Interplay of Low-Density Lipoprotein Receptors, LRPs, and Lipoproteins in Pulmonary Hypertension

Abstract

The low-density lipoprotein receptor (LDLR) gene family includes LDLR, very LDLR, and LDL receptor-related proteins (LRPs) such as LRP1, LRP1b (aka LRP-DIT), LRP2 (aka megalin), LRP4, and LRP5/6, and LRP8 (aka ApoER2). LDLR family members constitute a class of closely related multifunctional, transmembrane receptors, with diverse functions, from embryonic development to cancer, lipid metabolism, and cardiovascular homeostasis. While LDLR family members have been studied extensively in the systemic circulation in the context of atherosclerosis, their roles in pulmonary arterial hypertension (PAH) are understudied and largely unknown. Endothelial dysfunction, tissue infiltration of monocytes, and proliferation of pulmonary artery smooth muscle cells are hallmarks of PAH, leading to vascular remodeling, obliteration, increased pulmonary vascular resistance, heart failure, and death. LDLR family members are entangled with the aforementioned detrimental processes by controlling many pathways that are dysregulated in PAH; these include lipid metabolism and oxidation, but also platelet-derived growth factor, transforming growth factor β1, Wnt, apolipoprotein E, bone morpohogenetic proteins, and peroxisome proliferator-activated receptor gamma. In this paper, we discuss the current knowledge on LDLR family members in PAH. We also review mechanisms and drugs discovered in biological contexts and diseases other than PAH that are likely very relevant in the hypertensive pulmonary vasculature and the future care of patients with PAH or other chronic, progressive, debilitating cardiovascular diseases.

Keywords: ApoE, apolipoprotein E; Apoer2; BMP; BMPR, bone morphogenetic protein receptor; BMPR2; COPD, chronic obstructive pulmonary disease; CTGF, connective tissue growth factor; HDL, high-density lipoprotein; KO, knockout; LDL receptor related protein; LDL, low-density lipoprotein; LDLR; LDLR, low-density lipoprotein receptor; LRP; LRP, low-density lipoprotein receptor–related protein; LRP1; LRP1B; LRP2; LRP4; LRP5; LRP6; LRP8; MEgf7; Mesd, mesoderm development; PAH; PAH, pulmonary arterial hypertension; PASMC, pulmonary artery smooth muscle cell; PDGF; PDGFR-β, platelet-derived growth factor receptor-β; PH, pulmonary hypertension; PPARγ; PPARγ, peroxisome proliferator-activated receptor gamma; PVD; RV, right ventricle/ventricular; RVHF; RVSP, right ventricular systolic pressure; TGF-β1; TGF-β1, transforming growth factor β1; TGFBR, transforming growth factor β1 receptor; TNF, tumor necrosis factor receptor; VLDLR; VLDLR, very low density lipoprotein receptor; VSMC, vascular smooth muscle cell; Wnt; apolipoprotein E receptor 2; endothelial cell; gp330; low-density lipoprotein receptor; mRNA, messenger RNA; megalin; monocyte; multiple epidermal growth factor-like domains 7; pulmonary arterial hypertension; pulmonary vascular disease; right ventricle heart failure; smooth muscle cell; very low density lipoprotein receptor; β-catenin.

Graphical abstract

Figure 1

The LDLR Family Illustration showing the domain structure of the low-density lipoprotein receptor (LDLR) family members for vertebrates organized as core, distant and far distant. The N-terminal part is on the top side (extracellular domain) and the C-terminal part is on the bottom side (intracellular domain). Members of the core are characterized by the presence of NPxY-motif, N-terminal ligand binding domain, and epidermal growth factor (EGF) precursor homology domain composed of EGF repeats and YWTD/b-propeller domain. LDLR, very LDLR (VLDLR), and ApoER2 express an additional extracellular O-linked sugar domain adjacent to the transmembrane segment. Distant members are the LDLR-related protein 5 (LRP5) and LRP6 lacking NPxY-motif as well as SorLA (or SORL1, SORLA1, LR11) with additional fibronectin repeats and VPS 10 motif. The 4 far distant members only harbor ligand binding-type repeats with the CUB domain (binding complement C1r/C1s, Uegf, and Bmp1) for LRP3, LRP12, and LRP10. Adapted with permission from Herz (8) and Pohlkamp et al (125).

