Temporal changes in soluble angiotensin-converting enzyme 2 associated with metabolic health, body composition, and proteome dynamics during a weight loss diet intervention: a randomized trial with implications for the COVID-19 pandemic

Nicholas Cauwenberghs, Mary Prunicki, František Sabovčik, Dalia Perelman, Kévin Contrepois, Xiao Li, Michael P Snyder, Kari C Nadeau, Tatiana Kuznetsova, Francois Haddad, Christopher D Gardner, Nicholas Cauwenberghs, Mary Prunicki, František Sabovčik, Dalia Perelman, Kévin Contrepois, Xiao Li, Michael P Snyder, Kari C Nadeau, Tatiana Kuznetsova, Francois Haddad, Christopher D Gardner

Abstract

Background: Angiotensin-converting enzyme 2 (ACE2) serves protective functions in metabolic, cardiovascular, renal, and pulmonary diseases and is linked to COVID-19 pathology. The correlates of temporal changes in soluble ACE2 (sACE2) remain understudied.

Objectives: We explored the associations of sACE2 with metabolic health and proteome dynamics during a weight loss diet intervention.

Methods: We analyzed 457 healthy individuals (mean ± SD age: 39.8 ± 6.6 y) with BMI 28-40 kg/m2 in the DIETFITS (Diet Intervention Examining the Factors Interacting with Treatment Success) study. Biochemical markers of metabolic health and 236 proteins were measured by Olink CVDII, CVDIII, and Inflammation I arrays at baseline and at 6 mo during the dietary intervention. We determined clinical and routine biochemical correlates of the diet-induced change in sACE2 (ΔsACE2) using stepwise linear regression. We combined feature selection models and multivariable-adjusted linear regression to identify protein dynamics associated with ΔsACE2.

Results: sACE2 decreased on average at 6 mo during the diet intervention. Stronger decline in sACE2 during the diet intervention was independently associated with female sex, lower HOMA-IR and LDL cholesterol at baseline, and a stronger decline in HOMA-IR, triglycerides, HDL cholesterol, and fat mass. Participants with decreasing HOMA-IR (OR: 1.97; 95% CI: 1.28, 3.03) and triglycerides (OR: 2.71; 95% CI: 1.72, 4.26) had significantly higher odds for a decrease in sACE2 during the diet intervention than those without (P ≤ 0.0073). Feature selection models linked ΔsACE2 to changes in α-1-microglobulin/bikunin precursor, E-selectin, hydroxyacid oxidase 1, kidney injury molecule 1, tyrosine-protein kinase Mer, placental growth factor, thrombomodulin, and TNF receptor superfamily member 10B. ΔsACE2 remained associated with these protein changes in multivariable-adjusted linear regression.

Conclusions: Decrease in sACE2 during a weight loss diet intervention was associated with improvements in metabolic health, fat mass, and markers of angiotensin peptide metabolism, hepatic and vascular injury, renal function, chronic inflammation, and oxidative stress. Our findings may improve the risk stratification, prevention, and management of cardiometabolic complications.This trial was registered at clinicaltrials.gov as NCT01826591.

Keywords: angiotensin-converting enzyme 2; body composition; metabolic health; proteomics; weight loss diet intervention.

© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.

