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Article ; Online: ACE2 level as a marker of CVD.

Fernández-Ruiz, Irene

2020 Volume 17, Issue 12, Page(s) 759

MeSH term(s)	Angiotensin-Converting Enzyme 2 ; Biomarkers ; Cardiovascular Diseases/diagnosis ; Cardiovascular Diseases/epidemiology ; Humans ; Peptidyl-Dipeptidase A/genetics
Chemical Substances	Biomarkers ; Peptidyl-Dipeptidase A (EC 3.4.15.1) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23)
Keywords	covid19
Language	English
Publishing date	2020-10-19
Publishing country	England
Document type	Journal Article ; Comment
ZDB-ID	2490375-9
ISSN	1759-5010 ; 1759-5002
ISSN (online)	1759-5010
ISSN	1759-5002
DOI	10.1038/s41569-020-00468-2
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Article ; Online: Age-associated difference in circulating ACE2, the gateway for SARS-COV-2, in humans: results from the InCHIANTI study.

AlGhatrif, Majd / Tanaka, Toshiko / Moore, Ann Zenobia / Bandinelli, Stefania / Lakatta, Edward G / Ferrucci, Luigi

GeroScience

2021 Volume 43, Issue 2, Page(s) 619–627

Abstract: ... Data on age-associated differences in circulating ACE2 levels in humans and the role of CVD and ... association of ACE2 with age, CVD, and RAAS antagonist use. Age was independently associated with lower log ... Interestingly, ACE2 was elevated in PAD and positively associated with inflammatory markers, suggesting ...

Abstract	Levels of angiotensin-converting enzyme 2 (ACE2), the gateway for COVID-19 virus into the cells, have been implicated in worse COVID-19 outcomes associated with aging and cardiovascular disease (CVD). Data on age-associated differences in circulating ACE2 levels in humans and the role of CVD and medications is limited. We analyzed data from 967 participants of the InCHIANTI study, a community-dwelling cohort in the Chianti region, Italy. Relative abundance of ACE2 in plasma was assessed using a proteomics platform. CVD diagnoses, use of renin-angiotensin-aldosterone system (RAAS) antagonists: ACEi, ARBs, and aldosterone antagonists, were ascertained. Multiple linear analyses were performed to examine the independent association of ACE2 with age, CVD, and RAAS antagonist use. Age was independently associated with lower log (ACE2) in persons aged ≥ 55 years (STD β = - 0.12, p = 0.0002). ACEi treatment was also independently associated with significantly lower ACE2 levels, and ACE2 was inversely associated with weight, and positively associated with peripheral artery disease (PAD) status. There was a trend toward higher circulating ACE2 levels in hypertensive individuals, but it did not reach statistical significance. In a stratified analysis, the association between log (ACE2) and log (IL-6) was more evidenced in participants with PAD. Circulating ACE2 levels demonstrate curvilinear association with age, with older individuals beyond the sixth decade age having lower levels. ACEi was associated with greater circulating ACE2 levels. Interestingly, ACE2 was elevated in PAD and positively associated with inflammatory markers, suggesting compensatory upregulation in the setting of chronic inflammation. Further studies are needed to comprehensively characterize RAAS components with aging and disease, and assess its prognostic role in predicting COVID-19 outcomes.
MeSH term(s)	Aged ; Angiotensin Receptor Antagonists ; Angiotensin-Converting Enzyme 2 ; Angiotensin-Converting Enzyme Inhibitors/therapeutic use ; COVID-19 ; Humans ; Italy/epidemiology ; Peptidyl-Dipeptidase A ; SARS-CoV-2
Chemical Substances	Angiotensin Receptor Antagonists ; Angiotensin-Converting Enzyme Inhibitors ; Peptidyl-Dipeptidase A (EC 3.4.15.1) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23)
Language	English
Publishing date	2021-01-18
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	2886586-8
ISSN	2509-2723 ; 2509-2715
ISSN (online)	2509-2723
ISSN	2509-2715
DOI	10.1007/s11357-020-00314-w
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Article ; Online: The combination of ACE I/D and ACE2 G8790A polymorphisms revels susceptibility to hypertension: A genetic association study in Brazilian patients.

Pinheiro, Denise S / Santos, Rodrigo S / Jardim, Paulo C B Veiga / Silva, Elisangela G / Reis, Angela A S / Pedrino, Gustavo R / Ulhoa, Cirano J

PloS one

2019 Volume 14, Issue 8, Page(s) e0221248

Abstract: ... alterations indicate that this can be a marker of poor prognostic on SAH evolution and contribute to CVD ... the physiological interaction of functions. Angiotensin I-converting enzymes, ACE and ACE2, are key regulators ... G8790A of ACE2 gene have been associated with susceptibility to SAH, but the literature is controversial ...

