The anthracycline antibiotic doxorubicin (DOX) is a potent cancer chemotherapeutic agent that exerts both acute and chronic cardiotoxicity. Here we show that in adult mouse cardiomyocytes, DOX activates (i) the pro-apoptotic p53, (ii) p38MAPK and JNK, (iii) Bax translocation, (iv) cytochrome c release, and (v) caspase 3. Further, it (vi) inhibits expression of anti-apoptotic Akt, Bcl-2 and Bcl-xL, and (vii) induces internucleosomal degradation and cell death. WNT1-Inducible Signaling Pathway Protein-1 (WISP1), a CCN family member and a matricellular protein, inhibits DOX-mediated cardiomyocyte death. WISP1 inhibits DOX-induced p53 activation, p38 MAPK and JNK phosphorylation, Bax translocation to mitochondria, and cytochrome c release into cytoplasm. Additionally, WISP1 reverses DOX-induced suppression of Bcl-2 and Bcl-xL expression and Akt inhibition. The pro-survival effects of WISP1 were recapitulated by the forced expression of mutant p53, wild-type Bcl-2, wild-type Bcl-xL, or constitutively active Akt prior to DOX treatment. WISP1 also induces the pro-survival factor Survivin via PI3K/Akt signaling. Overexpression of wild-type, but not mutant Survivin, blunts DOX cytotoxicity. Further, WISP1 stimulates PI3K-Akt-dependent GSK3β phosphorylation and β-catenin nuclear translocation. Importantly, WISP1 induces its own expression. Together, these results provide important insights into the cytoprotective effects of WISP1 in cardiomyocytes, and suggest a potential therapeutic role for WISP1 in DOX-induced cardiotoxicity.
C-reactive protein (CRP)2 is an acute phase reactant that is markedly increased during infection, inflammation, and tissue injury (1-5). It is synthesized and secreted mainly by the liver in response to circulating inflammatory mediators (6, 7). Elevated serum CRP levels serve as a risk marker for cardiovascular disease and predict future cardiovascular events and mortality (8, 9).Data obtained both in vivo and in vitro indicate that CRP plays a role in vascular inflammation (10 -12). CRP can be detected in human atherosclerotic plaques co-localized with modified low density lipoprotein (13,14). It can also associate with the terminal complex of complement in the arterial wall, inducing its activation in plaques. CRP promotes the uptake of low density lipoprotein by macrophages (15) and exerts a mitogenic effect on vascular smooth muscle cells (16). CRP stimulates chemokine and adhesion molecule expression in vascular endothelial cells and enhances platelet adhesion to endothelial cells (17). These data suggest that CRP is not just a marker of cardiovascular risk but is a risk factor in its own right, and CRP plays a causal role in atherosclerosis and thrombosis. In fact, transgenic overexpression of human CRP has been shown to promote atherosclerosis in apoE Ϫ/Ϫ mice (18), as does chronic administration (19). These data support an hypothesis that CRP is a proinflammatory and pro-atherogenic factor.Inflammation is an important component in all stages of atherosclerosis, with proinflammatory cytokines and chemokines playing critical roles. IL-17 is a member of a novel group of proinflammatory cytokines that is composed of six major isoforms, IL-17A, -B, -C, -D, -E (also known as IL-25), and -F (20). These isoforms are encoded by unique genes and share little homology with other interleukins. IL-17 signals via IL-17 receptors, products of unique genes, and includes IL-17RA, -B (also known as IL-25R), -C, -D, and -E (20).IL-17A is the most widely studied cytokine of the IL-17 family. It signals via IL-17RA and exerts proinflammatory, pro-apoptotic, and pro-mitogenic effects. Unlike IL-17, which is considered a T-cell-specific cytokine (21), many cell types in the body express the receptors and are therefore targets of . In this study we investigated whether IL-17 stimulates CRP expression in human hepatocytes and CASMC, and we determined the signal transduction pathways involved in * This work was supported in part by the Research Service of the Department of Veterans Affairs and NHLBI Grant HL68020 from the National Institutes of Health (to B. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 To whom correspondence should be addressed: Medicine/Cardiology,
WNT1-inducible signaling pathway protein-1 (WISP1), a member of the CYR61/CTGF/Nov family of growth factors, can mediate cell growth, transformation, and survival. Previously we demonstrated that WISP1 is up-regulated in post-infarct heart, stimulates cardiac fibroblast proliferation, and is induced by the proinflammatory cytokine tumor necrosis factor-␣ (TNF-␣).