Figures

FIGURE 1
FIGURE 1
Flowchart of the DIETFITS (Diet Intervention Examining the Factors Interacting with Treatment Success) substudy.
FIGURE 2
FIGURE 2
Multivariable-adjusted association between 6-mo changes (Δ) in sACE2 and metabolic health during a diet intervention. (A) Histogram of ΔsACE2 in the entire cohort (n = 457). (B) Multivariable-adjusted change in sACE2 by change in metabolic health profile. Mean ± SE ΔsACE2 was adjusted for sACE2 at baseline, age, sex, and clinical correlates of ΔsACE2 (Table 2) in a linear mixed model and compared using an independent-samples t test. *,**,***Significant changes in sACE2 during follow-up according to paired-sample t test: *P < 0.05,**P < 0.001, ***P < 0.0001. (C) Multivariable-adjusted risk of decrease in sACE2 by change in metabolic health profile in logistic regression. NPX, normalized protein expression; sACE2, soluble angiotensin-converting enzyme 2.
FIGURE 3
FIGURE 3
Proteins linked to sACE2 at baseline and follow-up and its changes at 6 mo in the diet intervention. The heat map presents the biomarkers that were important in PLS analysis (VIP >1.5) and/or XGBoost modeling (feature importance >0.010) for predicting the cross-sectional sACE2 and the 6-mo change (Δ) in sACE2. For PLS, red dots are positive and blue dots are negative correlation coefficients. Proteins selected for baseline sACE2, follow-up sACE2, and ΔsACE2 are in bold. Models for ΔsACE2 accounted for sACE2 at baseline. Larger dots reflect greater VIP score (for PLS) or greater feature importance (for XGBoost). AMBP, α-1-microglobulin/bikunin precursor; APN, aminopeptidase N; CCL3, C-C motif chemokine ligand 3; CDCP1, CUB domain containing protein 1; DCN, decorin; DNER, Δ and notch-like epidermal growth factor-related receptor; FABP2, fatty acid-binding protein 2; HAOX1, hydroxyacid oxidase 1; HGF, hepatocyte growth factor; hOSCAR, human osteoclast-associated immunoglobulin-like receptor; HO1, heme oxygenase 1; IGFBP, insulin-like growth factor-binding protein; IL1-RT2, interleukin 1 receptor type II; KIM-1, kidney injury molecule 1; MB, myoglobin; MERTK, tyrosine-protein kinase Mer; MMP, matrix metalloproteinase; PGF, placental growth factor; PLS, partial least squares; PRSS8, prostasin; PSGL1, P-selectin glycoprotein ligand-1; sACE2, soluble angiotensin-converting enzyme 2; SCF, stem cell factor; ST-2, soluble interleukin-1 receptor-like 1; TIMP4, tissue inhibitor of metalloproteinase 4; TNFRSF9, TNF receptor superfamily member 9; TPA, tissue-type plasminogen activator; TRAIL-R2, TNF receptor superfamily member 10B; TRAP, thrombospondin-related anonymous protein; TWEAK, TNF-related weak inducer of apoptosis; VIP, variable importance in projection; XGBoost, eXtreme Gradient Boosting.

