Disease relevance of ACE2

• Receptor and viral determinants of SARS-coronavirus adaptation to human ACE2 [1].
• Unexpectedly, ACE2 also serves as the cellular entry point for the severe acute respiratory syndrome (SARS) virus and the enzyme is therefore a prime target for pharmacological intervention on several disease fronts [2].
• Since its discovery in 2000, ACE2 has been implicated in heart function, hypertension and diabetes, with its effects being mediated, in part, through its ability to convert angiotensin II to angiotensin-(1-7) [2].
• The coronavirus that causes severe acute respiratory syndrome (SARS-CoV) utilizes the receptor angiotensin-converting enzyme 2 (ACE2) to infect cells [3].
• Myocardial infarction increases ACE2 expression in rat and humans [4].
• We conclude that the ACE2 T allele confers a high risk for hypertension and reduced antihypertensive response to ACE inhibitors [5].
• The ACE to ACE2 ratio was significantly higher in subjects with hypertension (HT) than that in subjects without HT [6].
• There was a relationship between urinary mRNA expression of ACE2 and the degree of proteinuria [7].

Psychiatry related information on ACE2

• In conclusion, the results of the present study indicate that common genetic variants in the ACE2 gene might impact on MI in females, and may possibly interact with alcohol consumption to affect the risk of CHD and MI in Chinese males [8].
• Mental health problems after tsunami disaster in Aceh and Nias; immediate responses and future programs [9].

High impact information on ACE2

• Genetic ablation of ACE on an ACE2 mutant background completely rescues the cardiac phenotype [10].
• Targeted disruption of ACE2 in mice results in a severe cardiac contractility defect, increased angiotensin II levels, and upregulation of hypoxia-induced genes in the heart [10].
• Here we show that angiotensin-converting enzyme 2 (ace2) maps to a defined quantitative trait locus (QTL) on the X chromosome in three different rat models of hypertension [10].
• Human angiotensin-converting enzyme 2 (ACE2) is a functional receptor for SARS coronavirus (SARS-CoV) [1].
• The zinc metallopeptidase angiotensin-converting enzyme 2 (ACE2) is the only known human homologue of the key regulator of blood pressure angiotensin-converting enzyme (ACE) [2].

Chemical compound and disease context of ACE2

• Tumor necrosis factor-alpha convertase (ADAM17) mediates regulated ectodomain shedding of the severe-acute respiratory syndrome-coronavirus (SARS-CoV) receptor, angiotensin-converting enzyme-2 (ACE2) [11].
• Our data suggest that the large S glycoprotein of SARS-CoV may use both ACE2 and CD209L in virus infection and pathogenesis [12].
• Here we show that SARS-CoV, but not HCoV-NL63, utilizes the enzymatic activity of the cysteine protease cathepsin L to infect ACE2-expressing cells [13].
• Alanine scanning mutagenesis analysis was performed to identify determinants on ACE2 critical for SARS-CoV infection [14].

Biological context of ACE2

• These kinetic data highlight that the flux of peptides through the RAS is complex, with the levels of ACE, ACE2 and NEP dictating whether vasoconstriction or vasodilation will predominate [15].
• We have examined the kinetics of angiotensin peptide cleavage by full-length human ACE, the separate N- and C-domains of ACE, the homologue of ACE, ACE2, and NEP (neprilysin) [15].
• ACE2 is a type I transmembrane protein, with an extracellular N-terminal domain containing the active site and a short intracellular C-terminal tail [11].
• An alignment of the ACE2 peptide substrates reveals a consensus sequence of: Pro-X((1-3 residues))-Pro-Hydrophobic, where hydrolysis occurs between proline and the hydrophobic amino acid [16].
• The angiotensin-converting enzyme (ACE)-related carboxypeptidase, ACE2, is a type I integral membrane protein of 805 amino acids that contains one HEXXH + E zinc-binding consensus sequence [17].

Anatomical context of ACE2

• Furthermore, ACE2 was present in arterial and venous endothelial cells and arterial smooth muscle cells in all organs studied [18].
• By day 28, increases in ACE (P = 0.005) and ACE2 (P = 0.006) mRNA were also seen in the viable myocardium of MI rats compared with myocardium of control rats [4].
• This epithelial expression, together with the presence of ACE2 in vascular endothelium, also provides a first step in understanding the pathogenesis of the main SARS disease manifestations [18].
• In conclusion, ACE2 is abundantly present in humans in the epithelia of the lung and small intestine, which might provide possible routes of entry for the SARS-CoV [18].
• ACE2 protein localized to macrophages, vascular endothelium, smooth muscle, and myocytes [4].

