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PEROXISOME PROLIFERATOR‐ACTIVATED RECEPTOR γ‐INDEPENDENT EFFECTS OF THIAZOLIDINEDIONES ON HUMAN CARDIAC MYOFIBROBLAST FUNCTION
Author(s) -
Mughal Romana S,
Warburton Philip,
O’Regan David J,
Ball Stephen G,
Turner Neil A,
Porter Karen E
Publication year - 2009
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/j.1440-1681.2008.05088.x
Subject(s) - troglitazone , ciglitazone , rosiglitazone , thiazolidinedione , peroxisome proliferator activated receptor , microbiology and biotechnology , cell growth , endocrinology , medicine , biology , receptor , chemistry , cancer research , biochemistry , insulin , type 2 diabetes , diabetes mellitus
SUMMARY1 Thiazolidinediones (TZDs) are peroxisome proliferator‐activated receptor (PPAR) γ agonists that are used to lower insulin resistance in Type 2 diabetic patients. Although TZDs exhibit beneficial effects on the vasculature, their effects on the heart are less clear and are the subject of current clinical debate. Thiazolidinediones have been reported to reduce adverse myocardial remodelling, a pathology in which cardiac myofibroblasts (CMF) are pivotal. 2 The aim of the present study was to investigate whether TZDs modulate specific human CMF functions of importance to the myocardial remodelling process and to determine whether any of these effects were mediated via PPARγ activation. 3 Immunoblotting of cultured human CMF homogenates revealed strong expression of PPARγ (approximately 50 kDa). Three different TZDs (ciglitazone, rosiglitazone and troglitazone) and the endogenous PPARγ ligand 15‐deoxy‐δ 12,14 ‐prostaglandin J 2 (15d‐PGJ 2 ) inhibited CMF proliferation (cell number and expression of proliferating cell nuclear antigen) in a concentration‐dependent manner (range 0.1–10 µmol/L) with similar potencies. This antiproliferative effect of TZDs was not reversed by the PPARγ antagonists GW9662 or T0070907 (10–25 µmol/L). None of the TZDs or 15d‐PGJ 2 affected cell migration or invasion (Boyden chamber assays without or with Matrigel barrier), matrix metalloproteinase‐2 or ‐9 secretion (gelatin zymography) or the actin cytoskeleton (rhodamine/phalloidin fluorescent confocal microscopy). 4 In conclusion, TZDs reduce human CMF proliferation via a PPARγ‐independent mechanism. Although TZDs do not inhibit CMF invasion, their antiproliferative activity may contribute to the ability of this class of drugs to modulate adverse myocardial remodelling.