Angiotensin converting enzyme activity is positively associated with IL-17a levels in patients with schizophrenia Ary Gadelha a,b,n , Camila M. Yonamine a,c , Marcela Nering c , Lucas Bortolotto Rizzo a , Cristiano Noto a,b , Hugo Cogo-Moreira a , Antônio Lúcio Teixeira d , Rodrigo Bressan a,b , Michael Maes e,f , Elisa Brietzke a , Mirian A.F. Hayashi a,c,nn a Interdisciplinary Laboratory of Clinical Neurosciences (LiNC), Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil b Schizophrenia Program (ProEsq), Department of Psychiatry, UNIFESP, São Paulo, Brazil c Department of Pharmacology, UNIFESP, São Paulo, Brazil d Translational Psychoneuroimmunology Group, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil e Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand f IMPACT Research Center, Deakin University, Geelong, Australia article info Article history: Received 15 December 2014 Received in revised form 17 July 2015 Accepted 11 August 2015 Keywords: Angiotensin Converting Enzyme (ACE) Interleukin-17 (IL-17) Schizophrenia Inflammatory response Inflammation Cytokine Biomarker abstract Previous studies of our group showed increased plasmatic Angiotensin-I Converting Enzyme (ACE) ac- tivity in schizophrenia (SCZ) patients compared to healthy controls, which was also associated to poor cognitive functioning. The ACE main product angiotensin II (Ang-II) has pro-inflammatory properties. Activated immune-inflammatory responses in SCZ and their association with disease progression and cognitive impairments are also well-described. Therefore, we examined here the association of plasma ACE activity and inflammatory mediators in 33 SCZ patients and 92 healthy controls. Non-parametric correlations were used to investigate the association of the enzyme activity and the peripheral levels of immune inflammatory markers as interleukins, tumor necrosis factor (TNF-α), and interferon (IFN-γ). Although no significant correlations could be observed for ACE activity and measured cytokines levels in healthy controls, a significant positive correlation for ACE enzymatic activity and IL-17a levels was ob- served in SCZ patients. Correcting for gender did not change these results. Moreover, a significant as- sociation for ACE activity and IFN-γ levels was also observed. To our knowledge, this is the first study to show a significant association between higher ACE activity and the levels of cytokines, namely IL-17a and IFN-γ, in patients with SCZ. & 2015 Published by Elsevier Ireland Ltd. 1. Introduction Renin–Angiotensin System (RAS) was classically described in the context of water and pressure homeostasis regulation (Basso and Terragno, 2001). Angiotensin-converting enzyme (ACE) is a zinc-dependent carboxydipeptidil peptidase responsible for the conversion of angiotensin I (Ang-I) to the hypertensive peptide angiotensin II (Ang-II), and it was therefore considered as the key element of RAS. More recently, some authors proposed the re- definition of RAS as a stress-response system, as it is extremely relevant to sustain homeostasis with actions on blood pressure, behavior and immune-regulatory system (Bali and Jaggi, 2013). The relevance RAS in brain has been recently underscored due the association with neurodegenerative diseases, including Par- kinson’s and Alzheimer’s diseases. Several lines of evidence also support a role for RAS in schizophrenia (SCZ), including the modulatory effects of RAS on brain dopamine pathways (Fineberg Contents lists available at ScienceDirect journal homepage: www.elsevier.com/locate/psychres Psychiatry Research http://dx.doi.org/10.1016/j.psychres.2015.08.018 0165-1781/& 2015 Published by Elsevier Ireland Ltd. Abbreviations: RAS, Renin–Angiotensin System; ACE, angiotensin-I converting enzyme; SCZ, schizophrenia; Ang-I, angiotensin-I; Ang-II, angiotensin-II; ACEi, ACE inhibitor; ARB, angiotensin receptor blocker; FRET, Fluorescence Resonance Energy Transfer; MCP-1, monocyte chemoattractant protein-1; NF-kB, Nuclear Factor Kappa-B; IL, interleukin; TNF, tumor necrosis factor; IFN, interferon; GWAS, Gen- ome-Wide Association studies; PANSS, Positive and Negative Syndrome Scale; SCID, Structured Clinical Interview for DSM-IV; CGI, Clinical Global Impression; GAF, Global Assessment of Functioning; CBA, cytometric bead array; Treg, antigen-spe- cific regulatory T cells; BMI, body mass index n Correspondence to: Departamento de Psiquiatria, Universidade Federal de São Paulo (UNIFESP/EPM), Ed. Pesquisas II, Rua Pedro de Toledo, 669, 3rd floor, CEP 04039-032, São Paulo, Brazil. Fax: þ55 11 5576 4499. nn Correspondence to: Departamento de Farmacologia, Universidade Federal de São Paulo (UNIFESP/EPM), Rua 3 de maio 100, Ed. INFAR, 3rd floor, CEP 04044-020, São Paulo, Brazil. Fax: þ55 11 5576 4499. E-mail addresses: aryararipe@yahoo.com.br, aryararipe@gmail.com (A. Gadelha), mhayashi@unifesp.br, mhayashi.unifesp@gmail.com (M.A.F. Hayashi). Please cite this article as: Gadelha, A., et al., Angiotensin converting enzyme activity is positively associated with IL-17a levels in patients with schizophrenia. Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2015.08.018i Psychiatry Research ∎ (∎∎∎∎) ∎∎∎–∎∎∎