Abstract	Background: Systemic arterial hypertension (SAH) is a multifactorial condition that already affects one third of the worldwide population. The identification of candidate genes for hypertension is a challenge for the next years. Nevertheless, the small contribution of each individual genetic factor to the disease brings the necessity of evaluate genes in an integrative manner and taking into consideration the physiological interaction of functions. Angiotensin I-converting enzymes, ACE and ACE2, are key regulators of blood pressure that have counterbalance roles by acting on vasoactive peptides from Renin-Angiotensin-Aldosterone System (RAAS). Insertion/deletion (I/D) polymorphism of ACE gene and single nucleotide polymorphism G8790A of ACE2 gene have been associated with susceptibility to SAH, but the literature is controversial. We proposed to evaluate these two polymorphisms jointly exploring the combined effects of ACE and ACE2 genotypes on SAH susceptibility, an approach that have not been done yet for ACE and ACE2 polymorphisms. Methods and findings: This genetic association study included 117 hypertensive (mean age 59.7 years) patients and 123 normotensive and diabetes-free controls (mean age 57.5 years). ACE and ACE2 polymorphisms were genotyped by SYBR Green real-time PCR and RFLP-PCR, respectively. Crude and adjusted odds ratio (OR) values were calculated to estimate the susceptibility to SAH development. It was obtained homogeneity regarding distribution by sex, age range, smoking, alcohol consumption and body mass index (BMI) between case and control groups. No-association was verified for each gene individually, but the combination of ACE and ACE2 polymorphisms on female gender revealed a significative association for DD/G_ carriers who had a 3-fold increased risk to SAH development (p = 0.03), with a stronger susceptibility on DD/GG carriers (7-fold increased risk, p = 0.01). The D allele of ACE showed association with altered levels of lipid profile variables on case group (VLDL-cholesterol, p = 0.01) and DD genotype in all individuals analysis (triglycerides, p = 0.01 and VLDL-cholesterol, p = 0.01). Conclusion: These findings indicate that the combination of ACE and ACE2 polymorphisms effects may play a role in SAH predisposition been the DD/G_ genotype the susceptibility profile. This result allowed us to raise the hypothesis that an increased activity of ACE (prohypertensive effects) in conjunction with reduced ACE2 activity (antihypertensive effects) could be the underlining mechanism. The association of ACE D allele with lipid alterations indicate that this can be a marker of poor prognostic on SAH evolution and contribute to CVD development. Although these preliminary findings must be confirmed by further researches with larger sample size, we could observe that the integrative analysis of ACE and ACE2 can be an informative tool in hypertension understanding that needs to be explored in new studies.
MeSH term(s)	Adult ; Age Factors ; Aged ; Aged, 80 and over ; Alleles ; Blood Pressure/genetics ; Brazil/epidemiology ; Case-Control Studies ; Dyslipidemias/epidemiology ; Dyslipidemias/genetics ; Female ; Follow-Up Studies ; Gene Frequency ; Genetic Association Studies ; Genetic Predisposition to Disease ; Humans ; Hypertension/epidemiology ; Hypertension/genetics ; INDEL Mutation ; Male ; Middle Aged ; Peptidyl-Dipeptidase A/genetics ; Polymorphism, Single Nucleotide ; Risk Factors ; Sex Factors ; Young Adult
Chemical Substances	ACE protein, human (EC 3.4.15.1) ; Peptidyl-Dipeptidase A (EC 3.4.15.1) ; angiotensin converting enzyme 2 (EC 3.4.17.-)
Language	English
Publishing date	2019-08-20
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0221248
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Article ; Online: Angiotensin-converting enzyme 2 (ACE2) levels in relation to risk factors for COVID-19 in two large cohorts of patients with atrial fibrillation.

Wallentin, Lars / Lindbäck, Johan / Eriksson, Niclas / Hijazi, Ziad / Eikelboom, John W / Ezekowitz, Michael D / Granger, Christopher B / Lopes, Renato D / Yusuf, Salim / Oldgren, Jonas / Siegbahn, Agneta

European heart journal

2020 Volume 41, Issue 41, Page(s) 4037–4046

Abstract: ... of the sACE2 level.: Conclusions: Male sex and clinical or biomarker indicators of biological ageing ... a higher plasma level of soluble ACE2 (sACE2) might reflect a higher cellular expression of ACE2 ... by the Olink Proteomics® Multiplex CVD II96 × 96 panel. Levels of the biomarkers high-sensitive cardiac ...

