107 research outputs found
The Role of Peroxisome Proliferator-Activated Receptors in Pulmonary Vascular Disease
Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear hormone
receptor superfamily that regulate diverse physiological processes ranging from lipogenesis to inflammation. Recent evidence has
established potential roles of PPARs in both systemic and pulmonary vascular disease and function. Existing treatment strategies
for pulmonary hypertension, the most common manifestation of pulmonary vascular disease, are limited by an incomplete
understanding of the underlying disease pathogenesis and lack of efficacy indicating an urgent need for new approaches to treat
this disorder. Derangements in pulmonary endothelial-derived mediators and endothelial dysfunction have been shown to play a
pivotal role in pulmonary hypertension pathogenesis. Therefore, the following review will focus on selected mediators implicated
in pulmonary vascular dysfunction and evidence that PPARs, in particular PPARγ, participate in their regulation and may provide
a potential novel therapeutic target for the treatment of pulmonary hypertension
HIV-1 transgene expression in rats causes oxidant stress and alveolar epithelial barrier dysfunction
<p>Abstract</p> <p>Background</p> <p>HIV-infected individuals are at increased risk for acute and chronic airway disease even though there is no evidence that the virus can infect the lung epithelium. Although HIV-related proteins including gp120 and Tat can directly cause oxidant stress and cellular dysfunction, their effects in the lung are unknown. The goal of this study was to determine the effects of HIV-1 transgene expression in rats on alveolar epithelial barrier function. Alveolar epithelial barrier function was assessed by determining lung liquid clearance <it>in vivo </it>and alveolar epithelial monolayer permeability <it>in vitro</it>. Oxidant stress in the alveolar space was determined by measuring the glutathione redox couple by high performance liquid chromatography, and the expression and membrane localization of key tight junction proteins were assessed. Finally, the direct effects of the HIV-related proteins gp120 and Tat on alveolar epithelial barrier formation and tight junction protein expression were determined.</p> <p>Results</p> <p>HIV-1 transgene expression caused oxidant stress within the alveolar space and impaired epithelial barrier function even though there was no evidence of overt inflammation within the airways. The expression and membrane localization of the tight junction proteins zonula occludens-1 and occludin were decreased in alveolar epithelial cells from HIV-1 transgenic rats. Further, treating alveolar epithelial monolayers from wild type rats <it>in vitro </it>with recombinant gp120 or Tat for 24 hours reproduced many of the effects on zonula occludens-1 and occludin expression and membrane localization.</p> <p>Conclusion</p> <p>Taken together, these data indicate that HIV-related proteins cause oxidant stress and alter the expression of critical tight junction proteins in the alveolar epithelium, resulting in barrier dysfunction.</p
Contractile force is enhanced in Aortas from pendrin null mice due to stimulation of angiotensin II-dependent signaling.
Pendrin is a Cl-/HCO3- exchanger expressed in the apical regions of renal intercalated cells. Following pendrin gene ablation, blood pressure falls, in part, from reduced renal NaCl absorption. We asked if pendrin is expressed in vascular tissue and if the lower blood pressure observed in pendrin null mice is accompanied by reduced vascular reactivity. Thus, the contractile responses to KCl and phenylephrine (PE) were examined in isometrically mounted thoracic aortas from wild-type and pendrin null mice. Although pendrin expression was not detected in the aorta, pendrin gene ablation changed contractile protein abundance and increased the maximal contractile response to PE when normalized to cross sectional area (CSA). However, the contractile sensitivity to this agent was unchanged. The increase in contractile force/cross sectional area observed in pendrin null mice was due to reduced cross sectional area of the aorta and not from increased contractile force per vessel. The pendrin-dependent increase in maximal contractile response was endothelium- and nitric oxide-independent and did not occur from changes in Ca2+ sensitivity or chronic changes in catecholamine production. However, application of 100 nM angiotensin II increased force/CSA more in aortas from pendrin null than from wild type mice. Moreover, angiotensin type 1 receptor inhibitor (candesartan) treatment in vivo eliminated the pendrin-dependent changes contractile protein abundance and changes in the contractile force/cross sectional area in response to PE. In conclusion, pendrin gene ablation increases aorta contractile force per cross sectional area in response to angiotensin II and PE due to stimulation of angiotensin type 1 receptor-dependent signaling. The angiotensin type 1 receptor-dependent increase in vascular reactivity may mitigate the fall in blood pressure observed with pendrin gene ablation
