Low-molecular-weight heparin inhibits hypoxic pulmonary hypertension and vascular remodeling in guinea pigs.
BACKGROUND
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.


OBJECTIVE
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 microg/mL) or with enoxaparin (1 microg/mL).


METHODS
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.


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.
Al-Ansari
Essam
E
Pulmonary and Critical Care Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Du
Hong-kai
HK
Yu
Lunyin
L
Ochoa
Cristhiaan D
CD
Garg
Hari G
HG
Quinn
Deborah A
DA
Hales
Charles A
CA
D000704:Analysis of Variance; D000818:Animals; D002417:Cattle; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D006168:Guinea Pigs; D006439:Hemodynamics / Q000187:drug effects; D006495:Heparin, Low-Molecular-Weight / Q000494:pharmacology*; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000503:physiopathology; D000860:Hypoxia / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D011651:Pulmonary Artery / Q000187:drug effects
D006495:Heparin, Low-Molecular-Weight