Abstract	Aims: The global COVID-19 pandemic is caused by the SARS-CoV-2 virus entering human cells using angiotensin-converting enzyme 2 (ACE2) as a cell surface receptor. ACE2 is shed to the circulation, and a higher plasma level of soluble ACE2 (sACE2) might reflect a higher cellular expression of ACE2. The present study explored the associations between sACE2 and clinical factors, cardiovascular biomarkers, and genetic variability. Methods and results: Plasma and DNA samples were obtained from two international cohorts of elderly patients with atrial fibrillation (n = 3999 and n = 1088). The sACE2 protein level was measured by the Olink Proteomics® Multiplex CVD II96 × 96 panel. Levels of the biomarkers high-sensitive cardiac troponin T (hs-cTnT), N-terminal probrain natriuretic peptide (NT-proBNP), growth differentiation factor 15 (GDF-15), C-reactive protein, interleukin-6, D-dimer, and cystatin-C were determined by immunoassays. Genome-wide association studies were performed by Illumina chips. Higher levels of sACE2 were statistically significantly associated with male sex, cardiovascular disease, diabetes, and older age. The sACE2 level was most strongly associated with the levels of GDF-15, NT-proBNP, and hs-cTnT. When adjusting for these biomarkers, only male sex remained associated with sACE2. We found no statistically significant genetic regulation of the sACE2 level. Conclusions: Male sex and clinical or biomarker indicators of biological ageing, cardiovascular disease, and diabetes are associated with higher sACE2 levels. The levels of GDF-15 and NT-proBNP, which are associated both with the sACE2 level and a higher risk for mortality and cardiovascular disease, might contribute to better identification of risk for severe COVID-19 infection.
MeSH term(s)	Aged ; Angiotensin-Converting Enzyme 2 ; Antithrombins/therapeutic use ; Atrial Fibrillation/blood ; Atrial Fibrillation/complications ; Atrial Fibrillation/drug therapy ; Betacoronavirus ; Biomarkers/blood ; COVID-19 ; Cohort Studies ; Coronavirus Infections/blood ; Coronavirus Infections/diagnosis ; Coronavirus Infections/epidemiology ; Dabigatran/therapeutic use ; Female ; Humans ; Male ; Middle Aged ; Pandemics ; Peptidyl-Dipeptidase A/blood ; Pneumonia, Viral/blood ; Pneumonia, Viral/diagnosis ; Pneumonia, Viral/epidemiology ; Pyrazoles/therapeutic use ; Pyridones/therapeutic use ; Risk Factors ; SARS-CoV-2 ; Stroke/prevention & control ; Warfarin/therapeutic use
Chemical Substances	Antithrombins ; Biomarkers ; Pyrazoles ; Pyridones ; apixaban (3Z9Y7UWC1J) ; Warfarin (5Q7ZVV76EI) ; Peptidyl-Dipeptidase A (EC 3.4.15.1) ; ACE2 protein, human (EC 3.4.17.23) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23) ; Dabigatran (I0VM4M70GC)
Keywords	covid19
Language	English
Publishing date	2020-09-28
Publishing country	England
Document type	Journal Article ; Randomized Controlled Trial
ZDB-ID	603098-1
ISSN	1522-9645 ; 0195-668X
ISSN (online)	1522-9645
ISSN	0195-668X
DOI	10.1093/eurheartj/ehaa697
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Article: Angiotensin-converting enzyme 2 (ACE2) levels in relation to risk factors for COVID-19 in two large cohorts of patients with atrial fibrillation

Eur Heart J

Abstract: ... of the sACE2 level. CONCLUSIONS: Male sex and clinical or biomarker indicators of biological ageing ... a higher plasma level of soluble ACE2 (sACE2) might reflect a higher cellular expression of ACE2 ... by the Olink Proteomics® Multiplex CVD II96 × 96 panel. Levels of the biomarkers high-sensitive cardiac ...