References

    1. Putnam K, Shoemaker R, Yiannikouris F, Cassis LA. The renin-angiotensin system: a target of and contributor to dyslipidemias, altered glucose homeostasis, and hypertension of the metabolic syndrome. Am J Physiol Heart Circ Physiol. 2012;302:H1219–H1230.
    1. Patel SK, Velkoska E, Freeman M, Wai B, Lancefield TF, Burrell LM. From gene to protein-experimental and clinical studies of ACE2 in blood pressure control and arterial hypertension. Front Physiol. 2014;5:227.
    1. Hooper NM, Lambert DW, Turner AJ. Discovery and characterization of ACE2 – a 20-year journey of surprises from vasopeptidase to COVID-19. Clin Sci. 2020;134:2489–2501.
    1. Walls AC, Park Y-J, Tortorici MA, Wall A, McGuire AT, Veesler D. Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell. 2020;181:281–292. e6.
    1. Hong PJ, Look DC, Tan P, Shi L, Hickey M, Gakhar L, Chappell MC, Wohlford-Lenane C, McCray PB., Jr Ectodomain shedding of angiotensin converting enzyme 2 in human airway epithelia. Am J Physiol Lung Cell Mol Physiol. 2009;297:L84.
    1. Cheng H, Wang Y, Wang G-Q. Organ-protective effect of angiotensin-converting enzyme 2 and its effect on the prognosis of COVID-19. J Med Virol. 2020;92:726–730.
    1. Richardson S, Hirsch JS, Narasimhan M, Crawford JM, McGinn T, Davidson KW, Barnaby DP, Becker LB, Chelico JD, Cohen SL, et al. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area. JAMA. 2020;323:2052–2059.
    1. Guo W, Li M, Dong Y, Zhou H, Zhang Z, Tian C, Qin R, Wang H, Shen Y, Du K, et al. Diabetes is a risk factor for the progression and prognosis of COVID-19. Diabetes Metab Res Rev. 2020;36:e3319.
    1. Ren H, Yang Y, Wang F, Yan Y, Shi X, Dong K, Yu X, Zhang S. Association of the insulin resistance marker TyG index with the severity and mortality of COVID-19. Cardiovasc Diabetol. 2020;19:58.
    1. Emami A, Javanmardi F, Pirbonyeh N, Akbari A. Prevalence of underlying diseases in hospitalized patients with COVID-19: a systematic review and meta-analysis. Arch Acad Emerg Med. 2020;8:e35.
    1. Kuznetsova T, Cauwenberghs N. Determinants of circulating angiotensin-converting enzyme 2 protein levels in the general population. Eur J Intern Med. 2020;84:104–105.
    1. Kornilov SA, Lucas I, Jade K, Dai CL, Lovejoy JC, Magis AT. Plasma levels of soluble ACE2are associated with sex, Metabolic Syndrome, and its biomarkers in a large cohort, pointing to a possible mechanism for increased severity in COVID-19. Crit Care. 2020;24:452.
    1. Narula S, Yusuf S, Chong M, Ramasundarahettige C, Rangarajan S, Bangdiwala SI, van Eikels M, Leineweber K, Wu A, Pigeyre M, et al. Plasma ACE2 and risk of death or cardiometabolic diseases: a case-cohort analysis. Lancet. 2020;396:968–976.
    1. Úri K, Fagyas M, Siket IM, Kertész A, Csanádi Z, Sándorfi G, Clemens M, Fedor R, Papp Z, Édes I, et al. New perspectives in the renin-angiotensin-aldosterone system (RAAS) IV: circulating ACE2 as a biomarker of systolic dysfunction in human hypertension and heart failure. PLoS One. 2014;9:e87845.
    1. Shao Z, Schuster A, Borowski AG, Thakur A, Li L, Wilson Tang WH. Soluble angiotensin converting enzyme 2 levels in chronic heart failure is associated with decreased exercise capacity and increased oxidative stress-mediated endothelial dysfunction. Transl Res. 2019;212:80–88.
    1. Soro-Paavonen A, Gordin D, Forsblom C, Rosengard-Barlund M, Waden J, Thorn L, Sandholm N, Thomas MC, Groop P-H. Circulating ACE2 activity is increased in patients with type 1 diabetes and vascular complications. J Hypertens. 2012;30:375–383.
    1. Chhabra KH, Chodavarapu H, Lazartigues E. Angiotensin converting enzyme 2: a new important player in the regulation of glycemia. IUBMB Life. 2013;65:731–738.
