TY - JOUR
T1 - Low-molecular-weight heparin inhibits hypoxic pulmonary hypertension and vascular remodeling in guinea pigs
AU - Al-Ansari, Essam
AU - Du, Hong Kai
AU - Yu, Lunyin
AU - Ochoa, Cristhiaan D.
AU - Garg, Hari G.
AU - Quinn, Deborah A.
AU - Hales, Charles A.
N1 - Funding Information:
This work was supported by National Institutes of Health grants HL39150 (Dr. Hales) and HL03920 (Dr. Quinn), and American Heart Association grant 0525926T (Dr. Al-Ansari).
Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2007/12
Y1 - 2007/12
N2 - Rationale: We have shown previously that antiproliferative unfractionated heparins block hypoxia-induced pulmonary arterial hypertension (PAH) and vascular remodeling, and hypothesized that low-molecular-weight heparins (LMWHs) would too. Objectives: To determine the potential role and mechanisms of dalteparin and enoxaparin (two LMWHs) in inhibiting hypoxic PAH and vascular remodeling. Methods: Male Hartley guinea pigs were exposed for 10 days to normobaric 10% oxygen with dalteparin (5 mg/kg), enoxaparin (5 mg/kg), or with an equivalent volume of normal saline solution. Normoxic control animals (n = 5) received room air for 10 days. Bovine pulmonary artery smooth-muscle cells (PASMCs) were grown in 10% fetal bovine serum without heparin, with dalteparin (1 μg/mL) or with enoxaparin (1 μg/mL). Measurements: Pulmonary arterial pressure (PAP), cardiac index, right ventricular heart weight divided by left ventricular plus septum weight (RV/LV+S), hematocrit, percentage of wall thickness of intraacinar vessels (%WT-IA), percentage of wall thickness of terminal bronchiole vessels (%WT-TA), and the percentage of thick-walled vessels (%Thick) were determined. In PASMCs, expression of p27 and cell growth were compared because in mice whole heparin depends on p27 for its antiproliferative action. Main results: In hypoxic animals, hematocrit, PAP, total pulmonary vascular resistance index, RV/LV+S, %WT-IA, %WT-TA, and %Thick all rose significantly vs normoxic control animals (p < 0.05); cardiac index was unchanged. Dalteparin but not enoxaparin significantly reduced PAP, total pulmonary vascular resistance index, and RV/LV + S (p < 0.05 vs hypoxia alone); inhibited PASMC growth; and upregulated p27 expression. Enoxaparin moderately reduced vascular remodeling, which did not translate into less pulmonary hypertension. Conclusions: Not all LMWHs are the same. Dalteparin was more effective than enoxaparin in inhibiting pulmonary hypertension and vascular remodeling in hypoxic guinea pigs.
AB - Rationale: We have shown previously that antiproliferative unfractionated heparins block hypoxia-induced pulmonary arterial hypertension (PAH) and vascular remodeling, and hypothesized that low-molecular-weight heparins (LMWHs) would too. Objectives: To determine the potential role and mechanisms of dalteparin and enoxaparin (two LMWHs) in inhibiting hypoxic PAH and vascular remodeling. Methods: Male Hartley guinea pigs were exposed for 10 days to normobaric 10% oxygen with dalteparin (5 mg/kg), enoxaparin (5 mg/kg), or with an equivalent volume of normal saline solution. Normoxic control animals (n = 5) received room air for 10 days. Bovine pulmonary artery smooth-muscle cells (PASMCs) were grown in 10% fetal bovine serum without heparin, with dalteparin (1 μg/mL) or with enoxaparin (1 μg/mL). Measurements: Pulmonary arterial pressure (PAP), cardiac index, right ventricular heart weight divided by left ventricular plus septum weight (RV/LV+S), hematocrit, percentage of wall thickness of intraacinar vessels (%WT-IA), percentage of wall thickness of terminal bronchiole vessels (%WT-TA), and the percentage of thick-walled vessels (%Thick) were determined. In PASMCs, expression of p27 and cell growth were compared because in mice whole heparin depends on p27 for its antiproliferative action. Main results: In hypoxic animals, hematocrit, PAP, total pulmonary vascular resistance index, RV/LV+S, %WT-IA, %WT-TA, and %Thick all rose significantly vs normoxic control animals (p < 0.05); cardiac index was unchanged. Dalteparin but not enoxaparin significantly reduced PAP, total pulmonary vascular resistance index, and RV/LV + S (p < 0.05 vs hypoxia alone); inhibited PASMC growth; and upregulated p27 expression. Enoxaparin moderately reduced vascular remodeling, which did not translate into less pulmonary hypertension. Conclusions: Not all LMWHs are the same. Dalteparin was more effective than enoxaparin in inhibiting pulmonary hypertension and vascular remodeling in hypoxic guinea pigs.
KW - Dalteparin
KW - Enoxaparin
KW - Hypoxia
KW - Low-molecular-weight heparin
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U2 - 10.1378/chest.06-0941
DO - 10.1378/chest.06-0941
M3 - Article
C2 - 18079223
AN - SCOPUS:37549005172
SN - 0012-3692
VL - 132
SP - 1898
EP - 1905
JO - CHEST
JF - CHEST
IS - 6
ER -