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Expression of selected angiogenesis-related small microRNAs in patients with abnormally increased secretion of glucocorticoids
Affiliations- Department of General Pathology, Pomeranian Medical University, Szczecin, Poland
- Department of Endocrinology, Metabolic Diseases, and Internal Diseases, Pomeranian Medical University, Szczecin, Poland
- Department of Gynaecological Surgery and Gynaecological Oncology, Pomeranian Medical University, Szczecin, Poland, Poland
- Department of Paediatrics, Endocrinology, Diabetology, Metabolic Diseases, and Cardiology of Developmental Age, Pomeranian Medical University, Szczecin, Poland
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Abstract
Introduction: Higher cortisol levels are associated with cardiovascular morbidity and mortality in the elderly, partially resulting from biologic effects of glucocorticoids (GCs) on endothelial cells observed in an experimental setting. These features are replicated in patients with endogenous GC excess (Cushing’s syndrome) or with exogenous hypercortisolism due to excessive pharmacological application of GCs. Both groups present also an increased cardiovascular disease event rate. GCs may also adversely influence recovery after myocardial infarction. Recently it was proposed that microRNAs (miRNAs) — small noncoding RNAs functioning as antisense regulators of gene expression by targeting mRNA — may have a central role in regulating endothelial function through multiple mechanisms. Thus, the purpose of this study was to evaluate the effects of chronic GC excess on the expression of selected endothelium-controlling miRNAs expressed in nucleated cells circulating in peripheral blood (PBNCs) of patients with endogenous hypercortisolism either due to corticotrophin‐independent or corticotrophin‐dependent Cushing’s syndrome (CS).
Material and methods: Peripheral blood nuclear cells were collected from 35 healthy subjects and 31 patients with endogenous hypercortisolism as a source of miRNAs. A self-validated individual quantitative RT-PCR study was then performed to evaluate the expression levels of selected miRNAs in PBNCs. Additionally, endothelin-1 (ET-1) expression in peripheral blood was assessed with respect to endothelial dysfunction using Western blotting.
Results: The ET-1 expression levels in CS were higher than in controls, confirming endothelial dysfunction in the CS group. Furthermore, miRNA analysis revealed a significantly decreased intracellular expression of selected endothelium-related miRNAs in patients with endogenous hypercortisolism, including miRNA-17-5p, miRNA-126-3p, and miRNA-126-5p, compared to controls. In contrast, two other angiogenic miRNAs, miRNA-150-5p and miRNA-223-3p, were significantly upregulated compared to controls.
Conclusions: Cardiovascular events related to hypercortisolism remain a challenging problem in medical practice. This study has demonstrated that the chronic excess of GCs in endogenous CS might induce significant dysregulation of selected miRNAs involved in the control of endothelium biology. However, the lack of knowledge about specific miRNA expression postpones the full understanding of the biological roles of such miRNAs in hypercortisolism. Moreover, dysregulated miRNAs seem to be promising targets for further research, especially to search for potential therapies for several GC-induced cardiovascular complications.
Abstract
Introduction: Higher cortisol levels are associated with cardiovascular morbidity and mortality in the elderly, partially resulting from biologic effects of glucocorticoids (GCs) on endothelial cells observed in an experimental setting. These features are replicated in patients with endogenous GC excess (Cushing’s syndrome) or with exogenous hypercortisolism due to excessive pharmacological application of GCs. Both groups present also an increased cardiovascular disease event rate. GCs may also adversely influence recovery after myocardial infarction. Recently it was proposed that microRNAs (miRNAs) — small noncoding RNAs functioning as antisense regulators of gene expression by targeting mRNA — may have a central role in regulating endothelial function through multiple mechanisms. Thus, the purpose of this study was to evaluate the effects of chronic GC excess on the expression of selected endothelium-controlling miRNAs expressed in nucleated cells circulating in peripheral blood (PBNCs) of patients with endogenous hypercortisolism either due to corticotrophin‐independent or corticotrophin‐dependent Cushing’s syndrome (CS).
Material and methods: Peripheral blood nuclear cells were collected from 35 healthy subjects and 31 patients with endogenous hypercortisolism as a source of miRNAs. A self-validated individual quantitative RT-PCR study was then performed to evaluate the expression levels of selected miRNAs in PBNCs. Additionally, endothelin-1 (ET-1) expression in peripheral blood was assessed with respect to endothelial dysfunction using Western blotting.
