Factor XIII expression within aortic valves and its plasma activity in patients with aortic stenosis: association with severity of disease

Summary

Aortic valve stenosis (AS) shares several similarities with atherosclerosis. Factor XIII (FXIII) has been detected within atherosclerotic plaques and may contribute to the development of atherosclerosis via multiple mechanisms. In the current study, we sought to investigate FXIII expression within human stenotic aortic valves and its association with severity of the disease. We prospectively enrolled 91 consecutive patients with AS scheduled for isolated valve replacement. Valvular FXIII subunit A (FXIII-A), fibrin and macrophages expression was evaluated by immunostaining. FXIII-A subunit transcripts and FXIII-A Val34Leu polymorphism was determined by real-time PCR. Plasma FXIII (pFXIII) activity was measured. We demonstrated that the valvular FXIII-A was predominantly expressed on the aortic side of leaflets, colocalized with alternatively activated macrophages (AAM). Areas stained for FXIII-A showed positive correlations with valvular fibrin presence, degree of calcification, pFXIII activity and the severity of AS, reflected by mean and maximum transvalvular gradients (all, p<0.001). The FXIII-A mRNA in the stenotic leaflets was significantly elevated compared to control leaflets. Interestingly, pFXIII activity was also positively correlated with mean (p<0.001) and maximum (p=0.001) transvalvular gradient. The FXIII-A Val34Leu polymorphism did not affect FXIII-A and fibrin expression in AS valves. In conclusion, the study is the first to show abundant expression of FXIII-A at the mRNA and protein levels within human stenotic aortic valves, which is associated with the severity of AS. Our findings might suggest that FXIII in the stenotic valves is presented in AAM and may be involved in the AS progression.

Keywords

Aortic valve stenosis - Calcification - factor XIII - alternatively activated macrophages

