Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.15.1 (ACE)
 18,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the course of maintaining a cloned murine myocardium-derived endothelial cell line (mouse heart endothelial cell clone 5; MHEC5) a spontaneously transformed variant has been identified (clone MHEC5-T). On injection into histocompatible mice, clone MHEC5-T uniformly generated epithelioid haemangioendotheliomas. Clone MHEC5-T underwent significant additional alterations in addition to the acquisition of tumour-forming potential in vivo along with the diagnostic correlate of loss of cellular contact inhibition in vitro. Whereas the transformed cells maintained lectin-binding properties characteristic of endothelial cells, they lost the cell surface receptor(s) for acetylated low density lipoprotein and no longer bound antibodies to either angiotensin converting enzyme or von Willebrand factor-associated antigen. Vascular cell adhesion molecule-1 (VCAM-1), expressed constitutively on the parent clone, was down-regulated in the transformed cell line. The transformed cells acquired immunoreactivity to antibodies directed against cytokeratin, and they showed a markedly increased response to migration-inducing factors in vitro. The cell line described in this report demonstrates that the in vitro transformation of myocardium-derived endothelial cells can lead through transitional stages of differentiation to a new stable phenotype characterized by endothelial--to--epithelioid transition. The study of MHEC5-T cells, in addition to providing insight into the biology of cardiac neoplasms, may help to elucidate regulatory mechanisms involved in endothelial cell activation, transition and transformation.
 ...
PMID:A transformed murine myocardial vascular endothelial cell clone: characterization of cells in vitro and of tumours derived from clone in situ. 765 44

The angiotensin converting enzyme (ACE) catalyzes the extracellular formation of angiotensin II, and degradation of bradykinin, thus regulating blood pressure and renal handling of electrolytes. We have previously shown that exogenously added ACE elicited transcriptional regulation independent of its enzymatic activity. Because transcriptional regulation generates from protein-DNA interactions within the cell nucleus we have investigated the initial cellular response to exogenous ACE and the putative internalization of the enzyme in smooth muscle cells (SMC) and endothelial cells (EC). The following phenomena were observed when ACE was added to cells in culture: 1) it bound to SMC and EC with high affinity (K(d) = 361.5 +/- 60.5 pM) and with a low binding occupancy (B(max) = 335.0 +/- 14.0 molecules/cell); 2) it triggered cellular signaling resulting in late activation of focal adhesion kinase and SHP2; 3) it modulated platelet-derived growth factor receptor-beta signaling; 4) it was endocytosed by SMC and EC; and 5) it transited through the early endosome, partially occupied the late endosome and the lysosome, and was localized to the nuclei. The incorporation of ACE or a fragment of it into the nuclei reached saturation at 120 min, and was preceded by a lag time of 40 min. Internalized ACE was partially cleaved into small fragments. These results revealed that extracellular ACE modulated cell signaling properties, and that SMC and EC have a pathway for delivery of extracellular ACE to the nucleus, most likely involving cell surface receptor(s) and requiring transit through late endosome/lysosome compartments.
 ...
PMID:Cell signaling, internalization, and nuclear localization of the angiotensin converting enzyme in smooth muscle and endothelial cells. 2002 59

