Özge PAMUKÇU, Derya AY, Kazım ÜZÜM, Didem BARLAK KETİ, Mehmet KÖSE, Ali BAYKAN, Süleyman SUNKAK, Nazmi NARİN

Role of kallistatin in pediatric patients with pulmonary arterial hypertension

Background and objectives. Kallistatin, a serine proteinase inhibitor, exerts its effect by vascular repair, angiogenesis inhibition, strong vasodilation, inhibition of vascular endothelial growth factor (VEGF), anti-inflammation, and anti-apoptosis. We hypothesized as to whether it has a protective role in pulmonary arterial hypertension (PAH). Methods. The study included 5 subgroups (78 patients; 44 male): Eisenmenger syndrome (n=16), PAH with left to right shunt (n=20), idiopathic PAH (n=7), patients with left to right shunt without PAH (n=19), and patients with innocent heart murmur (n=16). Physical examination, chest radiography, electrocardiography, and transthoracic echocardiography (TTE) were performed for each patient. PAH diagnosis was confirmed by catheterization. Serum kallistatin, tumor necrosis factor alpha (TNF-α), Interleukin-10 (IL-10) and N-terminal pro b-type natriuretic peptide (NT-proBNP) levels were studied for each patient.Results. The lowest median kallistatin value was found in Eisenmenger syndrome: 1.19 (0.87-3.30) μg/ml. The highest value belonged to control group with innocent murmur: 2.89 (1.19-5.66) μg/ml. Serum levels of kallistatin were significantly lower in patients with PAH (p

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1. Galie N, Simonneau G. The fifth world symposium on pulmonary hypertension. J Am Coll Cardiol 2013; 62 (Suppl 25): D1-D3.

2. Archer SL, Weir EK, Wilkins MR. Basic science of pulmonary arterial hypertension for clinicians: new concepts and experimental therapies. Circulation 2010; 121: 2045-2066.

3. Chao J, Schmaier A, Chen LM, Yang Z, Chao L. Kallistatin, a novel human tissue kallikrein inhibitor: Levels in body fluids, blood cells, and tissues in health and disease. J Lab Clin Med 1996; 127: 612- 620.

4. Miao RQ, Agata JA, Chao L. Chao J. Kallistatin is a new inhibitor of angiogenesis and tumor growth. Blood 2002; 100: 3245-3252.

5. Apitz C, Hansmann G, Schranz D. Hemodynamic assessment and acute pulmonary vasoreactivity testing in the evaluation of children with pulmonary vascular disease. Expert consensus statement on the diagnosis and treatment of paediatric pulmonary hypertension. The European Paediatric Pulmonary Vascular Disease Network, endorsed by ISHLT and DGPK. Heart 2016; 102(Suppl 2): 23-29.

6. Simonneau G, Gatzoulis MA, Adatia I, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2013; 24(Suppl 25): D34-D41.

7. Wolf WC, Harley RA, Sluce D, Chao L, Chao J. Cellular localization of kallistatin and tissue kallikrein in human pancreas and salivary glands. Histochem Cell Biol 1998; 110: 477-484.

8. Gao L, Li P, Zhang J, et al. Novel role of kallistatin in vascular repair by promoting mobility, viability, and function of endothelial progenitor cells. J Am Heart Assoc 2014; 3: e001194.

9. Liu X, McBride J, Zhou Y, Liu Z, Ma JX. Regulation of endothelial progenitor cell release by Wnt signaling in bone marrow. Invest Ophthalmol Vis Sci 2013; 54: 7386-7394.

10. Tse LY, Sun X, Jiang H, et al. Adeno-associated virusmediated expression of kallistatin suppresses local and remote hepatocellular carcinomas. J Gene Med 2008; 10: 508-517.

11. Li P, Guo Y, Bledsoe G, Yang Z, Chao L, Chao J. Kallistatin induces breast cancer cell apoptosis and autophagy by modulating Wnt signaling and microRNA synthesis. Exp Cell Res 2016; 340: 305- 314.

12. Chao J, Stallone JN, Liang YM, Chen LM, Wang DZ, Chao L. Kallistatin is a potent new vasodilator. J Clin Invest 1997; 100: 11-17.

13. Jiang X, Li H, Qiao H, Jiang H, Xu R, Sun X. Combining kallistatin gene therapy and meloxicam to treat hepatocellular carcinoma in mice. Cancer Sci 2009; 100: 2226-2233.

14. Soon E, Holmes AM, Treacy CM, et al. Elevated levels of inflammatory cytokines predict survival in idiopathic and familial pulmonary arterial hypertension. Circulation 2010; 122: 920-927.

15. Gao L, Yin H, S Smith R Jr, Chao L, Chao J. Role of kallistatin in prevention of cardiac remodeling after chronic myocardial infarction. Lab Invest 2008; 88: 1157-1166.

16. Shen B, Hagiwara M, Yao YY, Chao L, Chao J. Salutary effect of kallistatin in salt-induced renal injury, inflammation, and fibrosis via antioxidative stress. Hypertension 2008; 51: 1358-1365.

17. Diao Y, Zhao XF, Lin JS, Wang QZ, Xu RA. Protection of the liver against CCl4-induced injury by intramuscular electrotransfer of a kallistatinencoding plasmid. World J Gastroenterol 2011; 17: 111-117.

18. Liu Y, Bledsoe G, Hagiwara M, Shen B, Chao L, Chao J. Depletion of endogenous kallistatin exacerbates renal and cardiovascular oxidative stress, inflammation, and organ remodeling. Am J Physiol Renal Physiol 2012; 303: F1230-F1238.

19. Hsieh JL, Shen PC, Shiau AL, et al. Adenovirusmediated kallistatin gene transfer ameliorates disease progression in a rat model of osteoarthritis induced by anterior cruciate ligament transection. Hum Gene Ther 2009; 20: 147-158.

20. Lin WC, Chen CW, Huang YW, et al. Kallistatin protects against sepsis-related acute lung injury via inhibiting inflammation and apoptosis. Sci Rep 2015; 5: 12463.