Abstract	AIMS: The global COVID-19 pandemic is caused by the SARS-CoV-2 virus entering human cells using angiotensin-converting enzyme 2 (ACE2) as a cell surface receptor. ACE2 is shed to the circulation, and a higher plasma level of soluble ACE2 (sACE2) might reflect a higher cellular expression of ACE2. The present study explored the associations between sACE2 and clinical factors, cardiovascular biomarkers, and genetic variability. METHODS AND RESULTS: Plasma and DNA samples were obtained from two international cohorts of elderly patients with atrial fibrillation (n = 3999 and n = 1088). The sACE2 protein level was measured by the Olink Proteomics® Multiplex CVD II96 × 96 panel. Levels of the biomarkers high-sensitive cardiac troponin T (hs-cTnT), N-terminal probrain natriuretic peptide (NT-proBNP), growth differentiation factor 15 (GDF-15), C-reactive protein, interleukin-6, D-dimer, and cystatin-C were determined by immunoassays. Genome-wide association studies were performed by Illumina chips. Higher levels of sACE2 were statistically significantly associated with male sex, cardiovascular disease, diabetes, and older age. The sACE2 level was most strongly associated with the levels of GDF-15, NT-proBNP, and hs-cTnT. When adjusting for these biomarkers, only male sex remained associated with sACE2. We found no statistically significant genetic regulation of the sACE2 level. CONCLUSIONS: Male sex and clinical or biomarker indicators of biological ageing, cardiovascular disease, and diabetes are associated with higher sACE2 levels. The levels of GDF-15 and NT-proBNP, which are associated both with the sACE2 level and a higher risk for mortality and cardiovascular disease, might contribute to better identification of risk for severe COVID-19 infection.
Keywords	covid19
Publisher	WHO
Document type	Article
Note	WHO #Covidence: #800013
Database	COVID19

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Article ; Online: Angiotensin-converting enzyme 2 (ACE2) levels in relation to risk factors for COVID-19 in two large cohorts of patients with atrial fibrillation

European Heart Journal ; ISSN 0195-668X 1522-9645

2020

Abstract: ... of the sACE2 level. Conclusions Male sex and clinical or biomarker indicators of biological ageing ... and a higher plasma level of soluble ACE2 (sACE2) might reflect a higher cellular expression of ACE2 ... by the Olink Proteomics® Multiplex CVD II96 × 96 panel. Levels of the biomarkers high-sensitive cardiac ...

Abstract	Abstract Aims The global COVID-19 pandemic is caused by the SARS-CoV-2 virus entering human cells using angiotensin-converting enzyme 2 (ACE2) as a cell surface receptor. ACE2 is shed to the circulation, and a higher plasma level of soluble ACE2 (sACE2) might reflect a higher cellular expression of ACE2. The present study explored the associations between sACE2 and clinical factors, cardiovascular biomarkers, and genetic variability. Methods and results Plasma and DNA samples were obtained from two international cohorts of elderly patients with atrial fibrillation (n = 3999 and n = 1088). The sACE2 protein level was measured by the Olink Proteomics® Multiplex CVD II96 × 96 panel. Levels of the biomarkers high-sensitive cardiac troponin T (hs-cTnT), N-terminal probrain natriuretic peptide (NT-proBNP), growth differentiation factor 15 (GDF-15), C-reactive protein, interleukin-6, D-dimer, and cystatin-C were determined by immunoassays. Genome-wide association studies were performed by Illumina chips. Higher levels of sACE2 were statistically significantly associated with male sex, cardiovascular disease, diabetes, and older age. The sACE2 level was most strongly associated with the levels of GDF-15, NT-proBNP, and hs-cTnT. When adjusting for these biomarkers, only male sex remained associated with sACE2. We found no statistically significant genetic regulation of the sACE2 level. Conclusions Male sex and clinical or biomarker indicators of biological ageing, cardiovascular disease, and diabetes are associated with higher sACE2 levels. The levels of GDF-15 and NT-proBNP, which are associated both with the sACE2 level and a higher risk for mortality and cardiovascular disease, might contribute to better identification of risk for severe COVID-19 infection.
Keywords	Cardiology and Cardiovascular Medicine ; covid19
Language	English
Publisher	Oxford University Press (OUP)
Publishing country	uk
Document type	Article ; Online
DOI	10.1093/eurheartj/ehaa697
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Article ; Online: Interaction of diabetes and ACE2 in the pathogenesis of cardiovascular disease in experimental diabetes.

Tikellis, Chris / Pickering, Raelene / Tsorotes, Despina / Du, Xiao-Jun / Kiriazis, Helen / Nguyen-Huu, Thu-Phuc / Head, Geoffrey A / Cooper, Mark E / Thomas, Merlin C

Clinical science (London, England : 1979)

2012 Volume 123, Issue 8, Page(s) 519–529

Abstract: ... diabetes was induced in male C57BL6 mice and Ace2-KO (knockout) mice, and markers of RAS ... Local and systemic AngII (angiotensin II) levels are regulated by ACE2 (angiotensin-converting ... led to reduced ACE2 expression and activity in the heart, elevated circulating AngII levels and ...

