Abstract-Gene-expression changes in atrial fibrillation patients reflect both underlying heart-disease substrates and changes because of atrial fibrillation-induced atrial-tachycardia remodeling. These are difficult to separate in clinical investigations. This study assessed time-dependent mRNA expression-changes in canine models of atrial-tachycardia remodeling and congestive heart failure. Five experimental groups (5 dogs/group) were submitted to atrial (ATP, 400 bpm ϫ24 hours, 1 or 6 weeks) or ventricular (VTP, 240 bpm ϫ24 hours or 2 weeks) tachypacing. The expression of Ϸ21,700 transcripts was analyzed by microarray in isolated left-atrial cardiomyocytes and (for 18 genes) by real-time RT-PCR. Protein-expression changes were assessed by Western blot. In VTP, a large number of significant mRNA-expression changes occurred after both 24 hours (2209) and 2 weeks (2720). In ATP, fewer changes occurred at 24 hours (242) and fewer still (87) at 1 week, with no statistically-significant alterations at 6 weeks. Expression changes in VTP varied over time in complex ways. Extracellular matrix-related transcripts were strongly upregulated by VTP consistent with its pathophysiology, with 8 collagen-genes upregulated Ͼ10-fold, fibrillin-1 8-fold and MMP2 4.5-fold at 2 weeks (time of fibrosis) but unchanged at 24 hours. Other extracellular matrix genes (eg, fibronectin, lysine oxidase-like 2) increased at both time-points (Ϸ10, Ϸ5-fold respectively). In ATP, mRNA-changes almost exclusively represented downregulation and were quantitatively smaller. This study shows that VTP-induced congestive heart failure and ATP produce qualitatively different temporally-evolving patterns of gene-expression change, and that specific transcriptomal responses associated with atrial fibrillation versus underlying heart disease substrates must be considered in assessing gene-expression changes in man. Key Words: arrhythmia Ⅲ remodeling Ⅲ genomic A trial fibrillation (AF) is the most common sustained cardiac rhythm disorder, and with the aging of the population both the prevalence and economic impact of AF are increasing progressively. 1 Although the mechanistic basis of AF remains incompletely understood, active research promises to provide new insights that may lead to improved therapeutic options. 2,3 A variety of animal models have been used to assess AF pathophysiology under controlled conditions. Atrial tachyarrhythmias, including AF itself, alter atrial electrophysiology in ways that promote AF vulnerability. [4][5][6] Experimentally-induced congestive heart failure (CHF) also creates a substrate for AF maintenance, but by quite different mechanisms. 7 The atrial-tachycardia remodeling paradigm shows prominent changes in ion-channel function that lead to action-potential abbreviation and the promotion of atrial reentry. 8,9 CHF-induced ionic-current changes do not promote reentry but may favor ectopic-impulse formation, 10 and CHF-induced fibrosis promotes reentry by interfering with intraatrial conduction. 7 The molecular basis of AF ...

The liver is a major site of metastasis for human malignancies, yet the factors that regulate tumor cell survival and growth in this organ remain elusive. Previously, we reported that M-27 IGFÀIR murine lung carcinoma cells with ectopic insulin-like growth factor-1 (IGF-I) receptor overexpression acquired a site-specific, liver-metastasizing potential. Gene expression profiling and subsequent RNA and protein analyses revealed that this was associated with major changes to the expression of extracellular matrix (ECM) protein-encoding genes including type III, IV and XVIII collagen genes, and these changes were also observed in the respective tumors in vivo. Because type IV collagen was the most prominently altered ECM protein in this model, we further analyzed its functional relevance to liver metastasis. M-27 cells stably overexpressing type IV collagen a1 and a2 chains were generated and their growth and metastatic properties investigated. We found that these cells acquired a site-selective growth advantage in the liver and this was associated with cell rescue from anoikis in a collagen IV/a2 integrin/FAK-dependent manner and increased responsiveness to IGF-I. Conversely, collagen IV or focal adhesion kinase (FAK) silencing by smallinterfering RNA in highly metastatic tumor cells enhanced anoikis and decreased liver metastases formation. Moreover, analysis of human surgical specimens revealed uniformly high collagen IV expression in 65/65 hepatic metastases analyzed, regardless of tissue of origin, whereas it was variable and generally low in 50/50 primary colorectal carcinoma specimens examined. The results suggest that collagen IV-conveyed signals are essential cues for liver metastasis in diverse tumor types and identify mediators of collagen IV signaling as potential therapeutic targets in the management of hepatic metastases.

Background: Asthma pathogenesis and susceptibility involves a complex interplay between genetic and environmental factors. Their interaction modulates the airway inflammation and remodelling processes that are present even in mild asthma and governs the appearance and severity of symptoms of airway hyperresponsiveness. While asthma is felt to develop as the result of interaction among many different genes and signalling pathways, only a few genes have been linked to an increased risk of developing this condition.

