Vascular remodeling with hypertrophy, hyperplasia and distal extension of pulmonary artery smooth muscle cells (PASMC) is a major component of the pulmonary vascular resistance in pulmonary hypertension. Several agents have become available to treat remodeling but none have been very satisfactory. Heparin is a normal constituent of the lung and is antiproliferative for PASMC. This grant continues our studies to understand how the cluster of varying glycosaminoglycans known as heparin work as an antiproliferative agent and to develop them, or their derivatives, into effective therapies for pulmonary hypertension. Unfractionated heparin contains a central protein core with many carbohydrate side chains which vary in content from batch to batch. We have found some of these batches to be much more antiproliferative for PASMC than others and to be better at inhibiting the development of hypoxia induced hypertension and remodeling in mice, rats, guinea pigs and now pigs. Low molecular weight (LMW) heparins are the carbohydrate side chains of heparin cleaved off the protein core and are not very antiproliferative. We have created more potent antiproliferative LMW heparins by adding bulky hexanoylated (H) or butanoylated (B) groups. We have also shown that heparin inhibits PASM proliferation by stimulating the cyclin kinase p27. We have preliminary evidence that heparin may do this by suppressing ERK and Rho/ROCK activity. With this background we plan the following specific aims: 1. Determine the structures in heparin's carbohydrate side chains which mediate the antiproliferative action on PASMC by: a. identifying the importance of the 2-O sulfonate groups on the hexuronic acid residues as well as the proportions of basic sugar residues, i.e. N- acetylation and N-sulfonation of glucosamine in the repeating disaccharide units necessary to give maximum antiproliferative activity, b. altering the chemical structure of our H and B LMW heparins to match features identified as enhancing the antiproliferative strength in step 1a, to make these LMW heparin derivatives even more potent, and c. increasing the length of the H and B LMW heparins to octa and decanoylated chains to try to achieve even greater antiproliferative potency. 2. Determine in a preclinical model if potent antiproliferative heparins or heparin derivatives can inhibit or reverse established pulmonary hypertension in hypoxic pigs. 3. Determine the mechanism by which heparin enhances p27 activity (ERK, Rho/ROCK;etc), build on our pilot data that strongly antiproliferative heparins inhibit RhoA/ROCK while weakly antiproliferative heparins do not, and verify our findings in heparin treated hypoxic mice.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL039150-19
Application #
7586107
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Moore, Timothy M
Project Start
1987-07-01
Project End
2012-03-31
Budget Start
2009-04-01
Budget End
2010-03-31
Support Year
19
Fiscal Year
2009
Total Cost
$457,883
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Zhao, Gaofeng; Seng, Jingjing; Beagle, John et al. (2015) Heparin reduces overcirculation-induced pulmonary artery remodeling through p38 MAPK in piglet. Ann Thorac Surg 99:1677-84
Yu, Lunyin; Hales, Charles A (2011) Effect of chemokine receptor CXCR4 on hypoxia-induced pulmonary hypertension and vascular remodeling in rats. Respir Res 12:21
Yu, Lunyin; Hales, Charles A (2011) Silencing of sodium-hydrogen exchanger 1 attenuates the proliferation, hypertrophy, and migration of pulmonary artery smooth muscle cells via E2F1. Am J Respir Cell Mol Biol 45:923-30
Yu, Lunyin; Hales, Charles A (2011) Long-term exposure to hypoxia inhibits tumor progression of lung cancer in rats and mice. BMC Cancer 11:331
Yu, Lunyin; Hales, Charles A (2011) Hypoxia does neither stimulate pulmonary artery endothelial cell proliferation in mice and rats with pulmonary hypertension and vascular remodeling nor in human pulmonary artery endothelial cells. J Vasc Res 48:465-75
Ochoa, Christiaan D; Garg, Hari G; Hales, Charles A et al. (2011) Low molecular weight hyaluronan, via AP-1 and NF-ýýB signalling, induces IL-8 in transformed bronchial epithelial cells. Swiss Med Wkly 141:w13255
Garg, Hari G; Mrabat, Hicham; Yu, Lunyin et al. (2011) Anti-proliferative effects of O-acyl-low-molecular-weight heparin derivatives on bovine pulmonary artery smooth muscle cells. Glycoconj J 28:419-26
Leu, Shaw-Wei; Shi, Liyun; Xu, Changqing et al. (2011) TLR4 through IFN-? promotes low molecular mass hyaluronan-induced neutrophil apoptosis. J Immunol 186:556-62
Zhao, Gaofeng; Shaik, Rahamthulla S; Zhao, Hang et al. (2011) Low molecular weight (LMW) heparin inhibits injury-induced femoral artery remodeling in mouse via upregulating CD44 expression. J Vasc Surg 53:1359-1367.e3
Yu, Lunyin; Quinn, Deborah A; Garg, Hari G et al. (2011) Heparin inhibits pulmonary artery smooth muscle cell proliferation through guanine nucleotide exchange factor-H1/RhoA/Rho kinase/p27. Am J Respir Cell Mol Biol 44:524-30

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