• References

• 1 Rajamannan NM, Evans FJ, Aikawa E. et al. Calcific aortic valve disease: not simply a degenerative process. Circulation 2011; 124: 1783-1791.
• 2 Olszowska M. Pathogenesis and pathophysiology of aortic valve stenosis in adults. Pol Arch Med Wewn 2011; 121: 409-413.
• 3 Natorska J, Marek G, Hlawaty M. et al. Evidence for tissue factor expression in aortic valves in patients with aortic stenosis. Pol Arch Med Wew 2009; 119: 636-642.
• 4 Breyne J, Juthier F, Corseaux D. et al. Atherosclerotic-like process in aortic stenosis: activation of the tissue factor-thrombin pathway and potential role through osteopontin alteration. Atherosclerosis 2010; 213: 369-376.
• 5 Natorska J, Marek G, Hlawaty M. et al. Fibrin presence within aortic valves in patients with aortic stenosis: association with in vivo thrombin generation and fibrin clot properties. Thromb Haemost 2011; 105: 254-260.
• 6 Muszbek L, Bereczky Z, Bagoly Z. et al. Factor XIII: a coagulation factor with multiple plasmatic and cellular functions. Physiol Rev 2011; 91: 931-972.
• 7 Shemirani AH, Szornijak E, Csiki Z. et al. Elevated factor XIII level and the risk of peripheral artery disease. Haemotologica 2008; 93: 1430-1432.
• 8 Bereczky Z, Balogh E, Katona E. et al. Elevated factor XIII level and the risk of myocardial infarction in women. Haematologica 2007; 92: 287-288.
• 9 Bakker EN, Pistea A, Spaan JA. et al. Flow-dependent remodeling of small arteries in mice deficient for tissue-type transglutaminase: possible compensation by macrophage-derived factor XIII. Circ Res 2006; 99: 86-92.
• 10 Romanic AM, Arleth AJ, Willette RN. et al. Factor XIIIa cross-links Lipoprotein(a) with fibrinogen and is present in human atherosclerotic lesions. Circ Res 1998; 83: 264-269.
• 11 Sato Y, Hatakeyama K, Yamashita A. et al. Proportion of fibrin and platelets differs in thrombi on ruptured and eroded coronary atherosclerotic plaques in humans. Heart 2005; 91: 526-530.
• 12 Ma J, Liew CC. Gene profiling identifies secreted protein transcripts from peripheral blood cells in coronary artery disease. J Mol Cell Cardiol 2003; 35: 993-998.
• 13 Abdalla S, Lother H, Langer A. et al. Factor XIIIA transglutaminase crosslinks AT1 receptor dimers of monocytes at the onset of atherosclerosis. Cell 2004; 119: 343-354.
• 14 Töröcsik D, Bárdos H, Nagy L. et al. Identification of factor XIII-A as a marker of alternative macrophage activation. Cell Mol Life Sci 2005; 62: 2132-2139.
• 15 Töröcsik D, Szeles L, Paragh Jr. G. et al. Factor XIII-A is involved in the regulation of gene expression in alternatively activated human macrophages. Thromb Haemost 2010; 104: 709-717.
• 16 Lim BC, Ariëns RA, Carter AM. et al. Genetic regulation of fibrin structure and function: complex gene-environment interactions may modulate vascular risk. Lancet 2003; 361: 1424-1431.
• 17 Balogh I, Szoke G, Karpati L. et al. Val34Leu polymorphism of plasma factor XIII: biochemistry and epidemiology in amilial thrombophilia. Blood 2000; 96: 2479-2486.
• 18 Ariens RA, Philippou H, Nagaswami C. et al. The factor XIII Val34Leu polymorphism accelerates thrombin activation of factor XIII and affects crosslinked fibrin structure. Blood 2000; 96: 988-995.
• 19 Wartiovaara U, Mikkola H, Szôke G. et al. Effect of Val34Leu polymorphism on the activation of the coagulation factor XIII-A. Thromb Haemost 2000; 84: 595-600.
• 20 Vokó Z, Bereczky Z, Katona E. et al. Factor XIII Val34Leu variant protects against coronary artery disease. A meta-analysis Thromb Haemost 2007; 97: 458-463.
• 21 Bereczky Z, Balogh E, Katona E. et al. Modulation of the risk of coronary sclerosis/myocardial infarction by the interaction between factor XIII subunit A Val34Leu polymorphism and fibrinogen concentration in the high risk Hungarian population. Thromb Haemost 2007; 120: 567-573.
• 22 Sinning JM, Ghanem A, Steinhäuser H. et al. Renal function as predictor of mortality in patients after percutaneous transcatheter aortic valve implantation. JACC Cardiovasc Interv 2010; 3: 1141-1149.
• 23 Teirstein P, Yeager M, Yock PG. et al. Doppler echocardiographic measurement of aortic valve area in aortic stenosis: a noninvasive application of the Gorlin formula. J Am Coll Cardiol 1986; 8: 1059-1065.
• 24 Lamprecht MR, Sabatini DM, Carpenter AE. CellProfiler: versalite software for automated biological image analysis. BioTechniques 2007; 42: 71-75.
• 25 Clark-Greuel JN, Connolly JM, Sorichillo E. et al. Transforming growth factor beta-1 mechanisms in aortic valve calcification: increased alkaline phosphatase and related events. Ann Thorac Surg 2007; 7: 946-953.
• 26 Attié-Castro FA, Zago MA, Lavinha J. et al. Ethnic heterogeneity of the factor XIII Val34Leu polymorphism. Thromb Haemost 2000; 84: 601-603.
• 27 Jámbor C, Reul V, Schnider TW. et al. In vitro inhibition of factor XIII retards clot formation, reduces clot firmness, and increases fibrinolytic effects in whole blood. Anesth Analg 2009; 109: 1023-1028.
• 28 Al-Jallad HF, Myneni VD, Piercy-Kotb SA. et al. Plasma membrane factor XIIIA transglutaminase activity regulates osteoblast matrix secretion and deposition by affecting microtubule dynamics. PLoS One 2011; 20 (06) 15893.
• 29 Piercy-Kotb SA, Mousa A, Al-Jallad HF. et al. Factor XIIIA transglutaminase expression and secretion by osteoblasts is regulated by extracellular matrix collagen and the MAP kinase signaling pathway. J Cell Physiol 2012; 227: 2936-2946.
• 30 Al-Jallad HF, Nakano Y, Chen JL. et al. Transglutaminase activity regulates osteoblast differentiation and matrix mineralization in MC3T3-E1 osteoblast cultures. Matrix Biol 2006; 25: 135-148.
• 31 Porcheray F, Viaud A, Rimaniol AC. et al. Macrophage activation switching: an asset for the resolution of inflammation. Clin Exp Immunol 2005; 142: 481-489.
• 32 Cordell PA, Kile BT, Standeven KF. et al. Association of coagulation factor XIII-A with Golgi proteins within monocyte-macrophages: implications for subcellular trafficking and secretion. Blood 2010; 115: 2674-2681.
• 33 Gleissner GA, Shaked I, Erbel C. et al. CXCL4 downregulates the atheroprotective hemoglobin receptor CD163 in human macrophages. Circ Res 2010; 106: 203-211.
• 34 Ariëns RA, Kohler HP, Mansfield MW. et al. Subunit antigen and activity levels of blood coagulation factor XIII in healthy individuals. Relation to sex, age, smoking, and hypertension Arterioscler Thromb Vasc Biol 1999; 19: 2012-2016.
• 35 Petkow-Dimitrow P, Undas A. Coagulation abnormalities in valvular and subvalvular aortic stenosis - clinical implication. Kardiol Pol 2008; 66: 569-573.