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. Activation of the Reg family genes by pancreatic-specific IGF-I gene deficiency and after streptozotocin-induced diabetes in mouse pancreas. Am J Physiol Endocrinol Metab 291: E50 -E58, 2006. First published January 31, 2006 doi:10.1152/ajpendo.00596.2005.-We have recently reported that Pdx1-Cre-mediated whole pancreas inactivation of IGF-I gene [in pancreatic-specific IGF-I gene-deficient (PID) mice] results in increased ␤-cell mass and significant protection against both type 1 and type 2 diabetes. Because the phenotype is unlikely a direct consequence of IGF-I deficiency, the present study was designed to explore possible activation of proislet factors in PID mice by using a whole genome DNA microarray. As a result, multiple members of the Reg family genes (Reg2, -3␣, and -3␤, previously not known to promote islet cell growth) were significantly upregulated in the pancreas. This finding was subsequently confirmed by Northern blot and/or real-time PCR, which exhibited 2-to 8-fold increases in the levels of these mRNAs. Interestingly, these Reg family genes were also activated after streptozotocin-induced ␤-cell damage and diabetes (wild-type T1D mice) when islet cells were undergoing regeneration. Immunohistochemistry revealed increased Reg proteins in exocrine as well as endocrine pancreas and suggested their potential role in ␤-cell neogenesis in PID or T1D mice. Previously, other Reg proteins (Reg1 and islet neogenesis-associated protein) have been shown to promote islet cell replication and neogenesis. These uncharacterized Reg proteins may play a similar but more potent role, not only in normal islet cell growth in PID mice, but also in islet cell regeneration after T1D. pancreatic islets; DNA microarray; gene-targeted mice; insulin-like growth factor I INSULIN-LIKE GROWTH FACTOR I (IGF-I) is produced from hepatocytes and many other cells and tissues, including the pancreas (9, 14, 23). Acting through its receptor IGF-IR, which is expressed ubiquitously, IGF-I promotes cell proliferation and growth and inhibits cell apoptosis. In normal growth of the bone, muscle, reproductive systems, and the whole mammalian organisms, IGF-I plays an irreplaceable, essential role (25,33). In cultured cells, IGF-I causes pancreatic islet ␤-cell mitogenesis in a glucose-dependent manner via activation of phosphatidylinositol 3-kinase (PI3K), ERK1/2, and 70-kDa protein S6 kinase (p70 S6K ) (15, 24). Although IGF-I and IGF-IR are normally expressed in both endocrine and exocrine pancreas (8, 9), their in vivo role in islet cell growth has been questioned by the results of most gene-targeted studies. For example, combined inactivation of insulin receptor and IGF-IR genes in early embryos results in a 50% decrease in the size of the exocrine pancreas without affecting the development of endocrine cells (19). Combined ablation of IGF-I and IGF-II genes results in an identical phenotype (19). Moreover, islet ␤-cellspecific inactivation of IGF-IR gene causes no change in ␤-cell mass despite hyperinsulinemia, glucose intoleranc...

Peripheral blood mononuclear cells (PBMCs) offer a significant promise for gene expression analyses as a substitute for tissues that are not easily accessible. The objective of this study was to validate the use of PBMCs for gene expression analysis as a marker of nutritional intervention as an alternative to skeletal muscle tissue (SMT) biopsies. We performed a transcriptome comparison of PBMCs versus SMT after an 8-week supplementation with n-3 polyunsaturated fatty acid (PUFA) in 16 obese and insulin-resistant subjects. Expression levels of 48,803 transcripts were assessed by the Human-6 v3 Expression BeadChips (Illumina, San Diego, CA). In SMT, 36,738 (75%) transcripts were detected, whereas 34,182 (70%) transcripts were detected in PBMCs. Further, 88% (32,341) of these transcripts were coexpressed in both tissues. Importantly, a strong correlation (r = 0.84, p < 0.0001) was observed between transcript expression levels of PBMCs and SMT after n-3 PUFA supplementation. In conclusion, PBMCs express the majority of transcripts expressed in SMT subsequent to n-3 PUFA supplementation and their expression levels are comparable. In the interest of practicalities and cost, these results support the use of PBMCs as a surrogate model for SMT gene expression in nutrigenomic studies. Further research on PBMC and SMT gene expression in response to other nutritional exposures is warranted.

Transcriptional profiles of uropathogenic Escherichia coli CFT073 exposed to cranberry-derived proanthocyanidins (PACs) were determined. Our results indicate that bacteria grown on media supplemented with PACs were iron deprived. To our knowledge, this is the first time that PACs have been shown to induce a state of iron limitation in this bacterium.

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