Results: The ET-1 expression levels in CS were higher than in controls, confirming endothelial dysfunction in the CS group. Furthermore, miRNA analysis revealed a significantly decreased intracellular expression of selected endothelium-related miRNAs in patients with endogenous hypercortisolism, including miRNA-17-5p, miRNA-126-3p, and miRNA-126-5p, compared to controls. In contrast, two other angiogenic miRNAs, miRNA-150-5p and miRNA-223-3p, were significantly upregulated compared to controls.
Conclusions: Cardiovascular events related to hypercortisolism remain a challenging problem in medical practice. This study has demonstrated that the chronic excess of GCs in endogenous CS might induce significant dysregulation of selected miRNAs involved in the control of endothelium biology. However, the lack of knowledge about specific miRNA expression postpones the full understanding of the biological roles of such miRNAs in hypercortisolism. Moreover, dysregulated miRNAs seem to be promising targets for further research, especially to search for potential therapies for several GC-induced cardiovascular complications.
Keywords
endocrine diseases; Cushing’s syndrome; cardiovascular abnormalities; microRNA
About this articleTitle
Expression of selected angiogenesis-related small microRNAs in patients with abnormally increased secretion of glucocorticoids
Journal
Issue
Article type
Original paper
Pages
489-495
Published online
2019-11-26
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1706
Article views/downloads
952
DOI
Pubmed
Bibliographic record
Endokrynol Pol 2019;70(6):489-495.
Keywords
endocrine diseases
Cushing’s syndrome
cardiovascular abnormalities
microRNA
Authors
Miłosz P. Kawa
Anna Sobuś
Zofia Litwińska
Lilianna Osowicz-Korolonek
Aneta Cymbaluk-Płoska
Iwona Stecewicz
Edyta Zagrodnik
Hanna Romanowska
Mieczysław Walczak
Anhelli Syrenicz
Bogusław Machaliński
References (34)- Barnes PJ. Glucocorticosteroids: current and future directions. Br J Pharmacol. 2011; 163(1): 29–43.
- Fardet L, Petersen I, Nazareth I. Prevalence of long-term oral glucocorticoid prescriptions in the UK over the past 20 years. Rheumatology (Oxford). 2011; 50(11): 1982–1990.
- Ambroziak U, Bluszcz G, Bednarczuk T, et al. The influence of Graves' orbitopathy treatment with intravenous glucocorticoids on adrenal function. Endokrynol Pol. 2017; 68(4): 430–433.
- Miljic P, Miljic D, Cain JW, et al. Pathogenesis of vascular complications in Cushing's syndrome. Hormones (Athens). 2012; 11(1): 21–30.
- Wierzbicka-Chmiel J, Chmiel A, Rychlik S, et al. Vascular and cardiac function in young adults with classical congenital adrenal hyperplasia. Endokrynol Pol. 2017; 68(5): 505–511.
- Pivonello R, Isidori AM, De Martino MC, et al. Complications of Cushing's syndrome: state of the art. Lancet Diabetes Endocrinol. 2016; 4(7): 611–629.
- Ong SLH, Whitworth JA. How do glucocorticoids cause hypertension: role of nitric oxide deficiency, oxidative stress, and eicosanoids. Endocrinol Metab Clin North Am. 2011; 40(2): 393–407, ix.
- Kirilov G, Tomova A, Dakovska L, et al. Elevated plasma endothelin as an additional cardiovascular risk factor in patients with Cushing's syndrome. Eur J Endocrinol. 2003; 149(6): 549–553.
- Barbot M, Ceccato F, Scaroni C. The Pathophysiology and Treatment of Hypertension in Patients With Cushing's Syndrome. Front Endocrinol (Lausanne). 2019; 10: 321.
- Pereira AM, Delgado V, Romijn JA, et al. Cardiac dysfunction is reversed upon successful treatment of Cushing's syndrome. Eur J Endocrinol. 2010; 162(2): 331–340.
- Qin L, Zhu X, Liu X, et al. Evaluation of lipid profile and its relationship with blood pressure in patients with Cushing's disease. Endocr Connect. 2018; 7(5): 637–644.
- Akaza I, Yoshimoto T, Tsuchiya K, et al. Endothelial dysfunction aassociated with hypercortisolism is reversible in Cushing's syndrome. Endocr J. 2010; 57(3): 245–252.
- Lamarca B. The role of immune activation in contributing to vascular dysfunction and the pathophysiology of hypertension during preeclampsia. Minerva Ginecol. 2010; 62(2): 105–120.
