THE EXPRESSION OF NOVEL,LOAD-INDUCED EXTRACELLULAR MATRIX MODULATING FACTORSIN CARDIAC REMODELING, ACTA UNIVERSITATIS OULUENSIS D Medica 1066

Cardiac remodeling is defined as changes in the size, shape and function of the heart, caused mostcommonly by hypertension-induced left ventricular (LV) hypertrophy and myocardial infarction(MI). It is characterized by changes in cellular and extracellular compartments regulated by e.g.neurohumoral and inflammatory factors. In the present study the expression of novel, load inducedfactors, thrombospondin (TSP)-1 and -4, matrix Gla protein (MGP), tumor necrosis factor-likeweak inducer of apoptosis (TWEAK) and its receptor Fn14, was investigated during cardiacremodeling. Their expression in the heart was characterized using experimental models ofpressure overload, hypertensive hypertrophy and MI, and the effect of hypertrophic agonists andcellular stretch was studied in vitro. The effect of beta-blocker treatment on TSP expression wasalso examined. \nTSP-1 and -4 were rapidly upregulated in response to pressure overload, and the induction ofTSP-4 gene expression was attenuated in hypertrophied heart. After MI, TSP-1 and -4 mRNA andTSP-1 protein levels were increased, and the induction was attenuated by metoprolol. TSP-1 and-4 expression correlated with natriuretic peptide expression and LV remodeling after MI. Inhypertensive hypertrophy, only TSP-4 expression decreased after metoprolol treatment and wascorrelated with LV remodeling. \nMGP gene expression was increased in response to pressure overload and MI both in the earlyand late phase of cardiac remodeling. MGP protein levels were increased in the acute phase ofpost-MI remodeling and in hypertensive hypertrophy. In vitro, angiotensin II increased MGP geneexpression in myocytes and fibroblasts, whereas expression decreased in response to mechanicalstretch. \nIn response to increased cardiac load Fn14 expression was upregulated both acutely andchronically while TWEAK expression remained relatively constant. Fn14 localized mainly tofibroblasts in the inflammatory area while TWEAK localized to myocytes and endothelial cells.In myocytes, Fn14 expression was induced by hypertrophic agonists and mechanical stretch incontrast to stabile or decreased TWEAK expression. \nThis study provides new insights into the expression of the studied novel factors in cardiacremodeling. The distinct expression of TSPs in pressure overload and post-MI suggests that TSP-1 and -4 may have unique roles in the remodeling process. The results also imply that MGP is partof the common gene program of hypertrophic remodeling in vivo and contributes to the molecularbasis of cardiac hypertrophy. Finally, the study demonstrates differential regulation of TWEAKand Fn14 expression in the heart and emphasizes the importance of Fn14 as a mediator ofTWEAK/Fn14 signaling and as a potential target of therapeutic interventions.

ISBN-10:
978-951-42-6277-7
Kieli:
eng.
Sivumäärä:
176 s.
Tekijät:
MUSTONEN ERJA
Tuotekoodi 014002
21,50 €