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A growing body of evidence suggests the involvement of connective tissue growth factor (CTGF) in the development and maintenance of fibrosis and excessive scarring. As the expression of this protein requires an intact actin cytoskeleton, disruption of the cytoskeleton represents an attractive strategy to decrease CTGF expression and, consequently, excessive scarring. The small heat-shock-related protein (HSP20), when phosphorylated by cyclic nucleotide signaling cascades, displaces phospho-cofilin from the 14-3-3 scaffolding protein leading to activation of cofilin as an actin-depolymerizing protein. In the present study, we evaluated the effect of AZX100, a phosphopeptide analogue of HSP20, on transforming growth factor-beta-1 (TGF-beta1)-induced CTGF and collagen expression in human keloid fibroblasts. We also examined the effect of AZX100 on scar formation in vivo in dermal wounds in a Siberian hamster model. AZX100 decreased the expression of CTGF and type I collagen induced by TGF-beta1, endothelin, and lysophosphatidic acid. Treatment with AZX100 decreased stress fiber formation and altered the morphology of human dermal keloid fibroblasts. In vivo, AZX100 significantly improved collagen organization in a Siberian hamster scarring model. Taken together, these results suggest the potential use of AZX100 as a strategy to prevent excessive scarring and fibrotic disorders.
It is readily apparent that the process of heart development is an intricate one, in which cells derived from many embryonic sources coalesce and coordinate their behaviors and development, resulting in the mature heart. The behaviors and mechanisms of this process are complex, and still incompletely understood. However, it is readily apparent that communication between diverse cell types must be involved in this process. The signaling that emanates from epicardial and endocardial sources is the focus of this review.
Cumulative evidence suggests that Hirschsprung disease (HSCR) is the consequence of multiple gene interactions that modulate the ability of enteric neural crest (NC) cells to populate the developing gut. One of the essential genes for this process is the NC transcription factor Sox10. Sox10Dom mice on a mixed genetic background show variation in penetrance and expressivity of enteric aganglionosis that are analogous to the variable aganglionosis seen in human HSCR families. The phenotype of Sox10Dom mice in congenic lines indicates this variation arises from modifiers in the genetic background. To determine whether known HSCR susceptibility loci are acting as modifiers of Sox10, we tested for association between genes in the endothelin signaling pathway (EdnrB, Edn3, Ece1) and severity of aganglionosis in an extended pedigree of B6C3FeLe.Sox10Dom mice. Single locus association analysis in this pedigree identifies interaction between EdnrB and Sox10. Additional analysis of F2 intercross progeny confirms a highly significant effect of EdnrB alleles on the Sox10Dom/+ phenotype. The presence of C57BL/6J alleles at EdnrB is associated with increased penetrance and more severe aganglionosis in Sox10Dom mutants. Crosses between EdnrB and Sox10 mutants corroborate this gene interaction with double mutant progeny exhibiting significantly more severe aganglionosis. The background strain of the EdnrB mutant further influences the phenotype of Sox10/EdnrB double mutant progeny implying the action of additional modifiers on this phenotype. Our data demonstrates that Sox10-EdnrB interactions can influence development of the enteric nervous system in mouse models and suggests that this interaction could contribute to the epistatic network producing variation between patients with aganglionosis.
BACKGROUND - Thirty-nine percent of permanent altitude dwellers in the Andes experience acral paresthesias.
METHODS - Clinical examinations, sural nerve biopsies, and electrodiagnostic studies on peripheral nerves were performed on 15 men. Ten Cerro de Pasco (CP) natives living at 4,338 meters were biopsied. Three of these subjects had no burning feet/burning hands (BF/BH); three had BF/BH; and four had chronic mountain sickness (CMS), a maladaptation syndrome resulting from living in the Andes, all with BF/BH. Three patients with CMS were biopsied in Lima within hours after leaving CP. Two normal Lima natives were biopsied in Lima. Symptom scores for BF/BH and CMS score ratings were used. The nerves were assayed for Na+, K+ adenosine triphosphatase (ATPase), cytochrome oxidase (CO), substance P (SP), and endothelin (ET).
RESULTS - Low ATPase was inversely related to symptom scores and CMS scores (p < 0.001). Patients with CMS biopsied in normoxia (Lima) had ATPase levels similar to those of controls. Nerve motor conduction velocities and sensory action potentials were normal. CO was inversely related to age (p < 0.03) and no relation of SP to any variable was found. ET levels were lower in sea level natives (p = 0.04).
