Matrix metalloproteinases (MMPs) degrade collagen and mediate tissue remodeling. The novel cytokine IL-17 is expressed during various inflammatory conditions and modulates MMP expression. We investigated the effect of IL-17 on MMP-1 expression in primary human cardiac fibroblasts (HCF) and delineated the signaling pathways involved. HCF were treated with recombinant human IL-17. MMP-1 expression was analyzed by Northern blotting, RTquantitative PCR, Western blotting, and ELISA; transcriptional induction and transcription factor binding by EMSA, ELISA, and reporter assay; and p38 MAPK and ERK1/2 activation by protein kinase assays and Western blotting. Signal transduction pathways were investigated using pharmacological inhibitors, small interfering RNA (siRNA), and adenoviral dominant-negative expression vectors. IL-17 stimulated MMP-1 gene transcription, net mRNA levels, protein, and promoter-reporter activity in HCF. This response was blocked by IL-17 receptor-Fc chimera and IL-17 receptor antibodies, but not by IL-6, TNF-␣, or IL-1␤ antibodies. IL-17-stimulated type I collagenase activity was inhibited by the MMP inhibitor GM-6001 and by siRNA-mediated MMP-1 knockdown. IL-17 stimulated activator protein-1 [AP-1 (c-Fos, c-Jun, and Fra-1)], NF-B (p50 and p65), and CCAAT enhancer-binding protein (C/EBP)-␤ DNA binding and reporter gene activities, effects attenuated by antisense oligonucleotides, siRNA-mediated knockdown, or expression of dominantnegative signaling proteins. Inhibition of AP-1, NF-B, or C/EBP activation attenuated IL-17-stimulated MMP-1 expression. IL-17 induced p38 MAPK and ERK1/2 activation, and inhibition by SB-203580 and PD-98059 blunted IL-17-mediated transcription factor activation and MMP-1 expression. Our data indicate that IL-17 induces MMP-1 in human cardiac fibroblasts directly via p38 MAPKand ERK-dependent AP-1, NF-B, and C/EBP-␤ activation and suggest that IL-17 may play a critical role in myocardial remodeling. cytokines; interleukins; matrix metalloproteinases; fibrosis EXTRACELLULAR MATRIX (ECM) turnover in the normal heart is a tightly regulated process. The alteration in the delicate balance between matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) during myocardial injury and inflammation results in enhanced ECM degradation and remodeling (29,30).

Venkatachalam K, Mummidi S, Cortez DM, Prabhu SD, Valente AJ, Chandrasekar B. Resveratrol inhibits high glucoseinduced PI3K/Akt/ERK-dependent interleukin-17 expression in primary mouse cardiac fibroblasts. Am J Physiol Heart Circ Physiol 294: H2078-H2087, 2008. First published February 29, 2008 doi:10.1152/ajpheart.01363.2007.-We investigated the expression of the proinflammatory cytokine interleukin (IL)-17 in cardiac fibroblasts and its induction by high glucose (HG). Our results show that primary mouse cardiac fibroblasts (mCFs) secrete low basal levels of IL-17 and that HG (25 mM D-glucose) as opposed to low glucose (5 mM D-glucose ϩ 20 mM mannitol) significantly enhances its secretion. HG induces IL-17 mRNA expression by both transcriptional and posttranscriptional mechanisms. HG induces phosphoinositide 3-kinase [PI3K; inhibited by adenoviral (Ad).dominant negative (dn)PI3Kp85], Akt (inhibited by Ad.dnAkt1), and ERK (inhibited by PD-98059) activation and induces IL-17 expression via PI3K3 Akt3 ERK-dependent signaling. Moreover, mCFs express both IL-17 receptors A and C, and although IL-17RA is upregulated, HG fails to modulate IL-17RC expression. Furthermore, IL-17 stimulates net collagen production by mCFs. Pretreatment with the phytoalexin resveratrol blocks HG-induced PI3K-, Akt-, and ERK-dependent IL-17 expression. These results demonstrate that 1) cardiac fibroblasts express IL-17 and its receptors; 2) HG upregulates IL-17 and IL-17RA, suggesting a positive amplification loop in IL-17 signaling in hyperglycemia; 3) IL-17 enhances net collagen production; and 4) resveratrol can inhibit these HG-induced changes. Thus, in hyperglycemic conditions, IL-17 may potentiate myocardial inflammation, injury, and remodeling through autocrine and paracrine mechanisms, and resveratrol has therapeutic potential in ameliorating this effect. signal transduction; proinflammatory cytokines FIBROBLASTS ARE THE MOST ABUNDANT cell type in the mammalian heart, residing in the interstitium between contracting cardiomyocytes and providing structural support by regulating extracellular matrix deposition and turnover. They play a central role in the cardiac remodeling and fibrosis that follow pressure overload or myocardial injury, by generating high levels of proinflammatory cytokines, chemokines, and growth factors and by increasing the production of extracellular matrix (ECM) proteins (5,15,16,37,39,48). Both experimental and clinical studies have reported that diabetes mellitus (DM) is a causative as well as a compounding factor in cardiomyopathy. DM can result in cardiomyopathy in the absence of coronary artery disease, hypertension, and alcoholism (2, 3). Prolonged hyperglycemia results in left ventricular hypertrophy and cardiac fibrosis characterized by fibroblast migration, proliferation, and deposition of excess amounts of collagen and other ECM proteins (2, 3), indicating that DM is an independent risk factor in myocardial remodeling in vivo. In vitro, high glucose (HG) has also been shown to induce oxidative stress...

MicroRNAs (miRNAs) are a class of post-transcriptional regulators that provide a mechanism of gene silencing by translational repression or degradation of the targeted gene. Gene expression regulation by miRNAs is involved in most if not all physiological and pathophysiological processes. Atherosclerosis is a major cardiovascular disease pathology regulated by miRNAs. Recent miRNA profiling studies have implicated the potential use of miRNAs as biomarkers in patients with atherosclerosis, as both diagnostic and prognostic indicators. This review will discuss the clinical and basic science research information that has been gleaned regarding miRNA roles in dyslipidemia, diabetes, obesity, and insulin resistance which are the major stimulators for the development of atherosclerosis.

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