Pauli Ohukainen1,5, Juha Näpänkangas2,5, Pasi Ohtonen3,5, Heikki Ruskoaho1,4, Panu Taskinen3,5, Tuomas Peltonen1, Jaana Rysä1,5,6
1Department of Pharmacology and Toxicology, University of Oulu, 2Department of Pathology, Oulu University Hospital, University of Oulu, 3Department of Cardiovascular Surgery (P.T.) and Anesthesiology and Surgery (P.Oht.), Oulu University Hospital, University of Oulu, Oulu, 4Division of Pharmacology and Pharmacotherapy, University of Helsinki, 5Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, 6School of Pharmacy, University of Eastern Finland, Kuopio, Finland
Background and aim of the study: Calcified aortic valve disease (CAVD) is an actively regulated disease that shares pathophysiological hallmarks with atherosclerosis. One of these common features is extracellular matrix (ECM) remodeling, which consists of a dynamic degradation and deposition of the ECM composition. Granzymes (Grs) are ECM-degrading and pro-apoptotic proteases that have been detected in atherosclerotic lesions, but their role in CAVD remains unknown.
Methods: The expression of granzymes and perforin was characterized in heavily stenotic valves (n = 20) and control valves (n = 6) using quantitative RT-PCR and immunohistochemistry.
Results: Quantitative RT-PCR revealed that levels of granzymes A, B, H, K and M mRNA were 4.9-fold (p
<0.001), 7.1-fold (p <0.001), 4.6-fold (p <0.001), 4.7-fold (p <0.001) and 2.8-fold (p = 0.069) higher, respectively, in stenotic aortic valves than in control valves. Perforin mRNA levels were 3.6-fold (p <0.001) higher in stenotic valves than in control valves. Granzyme A immunohistochemical positivity was observed in mast cells and lymphocytes, granzyme H in mast cells but not in lymphocytes, and granzyme K in lymphocytes but not in mast cells. A statistical analysis was also performed to investigate the effect of statin treatment on granzyme expression, but no differences were found when compared to non-statin-treated patients.
Conclusions: The data acquired showed that CAVD is characterized by an increased expression of granzymes A, B, H, K, and perforin.
The Journal of Heart Valve Disease 2015;24:612-620
|Expression and Localization of Granzymes and Perforin in Human Calcific Aortic Valve Disease|
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