CONCLUSIONS - Acral paresthesias are associated with low ATPase in peripheral nerves. Lower ET levels of sea level natives likely reflect lowered release from vasa nervorum.
In the decade since the initial discovery and characterization of endothelin, its biology as a powerful vasoconstrictor has been dramatically demonstrated. Studies have clarified the existence of endothelin isoforms, complex mechanisms of biosynthesis, interaction with specific receptors, and pathogenic implications. We are on the brink of using endothelin antagonism as a clinical treatment for disease processes where endothelin plays an important role, including congestive heart failure and hypertension. Novel observations have been made about the unexpectedly profound contribution endothelins make to normal fetal maturation, especially in cardiac and enteric development.
The endothelin peptides comprise a family of potent and long-lasting vascoconstrictors, to which the renal microcirculation is particularly susceptible. Increased renal endothelin expression is observed after a variety of injurious stimuli, including ischemia, and persists for days after resolution of the initial injury. Autoinduction of its own production is likely to be a central mechanism underlying endothelin's prolonged effects. Furthermore, antagonizing endothelin reveals its role in maintaining the postischemic glomerular dysfunction that typifies ischemic acute renal failure.
Endothelin is a vasoconstrictor substance, initially isolated from porcine endothelial cell supernatant, which has a structure different from any other mammalian peptide. An extensive array of biological activities has been ascribed to endothelin which, besides having unrivaled vasoconstrictive effects, modulates neurotransmission, regulates other hormones and neurotransmitters, and also has potent hyperplastic/hypertrophic effects. These observations have suggested important roles for endothelin in pathophysiological conditions and also in normal development. Inhibition of endothelin activity can decrease vasoconstriction associated with pathophysiological settings. Inhibition of endothelin activity also decreases mitogenesis and therefore cellular proliferation and growth, thereby supporting a role for endothelin in processes which are an integral part of normal development.
OBJECTIVE - To determine whether the endothelin-1 or endothelin-3 genes are genetically linked with blood pressure and relative heart weight in segregating rat populations, in the context of an elevated dietary sodium chloride intake.
METHODS - Endothelin-1 and endothelin-3 genotypes of rats in segregating populations, derived from crosses of Dahl salt-sensitive (SS/Jr) rats with contrasting inbred strains, including Lewis rats, spontaneously hypertensive rats and Dahl salt-resistant (SR/Jr) rats, were determined using restriction fragment length polymorphisms. Segregating populations were fed a high (8%)-sodium chloride diet. Linkage of genotype with blood pressure or relative heart weight was determined by analysis of variance. Chromosomal location of the rat endothelin-3 gene was determined by genotyping a panel of recombinant inbred strains.
RESULTS - Two alleles for the endothelin-1 gene and three alleles for the endothelin-3 gene were identified. The endothelin-1 locus did not cosegregate with blood pressure or relative heart weight. The endothelin-3 locus cosegregated with blood pressure and relative heart weight in an SS/Jr x F1 (SS/Jr x SR/Jr) population, but not in populations containing a higher percentage of genes from the SR/Jr strain. The endothelin-3 and seminal vesicle protein-1 loci were linked and located on rat chromosome 3.
CONCLUSION - The endothelin-3 gene is, or is linked to, a locus on chromosome 3 that regulates blood pressure and relative heart weight in inbred Dahl rats, and these effects were strongly dependent on the genetic background.
Endothelin 2 (ET2), also referred to as vasoactive intestinal contractor peptide, is a member of a family of vasoactive peptides. ET2 is a potent constrictor of intestinal smooth muscle, and the mRNA that encodes it has been detected in murine intestinal extracts. To further investigate the potential physiological roles of ET2, we characterized the cellular distribution of ET2 gene expression in adult rat gastrointestinal tract. Using an RNAse protection assay, an overall proximal to distal gradient of increasing ET2 gene expression was observed from stomach to colon. In situ hybridization studies confirmed this finding and demonstrated ET2 mRNA localized in lamina propria stromal cells. Moreover, ET2 gene expression in stromal cells increased from crypt to villous tip. The results demonstrate that ET2 is produced by stromal cells in villi throughout the intestine. Increased ET2 gene expression at the villous tip is associated with more mature overlying epithelial cells, suggesting a possible role for this vasoactive peptide in intestinal epithelial differentiation or secretory activity.