TY - JOUR
T1 - Interplay of Low-Density Lipoprotein Receptors, LRPs, and Lipoproteins in Pulmonary Hypertension
AU - Calvier, Laurent
AU - Herz, Joachim
AU - Hansmann, Georg
N1 - Funding Information:
Dr Herz was supported by grants from the National Heart, Lung, and Blood Institute (R37 HL063762), the National Institute on Aging (RF AG053391), the National Institute on Neurological Disorders and Stroke and National Institute on Aging (R01 NS093382), and BrightFocus (A2016396S); the Bluefield Project to Cure FTD; and a Harrington Scholar Innovator Award (2019). Dr Hansmann has received financial support from the German Research Foundation (HA4348/2-2 and HA4348/6-2 KFO311), the Federal Ministry of Education and Research (BMBF ViP+ program-03VP08053; BMBF 01KC2001B), and the European Pediatric Pulmonary Vascular Disease Network. Dr Calvier and Dr Herz are shareholders of Reelin Therapeutics and co-inventors of a patent related to anti-Reelin strategies (application number 15/763,047 and publication number 20180273637). Dr Hansmann has reported that he has no relationships relevant to the contents of this paper to disclose.
Publisher Copyright:
© 2022 The Authors
PY - 2022/2
Y1 - 2022/2
N2 - 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.
AB - 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.
KW - Apoer2
KW - BMP
KW - BMPR2
KW - LDL receptor related protein
KW - LDLR
KW - LRP
KW - LRP1
KW - LRP1B
KW - LRP2
KW - LRP4
KW - LRP5
KW - LRP6
KW - LRP8
KW - MEgf7
KW - PAH
KW - PDGF
KW - PPARγ
KW - PVD
KW - RVHF
KW - TGF-β1
KW - VLDLR
KW - Wnt
KW - apolipoprotein E receptor 2
KW - endothelial cell
KW - gp330
KW - low-density lipoprotein receptor
KW - megalin
KW - monocyte
KW - multiple epidermal growth factor-like domains 7
KW - pulmonary arterial hypertension
KW - pulmonary vascular disease
KW - right ventricle heart failure
KW - smooth muscle cell
KW - very low density lipoprotein receptor
KW - β-catenin
UR - http://www.scopus.com/inward/record.url?scp=85124469714&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85124469714&partnerID=8YFLogxK
U2 - 10.1016/j.jacbts.2021.09.011
DO - 10.1016/j.jacbts.2021.09.011
M3 - Review article
C2 - 35257044
AN - SCOPUS:85124469714
SN - 2452-302X
VL - 7
SP - 164
EP - 180
JO - JACC: Basic to Translational Science
JF - JACC: Basic to Translational Science
IS - 2
ER -