TY - JOUR
T1 - Genetic deletion of toll-like receptor 4 on platelets attenuates experimental pulmonary hypertension
AU - Bauer, Eileen M.
AU - Chanthaphavong, R. Savanh
AU - Sodhi, Chhinder P.
AU - Hackam, David J.
AU - Billiar, Timothy R.
AU - Bauer, Philip M.
PY - 2014
Y1 - 2014
N2 - RATIONALE:: Recent studies demonstrate a role for toll-like receptor 4 (TLR4) in the pathogenesis of pulmonary hypertension (PH); however, the cell types involved in mediating the effects of TLR4 remain unknown. OBJECTIVES:: The objective of this study was to determine the contribution of TLR4 expressed on nonparenchymal cells to the pathogenesis of PH. METHODS AND RESULTS:: TLR4 bone marrow chimeric mice revealed an equal contribution of TLR4 on nonparenchymal and parenchymal cells in the pathogenesis of PH as determined by measuring right ventricular (RV) systolic pressure and RV hypertrophy. However, the deletion of TLR4 from myeloid lineage cells had no effect on the development of PH because we found no difference in RV systolic pressure or RV hypertrophy in wild-type versus LysM-TLR4 mice. To explore the potential role of platelet TLR4 in the pathogenesis of PH, platelet-specific TLR4 mice were generated (PF4-TLR4 mice). TLR4 platelets from either global TLR4 or PF4-TLR4 mice were functional but failed to respond to lipopolysaccharide, demonstrating a lack of TLR4. PF4-TLR4 mice demonstrated significant protection from hypoxia-induced PH, including attenuated increases in RV systolic pressure and RV hypertrophy, decreased platelet activation, and less pulmonary vascular remodeling. The deletion of TLR4 from platelets attenuated serotonin release after chronic hypoxia, and lipopolysaccharide-stimulated platelets released serotonin and promoted pulmonary artery smooth muscle cell proliferation in a serotonin-dependent manner. CONCLUSIONS:: Our data demonstrate that TLR4 on platelets contributes to the pathogenesis of PH and further highlights the role of platelets in PH.
AB - RATIONALE:: Recent studies demonstrate a role for toll-like receptor 4 (TLR4) in the pathogenesis of pulmonary hypertension (PH); however, the cell types involved in mediating the effects of TLR4 remain unknown. OBJECTIVES:: The objective of this study was to determine the contribution of TLR4 expressed on nonparenchymal cells to the pathogenesis of PH. METHODS AND RESULTS:: TLR4 bone marrow chimeric mice revealed an equal contribution of TLR4 on nonparenchymal and parenchymal cells in the pathogenesis of PH as determined by measuring right ventricular (RV) systolic pressure and RV hypertrophy. However, the deletion of TLR4 from myeloid lineage cells had no effect on the development of PH because we found no difference in RV systolic pressure or RV hypertrophy in wild-type versus LysM-TLR4 mice. To explore the potential role of platelet TLR4 in the pathogenesis of PH, platelet-specific TLR4 mice were generated (PF4-TLR4 mice). TLR4 platelets from either global TLR4 or PF4-TLR4 mice were functional but failed to respond to lipopolysaccharide, demonstrating a lack of TLR4. PF4-TLR4 mice demonstrated significant protection from hypoxia-induced PH, including attenuated increases in RV systolic pressure and RV hypertrophy, decreased platelet activation, and less pulmonary vascular remodeling. The deletion of TLR4 from platelets attenuated serotonin release after chronic hypoxia, and lipopolysaccharide-stimulated platelets released serotonin and promoted pulmonary artery smooth muscle cell proliferation in a serotonin-dependent manner. CONCLUSIONS:: Our data demonstrate that TLR4 on platelets contributes to the pathogenesis of PH and further highlights the role of platelets in PH.
KW - Blood platelets
KW - Hypertension, pulmonary
KW - Toll-like receptor 4
UR - http://www.scopus.com/inward/record.url?scp=84900867405&partnerID=8YFLogxK
U2 - 10.1161/CIRCRESAHA.114.303662
DO - 10.1161/CIRCRESAHA.114.303662
M3 - Article
C2 - 24637196
AN - SCOPUS:84900867405
SN - 0009-7330
VL - 114
SP - 1596
EP - 1600
JO - Circulation research
JF - Circulation research
IS - 10
ER -