    1. Bernardi S, Tikellis C, Candido R, Tsorotes D, Pickering RJ, Bossi F, Carretta R, Fabris B, Cooper ME, Thomas MC. ACE2 deficiency shifts energy metabolism towards glucose utilization. Metabolism. 2015;64:406–415.
    1. Lundberg M, Eriksson A, Tran B, Assarsson E, Fredriksson S. Homogeneous antibody-based proximity extension assays provide sensitive and specific detection of low-abundant proteins in human blood. Nucleic Acids Res. 2011;39:e102.
    1. Lee LC, Liong C-Y, Jemain AA. Partial least squares-discriminant analysis (PLS-DA) for classification of high-dimensional (HD) data: a review of contemporary practice strategies and knowledge gaps. Analyst. 2018;143:3526–3539.
    1. Chen T, Guestrin C. Proceedings of the 22nd ACM SIGKDD International Conference on Knowledge Discovery and Data Mining, San Francisco, CA, August 13–17. Association for Computing Machinery; New York (NY): 2016. XGBoost: a scalable tree boosting system; pp. 785–794.
    1. Stanton M, Robinson J, Kirkpatrick S, Farzinkhou S, Avery E, Rigdon J, Offringa L, Trepanowski J, Hauser M, Hartle J, et al. DIETFITS study (diet intervention examining the factors interacting with treatment success) – study design and methods. Contemp Clin Trials. 2017;53:151–161.
    1. Gardner CD, Trepanowski JF, Gobbo LCD, Hauser ME, Rigdon J, Ioannidis JPA, Desai M, King AC. Effect of low-fat vs low-carbohydrate diet on 12-month weight loss in overweight adults and the association with genotype pattern or insulin secretion: the DIETFITS randomized clinical trial. JAMA. 2018;319:667–679.
    1. Figarska SM, Rigdon J, Ganna A, Elmståhl S, Lind L, Gardner CD, Ingelsson E. Proteomic profiles before and during weight loss: results from randomized trial of dietary intervention. Sci Rep. 2020;10:7913.
    1. Langfelder P, Horvath S. WGCNA: an R package for weighted correlation network analysis. BMC Bioinformatics. 2008;9:559.
    1. McKinney W. Data structures for statistical computing in Python. [Internet]. In: van der Walt S, Millman J, editors. Proceedings of the 9th Python in Science Conference. Austin (TX), June 28–30. 2010. p. 56–61. [Accessed 2021 Jul 27]. Available from: .
    1. Bindom SM, Hans CP, Xia H, Boulares AH, Lazartigues E. Angiotensin I–converting enzyme type 2 (ACE2) gene therapy improves glycemic control in diabetic mice. Diabetes. 2010;59:2540–2548.
    1. Cao X, Lu X-M, Tuo X, Liu J-Y, Zhang Y-C, Song L-N, Cheng Z-Q, Yang J-K, Xin Z. Angiotensin-converting enzyme 2 regulates endoplasmic reticulum stress and mitochondrial function to preserve skeletal muscle lipid metabolism. Lipids Health Dis. 2019;18:207.
    1. Takeda M, Yamamoto K, Takemura Y, Takeshita H, Hongyo K, Kawai T, Hanasaki-Yamamoto H, Oguro R, Takami Y, Tatara Y, et al. Loss of ACE2 exaggerates high-calorie diet–induced insulin resistance by reduction of GLUT4 in mice. Diabetes. 2013;62:223–233.
    1. Yamamoto K, Takeshita H, Rakugi H. ACE2, angiotensin 1-7 and skeletal muscle: review in the era of COVID-19. Clin Sci. 2020;134:3047–3062.
    1. Park SE, Kim WJ, Park SW, Park JW, Lee N, Park C-Y, Youn B-S. High urinary ACE2 concentrations are associated with severity of glucose intolerance and microalbuminuria. Eur J Endocrinol. 2013;168:203–210.
    1. De Oliveira e Silva ER, Foster D, Harper MM, Seidman CE, Smith JD, Breslow JL, Brinton EA. Alcohol consumption raises HDL cholesterol levels by increasing the transport rate of apolipoproteins A-I and A-II. Circulation. 2000;102:2347–2352.
    1. Northcote J, Livingston M. Accuracy of self-reported drinking: observational verification of “last occasion” drink estimates of young adults. Alcohol Alcohol. 2011;46:709–713.
