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Identification of Transcriptomic Differences Between Lower International Journal of Molecular Sciences Article Identification of Transcriptomic Differences between Lower Extremities Arterial Disease, Abdominal Aortic Aneurysm and Chronic Venous Disease in Peripheral Blood Mononuclear Cells Specimens Daniel P. Zalewski 1,*,† , Karol P. Ruszel 2,†, Andrzej St˛epniewski 3, Dariusz Gałkowski 4, Jacek Bogucki 5 , Przemysław Kołodziej 6 , Jolanta Szyma ´nska 7 , Bartosz J. Płachno 8 , Tomasz Zubilewicz 9 , Marcin Feldo 9,‡ , Janusz Kocki 2,‡ and Anna Bogucka-Kocka 1,‡ 1 Chair and Department of Biology and Genetics, Medical University of Lublin, 4a Chod´zkiSt., 20-093 Lublin, Poland; [email protected] 2 Chair of Medical Genetics, Department of Clinical Genetics, Medical University of Lublin, 11 Radziwiłłowska St., 20-080 Lublin, Poland; [email protected] (K.P.R.); [email protected] (J.K.) 3 Ecotech Complex Analytical and Programme Centre for Advanced Environmentally Friendly Technologies, University of Marie Curie-Skłodowska, 39 Gł˛ebokaSt., 20-612 Lublin, Poland; [email protected] 4 Department of Pathology and Laboratory Medicine, Rutgers-Robert Wood Johnson Medical School, One Robert Wood Johnson Place, New Brunswick, NJ 08903-0019, USA; [email protected] 5 Chair and Department of Organic Chemistry, Medical University of Lublin, 4a Chod´zkiSt., Citation: Zalewski, D.P.; Ruszel, K.P.; 20-093 Lublin, Poland; [email protected] St˛epniewski,A.; Gałkowski, D.; 6 Laboratory of Diagnostic Parasitology, Chair and Department of Biology and Genetics, Medical University of Bogucki, J.; Kołodziej, P.; Szyma´nska, Lublin, 4a Chod´zkiSt., 20-093 Lublin, Poland; [email protected] J.; Płachno, B.J.; Zubilewicz, T.; Feldo, 7 Department of Integrated Paediatric Dentistry, Chair of Integrated Dentistry, Medical University of Lublin, M.; et al. Identification of 6 Chod´zkiSt., 20-093 Lublin, Poland; [email protected] 8 Transcriptomic Differences between Department of Plant Cytology and Embryology, Institute of Botany, Faculty of Biology, Lower Extremities Arterial Disease, Jagiellonian University in Kraków, 9 Gronostajowa St., 30-387 Cracow, Poland; [email protected] 9 Abdominal Aortic Aneurysm and Chair and Department of Vascular Surgery and Angiology, Medical University of Lublin, 11 Staszica St., 20-081 Lublin, Poland; [email protected] (T.Z.); [email protected] (M.F.) Chronic Venous Disease in Peripheral * Correspondence: [email protected]; Tel.: +48-81-448-7236 Blood Mononuclear Cells Specimens. † Both authors shared first authorship. Int. J. Mol. Sci. 2021, 22, 3200. ‡ These authors shared senior authorship. https://doi.org/10.3390/ ijms22063200 Abstract: Several human tissues are investigated in studies of molecular biomarkers associated with diseases development. Special attention is focused on the blood and its components due to combining Academic Editor: VojtˇechAdam abundant information about systemic responses to pathological processes as well as high accessibility. In the current study, transcriptome profiles of peripheral blood mononuclear cells (PBMCs) were used Received: 31 January 2021 Accepted: 18 March 2021 to compare differentially expressed genes between patients with lower extremities arterial disease Published: 21 March 2021 (LEAD), abdominal aortic aneurysm (AAA) and chronic venous disease (CVD). Gene expression patterns were generated using the Ion S5XL next-generation sequencing platform and were analyzed Publisher’s Note: MDPI stays neutral using DESeq2 and UVE-PLS methods implemented in R programming software. In direct pairwise with regard to jurisdictional claims in analysis, 21, 58 and 10 differentially expressed genes were selected from the comparison of LEAD published maps and institutional affil- vs. AAA, LEAD vs. CVD and AAA vs. CVD patient groups, respectively. Relationships between iations. expression of dysregulated genes and age, body mass index, creatinine levels, hypertension and medication were identified using Spearman rank correlation test and two-sided Mann–Whitney U test. The functional analysis, performed using DAVID website tool, provides potential implications of selected genes in pathological processes underlying diseases studied. Presented research provides Copyright: © 2021 by the authors. new insight into differences of pathogenesis in LEAD, AAA and CVD, and selected genes could Licensee MDPI, Basel, Switzerland. be considered as potential candidates for biomarkers useful in diagnosis and differentiation of This article is an open access article studied diseases. distributed under the terms and conditions of the Creative Commons Keywords: lower extremities arterial disease; chronic venous disease; abdominal aortic aneurysm; Attribution (CC BY) license (https:// gene expression; next