This project has focused on prostaglandin (PG) production by the cells from the pulmonary artery and by fibroblasts from the lung. The ultimate goal is to determine the mechanisms (intracellular and extracellular) which regulate PG production in these cells and to relate this production of PGs to their physiologic function. The working hypothesis is that prostaglandin synthesis is regulated by both the availability of arachidonate and the activity of the enzyme systems which convert arachidonate to PG's and that the regulation of these enzyme systems by the cells is accomplished through: 1) the existance of distinct pools of endoperoxide synthetase which by means of proximity to the sites of arachidonate release are differentially active, 2) the physiological state of the cell which may result in (a) differential turnover of these pools (b) differential turnover of the enzyme systems converting the endoperoxides to PGs (c) differential production of compounds such as hydroperoxy fatty acids from the lipoxygenase pathway which regulate the activity of these enzymes and 3) the production of effectors by certain cell types which regulate PG synthesis in neighboring cell types. The above hypothesis will be tested under cellular conditions of growth and function of cells from the pulmonary artery (smooth muscle, endothelal and fibroblast). These cellular conditions affect PG synthesis, especially prostacyclin (PGI2) synthesis. PGI2 is believed to be important in the function of the lung and the circulatory system. Experiments to be done are: 1) Smooth muscle cells from the pulmonary artery will be cultured under various conditions (growing- nongrowing, contractile-modulated). The other two cell types will also be placed into growing-nongrowing states. 2) PGI2 and synthesis of other PG's will be determined in response to vasoactive agents (bradykinin, angiotensins). 3) The turnover of endoperoxide synthetase pools will be examined under the above cellular conditions. A vasoactive agent responsive vs. unresponsive pool will be looked for. The effect of hydroperoxy compounds, particularly hydroperoxy fatty acids, on enzyme activity will be determined. 4) An inhibitor of endothelial cell PG synthesis extruded by smooth muscle cells and fibroblasts will be fully characterized. 5) The function of the smooth muscle contractile system will be examined with respect to PGI2 production and the effect of vasoactive agents (angiotensin, bradykinin). Hypertension and artherosclerosis are associated with smooth muscle proliferation and decreased PGI2 synthesis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL025776-06
Application #
3338238
Study Section
Pathology A Study Section (PTHA)
Project Start
1981-02-01
Project End
1988-02-29
Budget Start
1986-03-01
Budget End
1988-02-29
Support Year
6
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Boston University
Department
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Wilson, Jamie L; Warburton, Rod; Taylor, Linda et al. (2018) Unraveling endothelin-1 induced hypercontractility of human pulmonary artery smooth muscle cells from patients with pulmonary arterial hypertension. PLoS One 13:e0195780
Wilson, Jamie L; Rupasinghe, Chamila; Usheva, Anny et al. (2015) Modulating the dysregulated migration of pulmonary arterial hypertensive smooth muscle cells with motif mimicking cell permeable peptides. Curr Top Pept Protein Res 16:1-17
Wilson, Jamie L; Yu, Jun; Taylor, Linda et al. (2015) Hyperplastic Growth of Pulmonary Artery Smooth Muscle Cells from Subjects with Pulmonary Arterial Hypertension Is Activated through JNK and p38 MAPK. PLoS One 10:e0123662
Yu, Jun; Wilson, Jamie; Taylor, Linda et al. (2015) DNA microarray and signal transduction analysis in pulmonary artery smooth muscle cells from heritable and idiopathic pulmonary arterial hypertension subjects. J Cell Biochem 116:386-97
Yu, Jun; Rupasinghe, Chamila; Wilson, Jamie L et al. (2015) Targeting receptor tyrosine kinases and their downstream signaling with cell-penetrating peptides in human pulmonary artery smooth muscle and endothelial cells. Chem Biol Drug Des 85:586-97
Yao, Chunxiang; Yu, Jun; Taylor, Linda et al. (2015) Protein Expression by Human Pulmonary Artery Smooth Muscle Cells Containing a BMPR2 Mutation and the Action of ET-1 as Determined by Proteomic Mass Spectrometry. Int J Mass Spectrom 378:347-359
Green, Daniel S; Rupasinghe, Chamila; Warburton, Rod et al. (2013) A cell permeable peptide targeting the intracellular loop 2 of endothelin B receptor reduces pulmonary hypertension in a hypoxic rat model. PLoS One 8:e81309
Yatawara, Achani; Wilson, Jamie L; Taylor, Linda et al. (2013) C-terminus of ETA/ETB receptors regulate endothelin-1 signal transmission. J Pept Sci 19:257-62
Yu, Jun; Taylor, Linda; Wilson, Jamie et al. (2013) Altered expression and signal transduction of endothelin-1 receptors in heritable and idiopathic pulmonary arterial hypertension. J Cell Physiol 228:322-9
Wilson, Jamie L; Taylor, Linda; Polgar, Peter (2012) Endothelin-1 activation of ETB receptors leads to a reduced cellular proliferative rate and an increased cellular footprint. Exp Cell Res 318:1125-33

Showing the most recent 10 out of 53 publications