Associations of ACE2 with chemical compounds

• ACEH/ACE2 is a novel mammalian metallocarboxypeptidase and a homologue of angiotensin-converting enzyme insensitive to ACE inhibitors [19].
• Ang II was cleaved efficiently by ACE2 to Ang (1-7) (kcat/K(m) of 2.2x10(6) M(-1) x s(-1)) and was cleaved by NEP (kcat/K(m) of 2.2x10(5) M(-1) x s(-1)) to several degradation products [15].
• The coronaviral surface spike protein S is a type I transmembrane glycoprotein that mediates initial host binding via the cell surface receptor angiotensin-converting enzyme 2 (ACE2), as well as the subsequent membrane fusion events required for cell entry [20].
• ACE2 also efficiently hydrolyzes des-Arg(9)-bradykinin (k(cat)/K(m) = 1.3 x 10(5) m(-1) s(-1)), but it does not hydrolyze bradykinin [16].
• A point mutation at aspartic acid 454 abolished association of the full S1 domain and of the 193-residue fragment with ACE2 [21].

Enzymatic interactions of ACE2

• ACE2 can also cleave des-Arg bradykinin and neurotensin but not bradykinin or 15 other vasoactive and hormonal peptides tested [22].

Co-localisations of ACE2

• ACE2 co-localized with glomerular epithelial cell (podocyte) markers, and its localization within the podocyte was confirmed by immunogold labeling [23].

Regulatory relationships of ACE2

• Taken together, these data provided direct evidence for the involvement of ADAM17 in the regulated ectodomain shedding of ACE2 [11].
• When human ACE2 cDNA was transduced into NIH3T3 cells, the ACE2 expressing NIH3T3 cells could be infected with HIV/SARS pseudovirus [24].
• Northern blot analysis revealed that the ace1 gene was expressed much higher than the ace2 in all examined body parts [25].
• Moreover, ACE2 expression is downregulated in the kidneys of diabetic and pregnant rats and ACE2 mutant mice develop late onset glomerulonephritis resembling diabetic nephropathy [26].

Other interactions of ACE2

• Infection of human airway epithelia by SARS coronavirus is associated with ACE2 expression and localization [27].
• Evaluation of angiotensin-converting enzyme (ACE), its homologue ACE2 and neprilysin in angiotensin peptide metabolism [15].
• By using inhibitors with differing potency toward different members of the ADAM (a disintegrin and metalloproteinase) family of proteases, we identified ADAM17 as a candidate mediator of stimulated ACE2 shedding [11].
• ACE-1 is an amphiphilic tetramer associated with a hydrophobic non-catalytic subunit, analogous to vertebrate T enzymes, whereas ACE-2 and ACE-3 are glycosylphosphatidylinositol-linked amphiphilic dimers [28].
• RESULTS: There was higher ACE and chymase mRNA expression and mast cell density in failing than in control myocardium and no changes in ACE2 expression were detected. eNOS mRNA levels were lower in failing hearts [29].

Analytical, diagnostic and therapeutic context of ACE2

• Cardiac gene and protein expression of ACE and ACE2 were assessed by quantitative real-time reverse transcriptase-polymerase chain reaction and immunohistochemistry/activity assays/in vitro autoradiography, respectively [4].
• These data imply that a mouse transgenically expressing human ACE2 may be a useful animal model of SARS [3].
• ACE2 catalytic activity was present in membrane preparations of whole testes and Leydig cells from adult rats; expression of the protein in Leydig cells was confirmed by Western immunoblot analysis [30].
• Using immunohistochemistry, ACE2 expression was confined to the Leydig cells in the rat testis and to Leydig and Sertoli cells in the human testis [30].
• This article will focus on angiotensin-converting enzyme 2 (ACE2) as a new, potential target of gene therapy for hypertensive disorders [31].
• To better understand the tissue distribution and activity of enzymes involved in angiotensin II (Ang II) processing, we developed a novel molecular imaging method using matrix-assisted laser desorption ionization-time-of-flight (MALDI-TOF) mass spectrometry [32]

References