For both men and women, ischemic heart disease is one of the leading causes of death in the United States today, and its pathobiology has been attributed to many factors, including proinflammatory cytokines. Interleukin (IL) 2 -18 is a pleiotropic cytokine belonging to the IL-1 family (1-5), whose expression is up-regulated in numerous immune, infectious, and inflammatory conditions (1-5), which may further amplify the inflammatory cascade by inducing additional cytokines, chemokines, and adhesion molecules (1-5). Elevated plasma IL-18 levels have been detected in patients with acute coronary syndromes (6), and a direct correlation between IL-18 levels and the severity of myocardial dysfunction has been reported. Circulating IL-18 levels have been shown to be independent predictors of coronary events in humans, with increased basal levels of IL-18 observed in individuals who later developed coronary events (7). Increased circulating IL-18 levels have also been measured during heart failure as well as in stroke patients (8, 9). IL-18 signals via the IL-18 receptor, a heterodimer consisting of a ligand binding ␣-subunit and a signal-transducing -subunit (10, 11). Binding of IL-18 to IL-18R␣ recruits IL-18R, and this activated complex initiates pleiotropic signal transduction events. Similar to IL-1 receptor antagonist that blocks IL-1 signaling, IL-18-binding protein (IL-18BP) binds IL-18 with high affinity, inhibits IL-18 bioavailability (12), neutralizes IL-18 effects, and thus reduces inflammation. Interestingly, transgenic mice overexpressing human IL-18BP exhibit reduced inflammation and disease severity (13).Cytotoxic free radicals and proinflammatory cytokines are produced during ischemia/reperfusion (I/R) injury. Using isolated adult rat cardiomyocytes, we have recently described NF-B-dependent IL-18 and IL-18R expression following hydrogen peroxide and TNF-␣ treatment in vitro (14). Moreover, although IL-18BP gene expression under basal conditions in these cells is undetectable, TNF-␣ and H 2 O 2 each induce IL-18BP mRNA in a delayed but persistent manner (14), which suggests tight regulation of IL-18 bioavailability. However, the precise role of IL-18 in I/R injury and its regulation in vivo are incompletely understood, and the signal transduction path-* This work was supported in part by the Research Service of the Department of Veterans Affairs. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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...
Wax apple fruit (Syzygium aqueum Alston cv. Taaptimjan) is a tropical fruit with many nutritional bioactive compounds and high economic value. However, when fully ripe, the thin-skinned fruit is highly susceptible to physical damage and microbial spoilage that significantly reduce its commercial value. The present study was aimed to find a suitable ripening stage between the ripe and overripe wax apple fruits for developing a value-added beverage specifically cider. The chemical profiles of ripe and overripe wax apple juice and cider were determined by measuring sugar, acid, alcohol, mineral, proximate, ascorbic acid, amino acid, antioxidant, and volatile levels. Overall, the results showed significant variations. The physicochemical and proximate analysis showed highest values for ripe fruit juice than overripe fruit juice and the cider samples. The amino acids in the samples were found almost at similar levels. Polyphenolic content and antioxidant activities were higher in ciders than in unfermented juices. In addition, the overripe fruit cider had more volatile compounds than ripe fruit cider and unfermented juices. Overall, the overripe fruit is suitable for producing cider, whereas the ripe fruit is more suitable for the unfermented beverages.
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