor-1α in old cells is attenuated compared to young, and these dysfunctions were reversed by Ang-(1-7). Ischemia increased the number of circulating LSK cells in young mice, and blood flow to ischemic areas was recovered. These responses were impaired in old mice but were restored by treatment with Ang-(1-7). These results suggest that activation of ACE2 or MasR would be a promising approach for enhancing ischemic vascular repair in aging.
Keywords
- ACE2
- Aging
- Angiotensin-(1-7)
- Hematopoietic stem/progenitor cells
- Ischemia
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 mediated by the interaction between angiotensin-converting enzyme 2 (ACE2) and desintegrin and metalloproteinase domain 17 (ADAM17), along with specific genetic factors mainly associated with type II transmembrane serine protease (TMPRSS2) expression, could be decisive for the clinical outcome of COVID-19. Indeed, the exacerbated ADAM17-mediated ACE2, TNF-α, and IL-6R secretion emerges as a possible underlying mechanism for the acute inflammatory immune response and the activation of the coagulation cascade. Therefore, in this review, we focus on the main pathophysiological aspects of ACE2, ADAM17, and TMPRSS2 host proteins in COVID-19. Additionally, we discuss a possible mechanism to explain the deleterious effect of ADAM17 and TMPRSS2 over-activation in the COVID-19 outcome.
MeSH Terms
- ADAM17 Protein
- Aged
- Aging
- Angiotensin-Converting Enzyme 2
- Betacoronavirus
- COVID-19
- Comorbidity
- Coronavirus Infections
- Female
- Humans
- Male
- Pandemics
- Peptidyl-Dipeptidase A
- Pneumonia, Viral
- Receptors, Interleukin-6
- Risk Factors
- SARS-CoV-2
- Serine Endopeptidases
- Tumor Necrosis Factor-alpha
Keywords
- ACE2
- ADAM17
- COVID-19 pathophysiology
- SARS-CoV-2
- TMPRSS2
The World Health Organization declared the COVID-19 epidemic a public health emergency of international concern on March 11th, 2020, and the pandemic is rapidly spreading worldwide. COVID-19 is caused by a novel coronavirus SARS-CoV-2, which enters human target cells via angiotensin converting enzyme 2 (ACE2). We used a number of bioinformatics tools to computationally characterize ACE2 by determining its cell-specific expression in trachea, lung, and small intestine, derive its putative functions, and predict transcriptional regulation. The small intestine expressed higher levels of ACE2 mRNA than any other organ. By immunohistochemistry, duodenum, kidney and testis showed strong signals, whereas the signal was weak in the respiratory tract. Single cell RNA-Seq data from trachea indicated positive signals along the respiratory tract in key protective cell types including club, goblet, proliferating, and ciliary epithelial cells; while in lung the ratio of ACE2-expressing cells was low in all cell types (<2.6%), but was highest in vascular endothelial and goblet cells. Gene ontology analysis suggested that, besides its classical role in the renin-angiotensin system, ACE2 may be functionally associated with angiogenesis/blood vessel morphogenesis. Using a novel tool for the prediction of transcription factor binding sites we identified several putative binding sites within two tissue-specific promoters of the ACE2 gene as well as a new putative short form of ACE2. These include several interferon-stimulated response elements sites for STAT1, IRF8, and IRF9. Our results also confirmed that age and gender play no significant role in the regulation of ACE2 mRNA expression in the lung.
MeSH Terms
- Aging
- Angiotensin-Converting Enzyme 2
- Betacoronavirus
- Binding Sites
- COVID-19
- Carrier Proteins
- Computational Biology
- Coronavirus Infections
- Female
- Gene Expression Regulation, Enzymologic
- Gene Ontology
- Humans
- Interferons
- Lung
- Male
- Metalloproteases
- Neovascularization, Physiologic
- Organ Specificity
- Pandemics
- Peptidyl-Dipeptidase A
- Pneumonia, Viral
- Promoter Regions, Genetic
- RNA, Messenger
- Receptors, Virus
- Renin-Angiotensin System
- SARS-CoV-2
- Sex Characteristics
- Single-Cell Analysis
- Transcription Factors
- Transcription Initiation Site
- Virus Attachment
COVID-19 is an ongoing pandemic caused by the SARS-CoV-2 coronavirus that poses one of the greatest challenges to public health in recent years. SARS-CoV-2 is known to preferentially target older subjects and those with pre-existing conditions, but the reason for this age dependence is unclear. Here, we found that the case fatality rate for COVID-19 grows exponentially with age in all countries tested, with the doubling time approaching that of all-cause human mortality. In addition, men and those with multiple age-related diseases are characterized by increased mortality. Moreover, similar mortality patterns were found for all-cause pneumonia. We further report that the gene expression of ACE2, the SARS-CoV-2 receptor, grows in the lung with age, except for subjects on a ventilator. Together, our findings establish COVID-19 as an emergent disease of aging, and age and age-related diseases as its major risk factors. In turn, this suggests that COVID-19, and deadly respiratory diseases in general, may be targeted, in addition to antiviral approaches, by approaches that target the aging process.
MeSH Terms
- Age Factors
- Aged
- Aging
- Angiotensin-Converting Enzyme 2
- Betacoronavirus
- COVID-19
- Coronavirus Infections
- Female
- Global Health
- Humans
- Male
- Pandemics
- Peptidyl-Dipeptidase A
- Pneumonia, Viral
- SARS-CoV-2
- Sex Factors
Keywords
- COVID-19
- age-related diseases
- gene expression
- lifespan
- pneumonia
- viral infection
{{medline-entry |title=Age-Dependent Assessment of Genes Involved in Cellular Senescence, Telomere, and Mitochondrial Pathways in Human Lung Tissue of Smokers, COPD, and IPF: Associations With SARS-CoV-2 COVID-19 ACE2-TMPRSS2-Furin-DPP4 Axis. |pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33013423 |abstract=Aging is one of the key contributing factors for chronic obstructive pulmonary diseases (COPD) and other chronic inflammatory lung diseases. Here, we determined how aging contributes to the altered gene expression related to mitochondrial function, cellular senescence, and telomeric length processes that play an important role in the progression of COPD and idiopathic pulmonary fibrosis (IPF). Total RNA from the human lung tissues of non-smokers, smokers, and patients with COPD and IPF were processed and analyzed using a Nanostring platform based on their ages (younger: <55 years and older: >55 years). Several genes were differentially expressed in younger and older smokers, and patients with COPD and IPF compared to non-smokers which were part of the mitochondrial biogenesis/function ([i]HSPD1[/i], [i]FEN1[/i], [i]COX18[/i], [i]COX10[/i], [i]UCP2