    1. Wolke C, Teumer A, Endlich K, Endlich N, Rettig R, Stracke S, Fiene B, Aymanns S, Felix SB, Hannemann A, et al. Serum protease activity in chronic kidney disease patients: the GANI_MED renal cohort. Exp Biol Med. 2017;242:554–563.
    1. de Borst MH, van Timmeren MM, Vaidya VS, de Boer RA, van Dalen MBA, Kramer AB, Schuurs TA, Bonventre JV, Navis G, van Goor H. Induction of kidney injury molecule-1 in homozygous Ren2 rats is attenuated by blockade of the renin-angiotensin system or p38 MAP kinase. Am J Physiol Renal Physiol. 2007;292:F313–F320.
    1. Recalcati S, Tacchini L, Alberghini A, Conte D, Cairo G. Oxidative stress-mediated down-regulation of rat hydroxyacid oxidase 1, a liver-specific peroxisomal enzyme. Hepatology. 2003;38:1159–1166.
    1. Murray MS, Holmes RP, Lowther WT. Active site and loop 4 movements within human glycolate oxidase: implications for substrate specificity and drug design. Biochemistry. 2008;47:2439–2449.
    1. Wevers BA, Hoek L. Renin–angiotensin system in human coronavirus pathogenesis. Future Virol. 2010;5:145–161.
    1. Reguera J, Santiago C, Mudgal G, Ordoño D, Enjuanes L, Casasnovas JM. Structural bases of coronavirus attachment to host aminopeptidase N and its inhibition by neutralizing antibodies. PLoS Pathog. 2012;8:e1002859.
    1. Koenig JB, Jaffe IZ. Direct role for smooth muscle cell mineralocorticoid receptors in vascular remodeling: novel mechanisms and clinical implications. Curr Hypertens Rep. 2014;16:427.
    1. Pan P, Fu H, Zhang L, Huang H, Luo F, Wu W, Guo Y, Liu X. Angiotensin II upregulates the expression of placental growth factor in human vascular endothelial cells and smooth muscle cells. BMC Cell Biol. 2010;11:36.
    1. Jaffe IZ, Newfell BG, Aronovitz M, Mohammad NN, McGraw AP, Perreault RE, Carmeliet P, Ehsan A, Mendelsohn ME. Placental growth factor mediates aldosterone-dependent vascular injury in mice. J Clin Invest. 2010;120:3891–3900.
    1. Pruthi D, McCurley A, Aronovitz M, Galayda C, Karumanchi SA, Jaffe IZ. Aldosterone promotes vascular remodeling by direct effects on smooth muscle cell mineralocorticoid receptors. Arterioscler Thromb Vasc Biol. 2014;34:355–364.
    1. McShane L, Tabas I, Lemke G, Kurowska-Stolarska M, Maffia P. TAM receptors in cardiovascular disease. Cardiovasc Res. 2019;115:1286–1295.
    1. Roldán V, Marín F, Lip GYH, Blann AD. Soluble E-selectin in cardiovascular disease and its risk factors. A review of the literature. Thromb Haemost. 2003;90:1007–1020.
    1. Martin FA, Murphy RP, Cummins PM. Thrombomodulin and the vascular endothelium: insights into functional, regulatory, and therapeutic aspects. Am J Physiol Heart Circ Physiol. 2013;304:H1585–H1597.
    1. Kristiansson A, Gram M, Flygare J, Hansson SR, Åkerström B, Storry JR. The role of α1-microglobulin (A1M) in erythropoiesis and erythrocyte homeostasis—therapeutic opportunities in hemolytic conditions. Int J Mol Sci. 2020;21:7234.
    1. Mattisson IY, Björkbacka H, Wigren M, Edsfeldt A, Melander O, Fredrikson GN, Bengtsson E, Gonçalves I, Orho-Melander M, Engström G, et al. Elevated markers of death receptor-activated apoptosis are associated with increased risk for development of diabetes and cardiovascular disease. EBioMedicine. 2017;26:187–197.
    1. Aminian A, Fathalizadeh A, Tu C, Butsch WS, Pantalone KM, Griebeler ML, Kashyap SR, Rosenthal RJ, Burguera B, Nissen SE. Association of prior metabolic and bariatric surgery with severity of coronavirus disease 2019 (COVID-19) in patients with obesity. Surg Obes Relat Dis. 2021;17:208–214.

Source: PubMed

Sponsorer og samarbeidspartnere

Medisinsk tilstand

Legemiddelintervensjoner

3
Abonnere