Peroxisome proliferator-activated receptor gamma-independent effects of thiazolidinediones on human cardiac myofibroblast function.
1. Thiazolidinediones (TZDs) are peroxisome proliferator-activated receptor (PPAR) gamma 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 PPARgamma activation. 3. Immunoblotting of cultured human CMF homogenates revealed strong expression of PPARgamma (approximately 50 kDa). Three different TZDs (ciglitazone, rosiglitazone and troglitazone) and the endogenous PPARgamma ligand 15-deoxy-delta(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 micromol/L) with similar potencies. This antiproliferative effect of TZDs was not reversed by the PPARgamma antagonists GW9662 or T0070907 (10-25 micromol/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 PPARgamma-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.
Mughal
Romana S
RS
Division of Cardiovascular and Neuronal Remodelling, Leeds Institute of Genetics, Health and Therapeutics (LIGHT), University of Leeds, Leeds, UK.
Warburton
Philip
P
O'Regan
David J
DJ
Ball
Stephen G
SG
Turner
Neil A
NA
Porter
Karen E
KE
D041721:3T3-L1 Cells; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D045162:Thiazolidinediones / Q000494:pharmacology*
D007004:Hypoglycemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9