The viral spike coat protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) engages the human ACE (angiotensin-converting enzyme) 2 cell surface receptor to infect the host cells. Thus, concerns arose regarding theoretically higher risk for coronavirus disease-19 (COVID-19) in patients taking ACE inhibitors/angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]). We systematically assessed case-population and cohort studies from MEDLINE (Ovid), Cochrane Database of Systematic Reviews PubMed, Embase, medRXIV, the World Health Organization database of COVID-19 publications, and ClinicalTrials.gov through June 1, 2020, with planned ongoing surveillance. We rated the certainty of evidence according to Cochrane methods and the Grading of Recommendations Assessment, Development and Evaluation approach. After pooling the adjusted odds ratios from the included studies, no significant increase was noted in the risk of SARS-CoV-2 infection by the use of ACE inhibitors (adjusted odds ratio, 0.95 [95% CI, 0.86-1.05]) or ARBs (adjusted odds ratio, 1.05 [95% CI, 0.97-1.14]). However, the random-effects meta-regression revealed that age may modify the SARS-CoV-2 infection risk in subjects with the use of ARBs (coefficient, -0.006 [95% CI, -0.016 to 0.004]), that is, the use of ARBs, as opposed to ACE inhibitors, specifically augmented the risk of SARS-CoV-2 infection in younger subjects (<60 years old). The use of ACE inhibitors might not increase the susceptibility of SARS-CoV-2 infection, severity of disease, and mortality in case-population and cohort studies. Additionally, we discovered for the first time that the use of ARBs, as opposed to ACE inhibitors, specifically augmented the risk of SARS-CoV-2 infection in younger subjects, without obvious effects on COVID-19 outcomes.
 ...
PMID:Renin-Angiotensin-Aldosterone System Inhibitors and Risks of Severe Acute Respiratory Syndrome Coronavirus 2 Infection: A Systematic Review and Meta-Analysis. 3286 73

SARS-CoV-2 has shown its potential to cause severe manifestations among individuals with underlying cardiovascular disease (CVD). The patients infected with SARS-CoV-2 with pre-existing CVD are more likely to relapse. There are several reasons, including the prolonged hospitalization time as a consequence of their more severe illness and aberrant expression of angiotensin-converting enzyme 2 (ACE2) - the cell surface receptor of SARS-COV2 that is present on cardiac cells - and using drugs such as ACE inhibitors and angiotensin receptor blockers (ARBs) that alter the expression of ACE2. Besides, SARS-CoV-2 shares structural similarities with SARS-CoV-1, and that patients recovered from SARS-CoV1 have shown an increased risk of developing inflammatory, metabolic, and cardiac diseases. It makes some concerns that people who recovered from SARS-CoV2 are also liable to develop these chronic conditions later. Further studies should investigate the probability of recurrence of COVID-19 in patients with CVD and the development of approaches for the prevention of chronic inflammatory conditions in patients with CVD who recovered from COVID-19.
 ...
PMID:Cardiovascular system is at higher risk of affecting by COVID-19. 3292 15

SARS-CoV-2 is a novel highly virulent pathogen which gains entry to human cells by binding with the cell surface receptor - angiotensin converting enzyme (ACE2). We computationally contrasted the binding interactions between human ACE2 and coronavirus spike protein receptor binding domain (RBD) of the 2002 epidemic-causing SARS-CoV-1, SARS-CoV-2, and bat coronavirus RaTG13 using the Rosetta energy function. We find that the RBD of the spike protein of SARS-CoV-2 is highly optimized to achieve very strong binding with human ACE2 (hACE2) which is consistent with its enhanced infectivity. SARS-CoV-2 forms the most stable complex with hACE2 compared to SARS-CoV-1 (23% less stable) or RaTG13 (11% less stable). Notably, we calculate that the SARS-CoV-2 RBD lowers the binding strength of angiotensin 2 receptor type I (ATR1) which is the native binding partner of ACE2 by 44.2%. Strong binding is mediated through strong electrostatic attachments with every fourth residue on the N-terminus alpha-helix (starting from Ser19 to Asn53) as the turn of the helix makes these residues solvent accessible. By contrasting the spike protein SARS-CoV-2 Rosetta binding energy with ACE2 of different livestock and pet species we find strongest binding with bat ACE2 followed by human, feline, equine, canine and finally chicken. This is consistent with the hypothesis that bats are the viral origin and reservoir species. These results offer a computational explanation for the increased infection susceptibility by SARS-CoV-2 and allude to therapeutic modalities by identifying and rank-ordering the ACE2 residues involved in binding with the virus.
 ...
PMID:Computational biophysical characterization of the SARS-CoV-2 spike protein binding with the ACE2 receptor and implications for infectivity. 3298