generation sequencing; biomarker; transcriptome profiling creativecommons.org/licenses/by/ 4.0/). Int. J. Mol. Sci. 2021, 22, 3200. https://doi.org/10.3390/ijms22063200 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, 3200 2 of 28 1. Introduction Noncommunicable diseases such as cancer, diabetes mellitus, cardiovascular and chronic respiratory diseases are today the major contributors to the global burden of death instances [1,2]. Out of them conditions linked to cardiovascular system are one of the most common cause of death worldwide and their contribution will be even higher in future decades [1,3]. This work encompasses comparative gene expression analysis of three conditions from this vast group of diseases: lower extremities arterial disease (LEAD), abdominal aortic aneurysm (AAA) and chronic venous disease (CVD), which are complex and multifactorial vascular diseases burdened with high prevalence and severe life-threating consequences, making them major global health problems. LEAD is the most common manifestation of peripheral arterial disease (PAD), charac- terized by chronic degenerative changes due to vascular flow deficit caused by formation of atheromatous plaques in arteries of lower limbs [4,5]. Overall global prevalence of LEAD is estimated to 5.56% of individuals aged 25 years and older and exceeds 10% in people older than 70 years [6]. The risk factors for LEAD include age, dyslipidemia, diabetes, smoking, hypertension and cardiovascular disease history [4,6]. The typical symptom of LEAD is intermittent claudication, resulting from recurrent ischemia-reperfusion cycles during physical activity, however more than 50% of LEAD cases is asymptomatic [5,7]. One of the most severe complication of LEAD is chronic limb-threatening ischemia, which affects approximately 11% of patients with LEAD [4,8]. AAA is a focal dilatation of the abdominal aorta measuring 50% greater than the prox- imal normal segment, or >3 cm in maximum diameter [9]. The prevalence of AAA ranges between 4% and 8% in general population of men aged 65–80 years [10]. Identified risk factors for aneurysm development include older age, male gender, cigarette smoking, obe- sity, dysregulation of lipid levels, hypertension [9,11,12] and genetic predisposition [13,14]. Patients with AAA may report nonspecific symptoms such as abdominal and back pain; however, in many cases, disease progress is asymptomatic [15]. Globally, AAA rupture is responsible for 0.3–0.4% of all death causes and approximately 1% of deaths among men above 65 years [16]. AAA rupture is associated with high distensibility of aortic wall, higher peak wall stress and aortic calcification [17]. CVD is defined as a syndrome of chronic morphological and functional abnormalities of the venous system caused by venous wall remodeling related to vascular inflammation, leading to venous hypertension, venous valve incompetency and reflux in veins of lower limbs [18–21]. The disease encompasses a wide spectrum of clinical presentations such as telangiectasia, varicose veins, leg edema, skin changes and ulcers [22]. The prevalence of symptomatic CVD among general practitioner attendees was estimated as high as 60%. The common risk factors include age, obesity, low physical activity, periods of prolonged standing or sitting and positive family history [23]. Guidelines for LEAD, AAA and CVD management, accomplished by specialists in the field and regularly updated [4,9,20,24,25], indicate urgent need for more effective diagnostic, treatment and differentiating strategies. Despite different clinical onset of LEAD, AAA and CVD, these diseases share main pathological mechanisms, such as inflammation, endothelial dysfunction and vascular smooth muscle cells proliferation and apoptosis, potentially impeding identification of specific biomarkers able to distinguish individuals affected with LEAD, AAA and CVD. Elucidation of molecular aspects of these diseases, including alterations in gene expression patterns associated with vascular pathology, could provide more focused insight into pathological conditions governing variety of vascular diseases. Many studies have identified dysregulations of gene expression associated with vas- cular cell functions, including cell differentiation, proliferation, migration, and apoptosis exhibiting modulatory function of angiogenesis, endothelial cells dysfunction and response for ischemic events and oxidative stress [26–31]. Alterations in expression of numerous genes are considered as potential signatures of vascular diseases including atherosclero- sis [32–34], LEAD [35–37], AAA [38–42] and CVD [43–46]. Int. J. Mol. Sci. 2021, 22, 3200 3 of 28 Peripheral blood mononuclear cells (PBMCs) represent a white blood cell subpop- ulation that includes
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