Peroxisome Proliferator‐activated Receptor Γ‐independent Effects of Thiazolidinediones on Human Cardiac Myofibroblast Function

Abstract

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.

Effects of interleukin-1 on cardiac fibroblast function: Relevance to post-myocardial infarction remodelling

“…of specific genes in human CF to promote a pro-inflammatory, pro-angiogenic, promigratory, ECM degrading, non-differentiated fibroblast phenotype. Figure summarises results previously published by our group using human CF from multiple patients (Mughal et al, 2009;Turner et al, 2009;Turner et al, 2010;Turner et al, 2011;Maqbool et al, 2013;. See main text for details.…”

“…IL-1 is a chemoattractant for several cell types and has been shown to be a potent inducer of in vitro cell migration of both neonatal and adult rat CF (Mitchell et al, 2007;Brown et al, 2007), as well as adult human CF (Mughal et al, 2009). …”

“…Cells were cultured from atrial tissue biopsies from multiple patients undergoing coronary artery bypass surgery and were found to consistently co-express vimentin and SMA throughout culture over several passages (Mughal et al, 2009), characteristic of the myofibroblast phenotype. We studied the effects of IL-1 on expression of proinflammatory cytokines, chemokines, adhesion molecules, angiogenic factors and molecules involved in ECM synthesis and degradation (Figure 2).…”

The role of cardiac fibroblasts in the transition from inflammation to fibrosis following myocardial infarction

“…Interestingly, when grown in vitro in rigid culture vessels, CF spontaneously undergo transition to a myofibroblast phenotype which is maintained or enhanced with passaging (Mughal et al, 2009;Santiago et al, 2010;Teunissen et al, 2007). This in vitro phenotype shares many similarities with that of myofibroblasts found in the infarct area in vivo (Santiago et al, 2010).…”

Inflammatory and fibrotic responses of cardiac fibroblasts to myocardial damage associated molecular patterns (DAMPs)

“…Thus, CF may contribute to the inflammatory milieu that occurs in the myocardium early after MI [10,95]. In addition to this inflammatory response, we [7,88,93,94,[96][97][98] and others [61,99,100] have demonstrated that CF alter the balance of cardiac ECM turnover in favour of degradation in response to IL-1; for example by increasing secretion of MMPs, decreasing collagen synthesis and decreasing expression of profibrotic factors (e.g. connective tissue growth factor).…”