Abstract	Local and systemic AngII (angiotensin II) levels are regulated by ACE2 (angiotensin-converting enzyme 2), which is reduced in diabetic tissues. In the present study, we examine the effect of ACE2 deficiency on the early cardiac and vascular changes associated with experimental diabetes. Streptozotocin diabetes was induced in male C57BL6 mice and Ace2-KO (knockout) mice, and markers of RAS (renin-angiotensin system) activity, cardiac function and injury were assessed after 10 weeks. In a second protocol, diabetes was induced in male ApoE (apolipoprotein E)-KO mice and ApoE/Ace2-double-KO mice, and plaque accumulation and markers of atherogenesis assessed after 20 weeks. The induction of diabetes in wild-type mice led to reduced ACE2 expression and activity in the heart, elevated circulating AngII levels and reduced cardiac Ang-(1-7) [angiotensin-(1-7)] levels. This was associated structurally with thinning of the LV (left ventricular) wall and mild ventricular dilatation, and histologically with increased cardiomyocyte apoptosis on TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling) staining and compensatory hypertrophy denoted by an increased cardiomyocyte cross-sectional area. By contrast Ace2-KO mice failed to increase circulating AngII concentration, experienced a paradoxical fall in cardiac AngII levels and no change in Ang-(1-7) following the onset of diabetes. At the same time the major phenotypic differences between Ace2-deficient and Ace2-replete mice with respect to BP (blood pressure) and cardiac hypertrophy were eliminated following the induction of diabetes. Consistent with findings in the heart, the accelerated atherosclerosis that was observed in diabetic ApoE-KO mice was not seen in diabetic ApoE/Ace2-KO mice, which experienced no further increase in plaque accumulation or expression in key adhesion molecules beyond that seen in ApoE/Ace2-KO mice. These results point to the potential role of ACE2 deficiency in regulating the tissue and circulating levels of AngII and their sequelae in the context of diabetes, as well as the preservation or augmentation of ACE2 expression or activity as a potential therapeutic target for the prevention of CVD (cardiovascular disease) in diabetes.
MeSH term(s)	Angiotensin II/metabolism ; Animals ; Aortic Diseases/metabolism ; Aortic Diseases/pathology ; Apoptosis ; Biomarkers/metabolism ; Blood Pressure/physiology ; Cardiovascular Diseases/enzymology ; Cardiovascular Diseases/physiopathology ; Diabetes Mellitus, Experimental/enzymology ; Diabetes Mellitus, Experimental/pathology ; Diabetes Mellitus, Experimental/physiopathology ; Diabetic Angiopathies/enzymology ; Diabetic Angiopathies/pathology ; Diabetic Angiopathies/physiopathology ; Inflammation Mediators/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Myocardium/metabolism ; Myocardium/pathology ; Peptidyl-Dipeptidase A/deficiency ; Peptidyl-Dipeptidase A/metabolism ; Peptidyl-Dipeptidase A/physiology ; Plaque, Atherosclerotic/metabolism ; Plaque, Atherosclerotic/pathology ; Telemetry/methods
Chemical Substances	Biomarkers ; Inflammation Mediators ; Angiotensin II (11128-99-7) ; Peptidyl-Dipeptidase A (EC 3.4.15.1) ; angiotensin converting enzyme 2 (EC 3.4.17.-)
Language	English
Publishing date	2012-10
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	206835-7
ISSN	1470-8736 ; 0301-0538 ; 0009-0360 ; 0143-5221
ISSN (online)	1470-8736
ISSN	0301-0538 ; 0009-0360 ; 0143-5221
DOI	10.1042/CS20110668
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Article ; Online: ACE2 level as a marker of CVD.

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Article ; Online: Age-associated difference in circulating ACE2, the gateway for SARS-COV-2, in humans: results from the InCHIANTI study.

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Article ; Online: The combination of ACE I/D and ACE2 G8790A polymorphisms revels susceptibility to hypertension: A genetic association study in Brazilian patients.

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Article ; Online: Angiotensin-converting enzyme 2 (ACE2) levels in relation to risk factors for COVID-19 in two large cohorts of patients with atrial fibrillation.

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Article: Angiotensin-converting enzyme 2 (ACE2) levels in relation to risk factors for COVID-19 in two large cohorts of patients with atrial fibrillation

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Article ; Online: Angiotensin-converting enzyme 2 (ACE2) levels in relation to risk factors for COVID-19 in two large cohorts of patients with atrial fibrillation

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Article ; Online: Interaction of diabetes and ACE2 in the pathogenesis of cardiovascular disease in experimental diabetes.

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