P W Shaul

..It is postulated that these alterations in NOS expression and activity may contribute to the pathogenesis of CLD...

..Thus, in the baboon model of CLD, iNO improves early pulmonary function and alters lung growth and extracellular matrix deposition. As such, NO biosynthetic pathway dysfunction may contribute to the pathogenesis of CLD...

..A greater understanding of the mechanisms regulating PGI2 and NO synthesis in the developing lung will potentially lead to novel therapies for neonatal pulmonary hypertension aimed at optimizing endogenous vasodilator production...

..Further understanding of these mechanisms will enable us to take preventive and therapeutic advantage of the powerful actions of NO in multiple cell types...

..These processes may be critically involved in the earliest phases of atherogenesis, which recent studies suggest may occur during fetal life...

..Thus, the acute effect of estrogen on eNOS is mediated by ERalpha functioning in a novel, nongenomic manner to activate the enzyme via calcium-dependent, MAP kinase-dependent mechanisms...

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..Thus, there are developmental increases in pulmonary NOS expression and NO production during the early third trimester in the primate that may enhance airway and parenchymal function in the immediate postnatal period...

..Further studies with the cultured cell model will enable determination of the factors that directly regulate COX-1 expression in the developing pulmonary vasculature...

..We speculate that estrogen exposure during late gestation prepares the pulmonary circulation for postnatal adaptation...

..Thus, HDL activates eNOS via SR-BI through a process that requires ApoA-I binding. The resulting increase in nitric-oxide production might be critical to the atheroprotective properties of HDL and ApoA-I...

..This mechanism may modulate pulmonary PGI2 production in the perinatal period, and it may also play a role in the effects of glucocorticoids on the systemic circulation at a variety of ages...

..Thus, novel G protein coupling enables a subpopulation of ERalpha to initiate signal transduction at the cell surface. Similar mechanisms may underly the nongenomic actions of other steroid hormones...

..This process is due to an effect on cyclooxygenase activity, it causes marked parallel alterations in cAMP production, and it is specific to the pulmonary circulation...

..Paralleling the decline in eNOS protein expression, eNOS mRNA was decreased in CDH versus control lung (22 +/- 8 versus 100 +/- 31% of control, n = 4).(ABSTRACT TRUNCATED AT 250 WORDS)..

..In contrast, receptor density in BSM cells did not change from 1 to 13 days, but it increased 65% from 13 to 20 days, rose another 47% from 20 days to 3 mo, and increased an additional 24% from 3 to 6 mo.(ABSTRACT TRUNCATED AT 250 WORDS)..

..9 vs. 125.5 +/- 19.1 pmol of cAMP per mg of protein, P less than .001), as was basal adenylate cyclase activity (10.8 +/- 1.2 vs. 5.7 +/- 1.3 pmol of cAMP per mg of protein per min, P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)..

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..A new study shows that HDL-associated lysophospholipids stimulate the production of the potent antiatherogenic signaling molecule NO by the vascular endothelium...

..Thus, dimerization is not required for ERalpha coupling to eNOS; however, NLS2/NLS3 plays a role in Src activation, and the DNA binding region is involved in the dynamic interaction between ERalpha and PI3 kinase...

..Thus, HDL signaling requires cholesterol binding and efflux and C-terminal domains of SR-BI, and SR-BI serves as a cholesterol sensor on the plasma membrane...

..Thus, a deficiency in NO production and biological function in the premature baboon was not apparent by the detection and quantification of these surrogate markers of NO production...

..Overall, iNO did not alter the extent of brain damage but did result in the presence of hematomas. These results do not confirm any protective or major injurious effect of nitric oxide therapy on the developing brain...

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..NO-mediated regulation of AEC fate may have important implications in the pathophysiology and treatment of diseases such as IPF and BPD...

..These mechanisms may play a role in pulmonary vasodilation in the perinatal period...

..Besides a role in signal transduction events induced by estradiol, the membrane estrogen receptors may have an important role to play in translocation of the steroid to the cytosolic compartment...

..These findings in the ER-eNOS signaling paradigm indicate that endogenous ERbeta has nongenomic action in caveolae...

..Furthermore, ERbeta-deficient mice develop sustained systolic and diastolic hypertension as they age. These data support an essential role for ERbeta in the regulation of vascular function and blood pressure...

..These results indicate that HDL stimulates eNOS through common upstream, Src-mediated signaling, which leads to parallel activation of Akt and MAP kinases and their resultant independent modulation of the enzyme...

..Emphasizing the dependence on cell surface-associated receptors, these observations provide evidence for the existence of a steroid receptor fast-action complex, or SRFC, in caveolae...

..We postulate that E2-induced changes in ERalpha and ERbeta expression modify the effects of the hormone on vascular endothelium...

..In addition, they serve as excellent paradigms for further elucidation of novel mechanisms of steroid hormone action...

..NO treatment improves the apparent ability of hydrophobic SP to promote low surface tension, perhaps secondary to less protein inactivation of surfactant, and improves lung volume by a process unrelated to surfactant function...

..Thus, through direct interactions, ER alpha mediates a novel mechanism of G protein activation that provides greater diversity of function of both the steroid hormone receptor and G proteins...

..These new data establish that myoglobin is an important cytoplasmic cardiac hemoprotein that functions in regulating NO homeostasis within cardiomyocytes...

..As such, signaling initiated by HDL-SR-BI promotes endothelial repair, and this novel mechanism of action may be critically involved in the impact of the lipoprotein on vascular health and disease...

..Moreover, given the product-precursor relationship between 27HC and cholesterol, our findings have implications with respect to breast cancer risk in obese/hypercholesteremic individuals...

..Taken together, these studies point to 27HC as a contributing factor in the loss of estrogen protection from vascular disease...

..These findings increase our basic understanding of the role of ET-1 in pulmonary fibrosis and suggest potential roles for AEC-derived ET-1 in the pathogenesis of other alveolar epithelial-mediated lung diseases...

..Chronic elevations in circulating C-reactive protein (CRP) are associated with a greater risk of hypertension. Whether elevations in CRP cause hypertension is unknown...

..With further investigation and resulting greater depth of understanding, these mechanisms may be harnessed to provide new prophylactic and therapeutic strategies to combat atherosclerosis and thrombotic disorders...

..Thus, signaling events in caveolae invoked by known circulating cardiovascular disease risk factors have major impact on endothelial cell phenotypes of importance to cardiovascular health and disease...

..Thus FcgammaRIIB mediates CRP inhibition of eNOS via PP2A, providing a mechanistic link between CRP and endothelial dysfunction...

..The role of the patent ductus arteriosus in the development of chronic lung disease in surfactant-treated premature newborns remains unclear...

..These results demonstrate that CAV1 is not required for cholesterol absorption or ezetimibe sensitivity in the mouse...

..In addition, the process may be initiated by cytoplasmic ERalpha, and critical receptor elements reside within the amino terminus...

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..Thus, PDZK1 is uniquely required for HDL/SR-BI signaling in endothelium, and through these mechanisms, it is critically involved in the maintenance of endothelial monolayer integrity...