Involvement of Low‐Density Lipoprotein Receptor in the Pathogenesis of Pulmonary Hypertension

Abstract

Background Recently, we and others have reported a causal role for oxidized lipids in the pathogenesis of pulmonary hypertension ( PH ). However, the role of low‐density lipoprotein receptor ( LDL ‐R) in PH is not known. Methods and Results We examined the role of LDL ‐R in the development of PH and determined the efficacy of high‐density lipoprotein mimetic peptide 4F in mitigating PH . Explanted human lungs and plasma from patients with PH and control subjects were analyzed for gene expression, histological characteristics, and lipoprotein oxidation. Male LDL ‐R null ( LDL ‐R knockout) mice (12–15 months old) were fed chow, Western diet ( WD ), WD with 4F, and WD with scramble peptide for 12 weeks. Serial echocardiography, cardiac catheterization, oxidized LDL assay, real‐time quantitative reverse transcription–polymerase chain reaction, and histological analysis were performed. The effect of LDL ‐R knockdown and oxidized LDL on human pulmonary artery smooth muscle cell proliferation was assessed in vitro. LDL ‐R and CD 36 expression levels were significantly downregulated in the lungs of patients with PH. Patients with PH also had increased lung lipid deposits, oxidized LDL , E06 immunoreactivity, and plasma oxidized LDL / LDL ratio. LDL ‐R knockout mice on WD developed PH , right ventricular hypertrophy, right ventricular dysfunction, pulmonary vascular remodeling, fibrosis, and lipid deposition in lungs, aortic atherosclerosis, and left ventricular dysfunction, which were prevented by 4F. Interestingly, PH in WD group preceded left ventricular dysfunction. Oxidized LDL or LDL ‐R knockdown significantly increased proliferation of human pulmonary artery smooth muscle cells in vitro. Conclusions Human PH is associated with decreased LDL ‐R in lungs and increased oxidized LDL in lungs and plasma. WD‐ fed LDL ‐R knockout mice develop PH and right ventricular dysfunction, implicating a role for LDL ‐R and oxidized lipids in PH .

High-Fat Diet Attenuates the Improvement of Hypoxia-induced Pulmonary Artery Hypertension in Mice During Reoxygenation.

“…Recently, Umar et al reported that a western diet increased in ammation in the lungs, and led to the development of pulmonary hypertension in LDL receptor knockout mice [22]. In the present study, although in ammatory changes were not examined, TUNEL-positive cells in pulmonary artery smooth muscle cells and caspase-3 activity in the lung were decreased in the HFD group.…”

“…In the present study, although in ammatory changes were not examined, TUNEL-positive cells in pulmonary artery smooth muscle cells and caspase-3 activity in the lung were decreased in the HFD group. Since the role of native or oxidized LDL for apoptosis or proliferation of smooth muscle cells is controversial [22][23][24][25][26], further study is needed. In this study, the HFD group presented higher RVSP and higher HDL-C levels than the ND group; however, previous studies have shown an association of higher plasma HDL-C levels with good prognosis in human PAH [27,28].…”

“…Further, Umar et al showed that a western diet affects left ventricular systolic pressure and RVSP [22].…”

High-fat diet attenuates the improvement of hypoxia-induced pulmonary hypertension in mice during reoxygenation

“…Recently, Umar et al reported that a western diet increased the lung inflammation, leading to the development of PH in LDL receptor-knockout mice [ 22 ]. In this study, although inflammatory changes were not examined, TUNEL-positive cells in pulmonary artery smooth muscle cells and lung caspase-3 activity were more decreased in the HFD group than in the ND group.…”

“…In this study, although inflammatory changes were not examined, TUNEL-positive cells in pulmonary artery smooth muscle cells and lung caspase-3 activity were more decreased in the HFD group than in the ND group. Since the role of native or oxidized LDL for smooth muscle cell apoptosis or proliferation is controversial [ 22 – 26 ], further studies are needed.…”