Introduction: Recently, we and others reported a critical role for oxidized lipids in pathogenesis of pulmonary hypertension (PH). However, LDL and its receptor (LDL-R), which binds and internalizes LDL into the cell, have never been investigated for their role in PH. Therefore, in lung transplant patients with and without PH, we assess LDL and oxidized LDL in plasma and expression of LDL-R in their lungs. We also investigate the role of LDL-R in development of PH in LDL-R knockout (LDL-R KO) mice.
Methods: Human explanted lung samples from patients with PH (PH group, n=7) and without PH (non-PH group, n=7) undergoing lung transplants were used. Lung LDL-R and fatty acid transporter CD36 transcripts, and circulating LDL and oxidized LDL were assessed. Male LDL-R KO mice were fed either chow (n=16), Western diet alone (WD, n=9), WD together with Apolipoprotein A1 mimetic peptide 4F (4F, n=11), WD together with scramble peptide (n=7), or chow with 4F peptide (n=8) in drinking water for 12 weeks. T-test (2 groups) and ANOVA (>2 groups) were used to assess for statistical significance. Data are expressed as mean±SEM (p<0.05 significant).
Results: In humans, there was a significant decrease in lung LDL-R and CD36 mRNA expression in PH group compared to non-PH group (p<0.05). Moreover, RV systolic pressure (RVSP) inversely correlated with lung LDL-R (p<0.05) and CD36 (p<0.05). We also found an increase in pulmonary arterial lipid deposits in lungs of PH patients. The ratio of oxidized LDL/LDL was significantly increased in the blood of PH group vs. non-PH group (p<0.05). In LDL-R KO mice, mice on WD developed PH, RV hypertrophy and RV dysfunction that were prevented by 4F (RVSP: 41.05±3.49 in WD vs. 28.49±1.12mmHg in WD+4F, p<0.05; RV/(LV+IVS): 0.46±0.06 in WD vs. 0.28±0.01 in WD+4F; RVEF: 43.63±1.36% in WD vs. 65.5±1.05% in WD+4F, p<0.05). PH was associated with LV dysfunction, pulmonary vascular remodeling, fibrosis and lipid deposition in lungs that were prevented by 4F. WD+scramble group was similar to WD alone whereas Chow+4F was similar to Chow.
Conclusions: Human PH is associated with decreased lung LDL-R and CD36 and increased circulating oxidized LDL/LDL. LDL-R KO mice on WD develop PH, RV and LV dysfunction, further implicating role of LDL-R and oxidized lipids in PH.