Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018799 (heart disease)
 34,133 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Plasma concentrations of endothelin-1 (ET-1) are increased in children with congenital heart disease associated with increased pulmonary blood flow. However, the role of ET-1 in the pathophysiology of pulmonary hypertension remains unclear. Preproendothelin-1 gene expression is increased in adults with advanced pulmonary hypertension. To characterize potential early molecular alterations in the ET-1 cascade induced by increased pulmonary blood flow and pulmonary hypertension, fetal lambs underwent in utero placement of an aortopulmonary vascular graft (shunt). RNase protection assays and Western blot analysis were performed on lung tissue prepared from 4-wk-old shunt lambs and age-matched controls. Endothelin-converting enzyme-1 [the enzyme responsible for the production of active ET-1 from big ET-1, mRNA (411%, p<0.05)] and protein (170%, p<0.05) were increased in lung tissue prepared from shunt lambs, compared with age-matched controls. Endothelin type A receptor (the receptor that mediates vasoconstriction), mRNA (246%, p<0.05), and protein (176%, p<0.05) also were increased in lung tissue prepared from shunt lambs compared with age-matched controls. Conversely, endothelin type B receptor (the receptor that mediates vasodilation), mRNA (46%, p<0.05), and protein (65%, p<0.05) were decreased in shunt lambs. Both the mRNA and protein levels for preproendothelin-were unchanged. Thus we conclude that increased pulmonary blood flow and pulmonary hypertension induce early alterations in the ET-1 cascade that result in increased ET-1 production, increased ET-1-mediated vasoconstriction, and decreased vasodilation. These early alterations in gene expression may contribute to the development of pulmonary hypertension and its associated enhanced pulmonary vascular reactivity.
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PMID:Altered regulation of the ET-1 cascade in lambs with increased pulmonary blood flow and pulmonary hypertension. 1062 89

The risk and progression of pulmonary vascular disease in patients with congenital heart disease is dependent on the hemodynamics associated with different lesions. However, the underlying mechanisms are not understood. Endothelin-1 is a potent vasoconstrictor that plays a key role in the pathology of pulmonary vascular disease. We utilized two ovine models of congenital heart disease: (1) fetal aortopulmonary graft placement (shunt), resulting in increased flow and pressure; and (2) fetal ligation of the left pulmonary artery resulting in increased flow and normal pressure to the right lung, to investigate the hypothesis that high pressure and flow, but not flow alone, upregulates endothelin-1 signaling. Lung tissue and pulmonary arterial endothelial cells were harvested from control, shunt, and the right lung of left pulmonary artery lambs at 3-7 weeks of age. We found that lung preproendothelin-1 mRNA and protein expression were increased in shunt lambs compared to controls. Preproendothelin-1 mRNA expression was modestly increased, and protein was unchanged in left pulmonary artery lambs. These changes resulted in increased lung endothelin-1 levels in shunt lambs, while left pulmonary artery levels were similar to controls. Pulmonary arterial endothelial cells exposed to increased shear stress decreased endothelin-1 levels by five-fold, while cyclic stretch increased levels by 1.5-fold. These data suggest that pressure or an additive effect of pressure and flow, rather than increased flow alone, is the principal driver of increased endothelin signaling in congenital heart disease. Defining the molecular drivers of the pathobiology of pulmonary vascular disease due to differing mechanical forces will allow for a more targeted therapeutic approach.
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PMID:Mechanical forces alter endothelin-1 signaling: comparative ovine models of congenital heart disease. 3248 41