Central Illustration

Main LDLR Family Members Involved in PAH The low-density lipoprotein receptor (LDLR) family constitutes a class of closely related multifunctional receptors, with diverse functions, especially in cardiovascular homeostasis. However, their roles in pulmonary hypertension are understudied; here, we review emerging pulmonary hypertension publications on LDLR family members. PAH = pulmonary arterial hypertension.

Figure 2

LDLR Regulates Oxidized LDL Level and LRP1 Preserves Vascular Homeostasis (A) Illustration outlining the publications to date on LDLR functions in pulmonary arterial hypertension (PAH). In PAH, LDLR expression is reduced, affecting the LDL homeostasis and leading to accumulation of oxidized LDL (oxLDL) in the circulation and lungs. The impaired LDLR pathway and oxLDL induce the release of proinflammatory markers by endothelial cells (ECs) and smooth muscle cells (SMCs) followed by monocyte infiltration and differentiation into macrophages as well as SMC proliferation. Altogether, this creates an inflammatory environment and vascular remodeling. (B) Illustration outlining the publications to date on LRP1 function in pulmonary artery SMCs during PAH and pathways suspected to occur in pulmonary vasculature. Under normal conditions, LRP1 dampens the transforming growth factor (TGF)-β1 pathway by direct interaction with TGF-β receptor 1 (TGFBRI) in pulmonary artery SMCs and inhibits the differentiation of lung fibroblasts to a contractile phenotype. In PAH, LRP1 expression is reduced, disturbing the TGF-β1 balance and thus promoting proinflammatory and profibrotic genes such as connective tissue growth factor (CTGF). In fibroblasts, loss of LRP1 results in acquisition of a contractile phenotype and integrin- and protease-dependent release of active transforming growth factor TGF-β1 from the extracellular matrix (ECM) stores. Pioglitazone treatment (a peroxisome proliferator-activated receptor gamma [PPARγ] agonist) in smLRP1^–/– mice reverses PAH caused by LRP1 deficiency, restoring an inhibition on TGF-β1 signaling. Other pathways known in non-PAH context remain to be investigated in the pulmonary vasculature, such as LRP1 interaction with platelet-derived growth factor receptor (PDGFR), tumor necrosis factor receptor (TNFR), or bone morphogenetic protein receptor (BMPR). Abbreviations as in Figure 1.

Figure 3

LRP5/6-Wnt and LRP8-ApoE Roles in PAH (A) Illustration outlining the publications to date on LRP5/6 function in pulmonary artery SMCs (PASMCs) during PAH. Under normal conditions, Both Wnt/β-catenin (left) and Wnt/planar cell polarity (right) signaling pathways are suspected to be necessary for preservation of pulmonary vascular homeostasis and vascular regeneration in response to injury. However, loss of this balance and overactivation of the Wnt/β-catenin axis may lead to excessive PASMC growth, vessel obstruction, and PAH. (B) Illustration outlining the publications to date on LRP8 and apolipoprotein E (ApoE) functions in pulmonary artery endothelial cells and PASMCs during PAH. The PDGFR-β and YAP/TAZ pathways are profibrotic, while LRP8, LRP1, and BMPR2 preserve vascular homeostasis. Under BMP-2 or PPARγ activation, ApoE is expressed and binds on the one hand to PDGFR-β, blocking its signaling, and on the second hand to LRP8. miR-130/301 binds directly to LRP8 and PPARγ messenger RNA, blocking their expression. Abbreviations as in Figures 1 and 2.

Figure 4

VLDLR, LRP2, LRP4, and LRP1B Pathways Not Linked to PAH Yet Illustration outlining the publications to date on VLDLR, LRP2, LRP4, and LRP1B pathways in different cell types not yet linked to PAH but potentially relevant for the disease. Details on these interactions are documented in the Supplemental Appendix. APP = amyloid precursor protein; PAI = plasminogen activator inhibitor; RAP = receptor-associated protein; uPAR = urokinase receptor; VSMC = vascular smooth muscle cell; other abbreviations as in Figures 1, 2, and 3.