Abstract-Excessive fibrosis contributes to an increase in left ventricular stiffness. The goal of the present study was to investigate the role of connective tissue growth factor (CCN2/CTGF), a profibrotic cytokine of the CCN (Cyr61, CTGF, and Nov) family, and its functional interactions with brain natriuretic peptide (BNP), an antifibrotic peptide, in the development of myocardial fibrosis and diastolic heart failure. Histological examination on endomyocardial biopsy samples from patients without systolic dysfunction revealed that the abundance of CTGF-immunopositive cardiac myocytes was correlated with the excessive interstitial fibrosis and a clinical history of acute pulmonary congestion. In a rat pressure overload cardiac hypertrophy model, CTGF mRNA levels and BNP mRNA were increased in proportion to one another in the myocardium. Interestingly, relative abundance of mRNA for CTGF compared with BNP was positively correlated with diastolic dysfunction, myocardial fibrosis area, and procollagen type 1 mRNA expression. Investigation with conditioned medium and subsequent neutralization experiments using primary cultured cells demonstrated that CTGF secreted by cardiac myocytes induced collagen production in cardiac fibroblasts. Further, G protein-coupled receptor ligands induced expression of the CTGF and BNP genes in cardiac myocytes, whereas aldosterone and transforming growth factor- preferentially induced expression of the CTGF gene. Finally, exogenous BNP prevented the production of CTGF in cardiac myocytes. These data suggest that a disproportionate increase in CTGF relative to BNP in cardiac myocytes plays a central role in the induction of excessive myocardial fibrosis and diastolic heart failure. Key Words: extracellular matrix Ⅲ hypertrophy Ⅲ cardiac function Ⅲ connective tissue growth factor Ⅲ natriuretic peptide E pidemiological studies have established that 40% to 50% of patients with heart failure have normal or minimally impaired left ventricular (LV) ejection fraction, a clinical syndrome that is commonly referred to as diastolic heart failure (DHF). These patients typically have cardiac hypertrophy that is induced by long-standing hypertension or by primary hypertrophic cardiomyopathy, as well as increased passive LV stiffness. 1 Among various molecular mechanisms that regulate LV stiffness, 2 abnormalities in the transcriptional or posttranscriptional regulation of the collagen gene can result in the disproportionate accumulation of fibrous tissue and elevation of stiffness in the hypertrophied heart. 2,3 Recent studies have shown that, in addition to mechanical load, autocrine, paracrine, and endocrine factors, such as angiotensin II, aldosterone (Aldo), endothelin-1 (ET1), natriuretic peptides, osteopontin, and transforming growth factor-1 (TGF-), play important roles in the development of myocardial hypertrophy and fibrosis. 4,5 However, the precise molecular mechanisms that initiate and promote myocardial fibrosis and increases in ventricular stiffness remain largely unknown.Connec...
Background: Peroxisome proliferator-activated receptor-γ (PPARγ) ligands have been shown to possess potent anti-inflammatory actions. Idiopathic interstitial pneumonia is defined as a specific form of chronic fibrosing lung disease characterized by progressive fibrosis which leads to deterioration and destruction of the lungs. Objective: To investigate whether the PPARγ ligand pioglitazone (PGZ) inhibited bleomycin (BLM)-induced acute lung injury and subsequent fibrosis. Methods: BLM was administered intratracheally to Wistar rats which were then treated with PGZ. Rat alveolar macrophages were stimulated with BLM for 6 h with or without PGZ pretreatment for 18 h. MRC-5 cells (human lung fibroblasts) were treated with PGZ for 18 h. After the treatment, the cells were stimulated with transforming growth factor- β (TGF-β) for 6 h. Results: PGZ inhibited BLM-induced acute lung injury and subsequent lung fibrosis when it was administered from day –7. PGZ treatment suppressed the accumulation of inflammatory cells in lungs and the concentration of tumor necrosis factor-α (TNF-α) in bronchoalveolar lavage fluid on day 3. PGZ also inhibited BLM-induced TNF-α production in alveolar macrophages. Furthermore, PGZ inhibited fibrotic changes and an increase in hydroxyproline content in lungs after instillation of BLM, even when PGZ was administered in the period from day 7 to day 28. Northern blot analyses revealed that PGZ inhibited TGF-β-induced procollagen I and connective tissue growth factor (CTGF) expression in MRC-5 cells. Conclusion: These results suggest that activation of PPARγ ameliorates BLM-induced acute inflammatory responses and fibrotic changes at least partly through suppression of TNF-α, procollagen I and CTGF expression. Beneficial effects of this PPARγ ligand on inflammatory and fibrotic processes open new perspectives for a potential role of PPARγ as a molecular target in fibroproliferative lung diseases.
A Candida albicans gene encoding a novel DNA-binding protein that bound to the RPG box of Sacchammyces cerevisiae and the telomeric repeat sequence of C. albicans was previously cloned and designated RBFl (RPG-box-binding factor). In this report determination of the functional domains of the protein is described. The DNA-binding domain was 140 aa in length, was centrally located between two glutamine-rich regions, and correlated with transcriptional activation in S. cerevisiae. The results, together with the previous finding that showed its predominant localization in the nucleus, suggest that this DNA-binding protein could be a transcription factor. Disruption of the functional RBFl gene of C. albicans strains caused an alteration in cell morphology to the filamentous form on all solid and liquid media tested. Thus, we speculate that Rbflp may be involved in the regulation of the transition between yeast and filamentous forms at the level of transcription.
Azoxybacilin, produced by Bacillus cereus, has a broad spectrum of antifungal activity in methionine-free medium and has been suggested to inhibit sulfite fixation. We have further investigated the mode of action by which azoxybacilin kills fungi. The compound inhibited the incorporation of [35S] sulfate into acid-insoluble fractions of Saccharomyces cerevisiae under conditions in which virtually no inhibition was observed for DNA, RNA, or protein synthesis. It did not interfere with the activity of the enzymes for sulfate assimilation but clearly inhibited the induction of those enzymes when S. cerevisiae cells were transferred from rich medium to a synthetic methionine-free medium. Particularly strong inhibition was observed in the induction of sulfite reductase. Northern (RNA) analysis revealed that azoxybacilin decreased the level of mRNA of genes for sulfate assimilation, including MET10 for sulfite reductase and MET4, the transactivator of MET10 and other sulfate assimilation genes. When activities of azoxybacilin were compared for mRNA and enzyme syntheses from MET10, the concentration required for inhibition of transcription of the gene was about 10 times higher (50% inhibitory concentration = 30 micrograms/ml) than that required for inhibition of induction of enzyme synthesis (50% inhibitory concentration = 3 micrograms/ml). The data suggest that azoxybacilin acts on at least two steps in the expression of sulfite reductase; the transcriptional activation of MET4 and a posttranscriptional regulation in MET10 expression. We conclude that azoxybacilin exhibits antifungal activity by interfering with the regulation of expression of sulfite reductase activity.
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