Regulation of cardiac fibroblast-mediated maladaptive ventricular remodeling by β-arrestins

Cardiac fibroblasts (CF) play a critical role in post-infarction remodeling which can ultimately lead to pathological fibrosis and heart failure. Recent evidence demonstrates that remote (non-infarct) territory fibrosis is a major mechanism for ventricular dysfunction and arrhythmogenesis. β-arrestins are important signaling molecules involved in β-adrenergic receptor (β-AR) desensitization and can also mediate signaling in a G protein independent fashion. Recent work has provided evidence that β-arrestin signaling in the heart may be beneficial, however, these studies have primarily focused on cardiac myocytes and their role in adult CF biology has not been well studied. In this study, we show that β-arrestins can regulate CF biology and contribute to pathological fibrosis. Adult male rats underwent LAD ligation to induce infarction and were studied by echocardiography. There was a significant decline in LV function at 2–12 weeks post-MI with increased infarct and remote territory fibrosis by histology consistent with maladaptive remodeling. Collagen synthesis was upregulated 2.9- fold in CF isolated at 8 and 12 weeks post-MI and β-arrestin expression was significantly increased. β-adrenergic signaling was uncoupled in the post-MI CF and β-agonist-mediated inhibition of collagen synthesis was lost. Knockdown of β-arrestin1 or 2 in the post-MI CF inhibited transformation to myofibroblasts as well as basal and TGF-β-stimulated collagen synthesis. These data suggest that β-arrestins can regulate CF biology and that targeted inhibition of these signaling molecules may represent a novel approach to prevent postinfarction pathological fibrosis and the transition to HF

Cecal MicroRNAome response to Salmonella enterica serovar Enteritidis infection in White Leghorn Layer

Abstract Background Salmonella enterica serovar Enteritidis (SE) is a food-borne pathogen and of great threat to human health through consuming the contaminated poultry products. MicroRNAs (miRNAs) play an important role in different biological activities and have been shown to regulate the innate immunity in the bacterial infection. The objective of this study is to identify miRNAs associated with SE infection in laying chicken cecum. Results Average number of reads of three libraries constructed from infected and non-infected chickens was 12,476,156 and 10,866,976, respectively. There were 598 miRNAs including 194 potential novel miRNAs identified in which 37 miRNAs were significantly differentially expressed between infected and non-infected chickens. In total, 2897 unique target genes regulated by differentially expressed miRNAs were predicted, in which, 841 genes were uniquely regulated by up-regulated miRNAs (G1), 636 genes were uniquely regulated by down-regulated miRNAs (G2), and 1420 were co-regulated by both up and down- regulated miRNAs (G3). There were 118, 73 and 178 GO (Gene ontology) BP (Biological process) terms significantly enriched in G1, G2 and G3 groups, respectively. More immune-related GO BP terms than metabolism-related terms were found in G1. Expression of 12 immune-related genes of four differentially expressed miRNAs was detected through qRT-PCR. The regulatory direction of gga-miR-1416-5p, gga-miR-1662, and gga-miR-34a-5p were opposite with the target genes of TLR21 , BCL10 , TLR1LA , NOTCH2 and THBS1 , respectively. Conclusion The miRNAs contribute to the response to SE infection at the onset of egg laying through regulating the homeostasis between metabolism and immunity. The gga-miR-125b-5p, gga-miR-34a-5p, gga-miR-1416-5p and gga-miR-1662 could play an important role in SE infection through regulating their target genes. The finding herein will pave the foundation for the studies of microRNA regulation in SE infection in laying hens