Phylogenetic Distribution of Intron Positions in Alpha-Amylase Genes of Bilateria Suggests Numerous Gains and Losses
Most eukaryotes have at least some genes interrupted by introns. While it is well
accepted that introns were already present at moderate density in the last
eukaryote common ancestor, the conspicuous diversity of intron density among
genomes suggests a complex evolutionary history, with marked differences between
phyla. The question of the rates of intron gains and loss in the course of
evolution and factors influencing them remains controversial. We have
investigated a single gene family, alpha-amylase, in 55 species covering a
variety of animal phyla. Comparison of intron positions across phyla suggests a
complex history, with a likely ancestral intronless gene undergoing frequent
intron loss and gain, leading to extant intron/exon structures that are highly
variable, even among species from the same phylum. Because introns are known to
play no regulatory role in this gene and there is no alternative splicing, the
structural differences may be interpreted more easily: intron positions, sizes,
losses or gains may be more likely related to factors linked to splicing
mechanisms and requirements, and to recognition of introns and exons, or to more
extrinsic factors, such as life cycle and population size. We have shown that
intron losses outnumbered gains in recent periods, but that “resets”
of intron positions occurred at the origin of several phyla, including
vertebrates. Rates of gain and loss appear to be positively correlated. No phase
preference was found. We also found evidence for parallel gains and for intron
sliding. Presence of introns at given positions was correlated to a strong
protosplice consensus sequence AG/G, which was much weaker in the absence of
intron. In contrast, recent intron insertions were not associated with a
specific sequence. In animal Amy genes, population size and
generation time seem to have played only minor roles in shaping gene
structures
Contractile force is enhanced in Aortas from pendrin null mice due to stimulation of angiotensin II-dependent signaling.
PPARγ as a potential therapeutic target in pulmonary hypertension
Pulmonary hypertension (PH) is a progressive disorder of the pulmonary circulation associated with significant morbidity and mortality. The pathobiology of PH involves a complex series of derangements causing endothelial dysfunction, vasoconstriction and abnormal proliferation of pulmonary vascular wall cells that lead to increases in pulmonary vascular resistance and pressure. Recent evidence indicates that the ligand-activated transcription factor, peroxisome proliferator-activated receptor gamma (PPARγ) can have a favorable impact on a variety of pathways involved in the pathogenesis of PH. This review summarizes PPARγ biology and the emerging evidence that therapies designed to activate this receptor may provide novel approaches to the treatment of PH. Mediators of PH that are regulated by PPARγ are reviewed to provide insights into potential mechanisms underlying therapeutic effects of PPARγ ligands in PH
GDNF rescues hyperglycemia-induced diabetic enteric neuropathy through activation of the PI3K/Akt pathway
Diabetes can result in loss of enteric neurons and subsequent gastrointestinal complications. The mechanism of enteric neuronal loss in diabetes is not known. We examined the effects of hyperglycemia on enteric neuronal survival and the effects of glial cell line–derived neurotrophic factor (GDNF) on modulating this survival. Exposure of primary enteric neurons to 20 mM glucose (hyperglycemia) for 24 hours resulted in a significant increase in apoptosis compared with 5 mM glucose (normoglycemia). Exposure to 20 mM glucose resulted in decreased Akt phosphorylation and enhanced nuclear translocation of forkhead box O3a (FOXO3a). Treatment of enteric neurons with GDNF ameliorated these changes. In streptozotocin-induced diabetic mice, there was evidence of myenteric neuronal apoptosis and reduced Akt phosphorylation. Diabetic mice had loss of NADPH diaphorase–stained myenteric neurons, delayed gastric emptying, and increased intestinal transit time. The pathophysiological effects of hyperglycemia (apoptosis, reduced Akt phosphorylation, loss of inhibitory neurons, motility changes) were reversed in diabetic glial fibrillary acidic protein–GDNF (GFAP-GDNF) Tg mice. In conclusion, we demonstrate that hyperglycemia induces neuronal loss through a reduction in Akt-mediated survival signaling and that these effects are reversed by GDNF. GDNF may be a potential therapeutic target for the gastrointestinal motility disorders related to diabetes
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