- Fardet L, Fève B. Systemic glucocorticoid therapy: a review of its metabolic and cardiovascular adverse events. Drugs. 2014; 74(15): 1731–1745.
- Schober A, Nazari-Jahantigh M, Wei Y, et al. MicroRNA-126-5p promotes endothelial proliferation and limits atherosclerosis by suppressing Dlk1. Nat Med. 2014; 20(4): 368–376.
- Harris TA, Yamakuchi M, Ferlito M, et al. MicroRNA-126 regulates endothelial expression of vascular cell adhesion molecule 1. Proc Natl Acad Sci USA. 2008; 105(5): 1516–1521.
- Zampetaki A, Kiechl S, Drozdov I, et al. Plasma microRNA profiling reveals loss of endothelial miR-126 and other microRNAs in type 2 diabetes. Circ Res. 2010; 107(6): 810–817.
- Meng S, Cao JT, Zhang B, et al. Downregulation of microRNA-126 in endothelial progenitor cells from diabetes patients, impairs their functional properties, via target gene Spred-1. J Mol Cell Cardiol. 2012; 53(1): 64–72.
- Wang KC, Garmire LX, Young A, et al. Role of microRNA-23b in flow-regulation of Rb phosphorylation and endothelial cell growth. Proc Natl Acad Sci U S A. 2010; 107(7): 3234–3239.
- Zeller T, Keller T, Ojeda F, et al. Assessment of microRNAs in patients with unstable angina pectoris. Eur Heart J. 2014; 35(31): 2106–2114.
- Zhang R, Lan C, Pei H, et al. Expression of circulating miR-486 and miR-150 in patients with acute myocardial infarction. BMC Cardiovasc Disord. 2015; 15: 51.
- Haneklaus M, Gerlic M, Kurowska-Stolarska M, et al. Cutting edge: miR-223 and EBV miR-BART15 regulate the NLRP3 inflammasome and IL-1β production. J Immunol. 2012; 189(8): 3795–3799.
- Guignat L, Bertherat J. The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline: commentary from a European perspective. Eur J Endocrinol. 2010; 163(1): 9–13.
- Vanhoutte PM, Shimokawa H, Feletou M, et al. Endothelial dysfunction and vascular disease. Acta Physiol (Oxf). 2009; 196(2): 193–222.
- Denes J, Zsippai A, Kovacs L, et al. Comparison of adipose tissue derived genes in endogenous Cushing's syndrome versus diet-induced obesity. Endokrynol Pol. 2019; 70(2): 131–134.
- Nicoli S, Standley C, Walker P, et al. MicroRNA-mediated integration of haemodynamics and Vegf signalling during angiogenesis. Nature. 2010; 464(7292): 1196–1200.
- Mocharla P, Briand S, Giannotti G, et al. AngiomiR-126 expression and secretion from circulating CD34(+) and CD14(+) PBMCs: role for proangiogenic effects and alterations in type 2 diabetics. Blood. 2013; 121(1): 226–236.
- Jakob P, Doerries C, Briand S, et al. Loss of angiomiR-126 and 130a in angiogenic early outgrowth cells from patients with chronic heart failure: role for impaired in vivo neovascularization and cardiac repair capacity. Circulation. 2012; 126(25): 2962–2975.
- Witkowski M, Weithauser A, Tabaraie T, et al. Micro-RNA-126 Reduces the Blood Thrombogenicity in Diabetes Mellitus via Targeting of Tissue Factor. Arterioscler Thromb Vasc Biol. 2016; 36(6): 1263–1271.
- Elgheznawy A, Fleming I. Platelet-Enriched MicroRNAs and Cardiovascular Homeostasis. Antioxid Redox Signal. 2018; 29(9): 902–921.
- Zhu Ni, Zhang D, Chen S, et al. Endothelial enriched microRNAs regulate angiotensin II-induced endothelial inflammation and migration. Atherosclerosis. 2011; 215(2): 286–293.
- Boon RA, Vickers KC. Intercellular transport of microRNAs. Arterioscler Thromb Vasc Biol. 2013; 33(2): 186–192.
- Zhuang G, Meng C, Guo X, et al. A novel regulator of macrophage activation: miR-223 in obesity-associated adipose tissue inflammation. Circulation. 2012; 125(23): 2892–2903.
- Zampetaki A, Willeit P, Tilling L, et al. Prospective study on circulating MicroRNAs and risk of myocardial infarction. J Am Coll Cardiol. 2012; 60(4): 290–299.
