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Low-density lipoprotein receptor-related protein 6-mediated signaling pathways and associated cardiovascular diseases: diagnostic and therapeutic opportunities

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Abstract

Low-density lipoprotein receptor-related protein 6 (LRP6) is a member of the low-density lipoprotein receptors (LDLRs) family and accumulating evidence points to the critical role of LRP6 in cardiovascular health and homeostasis. In addition to presenting the well-appreciated roles in canonical signaling regulating blood pressure, blood glucose, lipid metabolism, atherosclerosis, cardiac valve disease, cardiac development, Alzheimer’s disease and tumorigenesis, LRP6 also inhibits non-canonical Wnt signals that promote arterial smooth muscle cell proliferation and vascular calcification. Noticeably, the role of LRP6 is displayed in cardiometabolic disease, an increasingly important clinical burden with aging and obesity. The prospect for cardiovascular diseases treatment via targeting LRP6-mediated signaling pathways may improve central blood pressure and lipid metabolism, and reduce neointima formation and myocardial ischemia–reperfusion injury. Thus, a deep and comprehensive understanding of LRP6 structure, function and signaling pathways will contribute to clinical diagnosis, therapy and new drug development for LRP6-related cardiovascular diseases.

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Abbreviations

APC:

Adenomatous polyposis coli

Axin:

Scaffold protein

CAD:

Coronary artery disease

CE:

Convergent extension

CK:

Casein kinase

Cx43:

Connexin 43

DKK:

Dickkopf-related protein

DORV:

Double outlet right ventricle

Drp1–mTOR–TFEB signaling:

Dynamin-related protein 1–rapamycin–transcription factor EB

DVL:

Dishevelled protein family

Fzd:

Frizzled family of receptors

GPCR:

G protein-coupled receptor

GSK-3β:

Glycogen synthase kinase-3β

HUVECs:

Human umbilical vein endothelial cells

IGF1–AKT–mTOR–SREBP1/2 signaling:

Insulin-like growth factor 1–protein kinase B–rapamycin–sterol regulatory element-binding protein 1/2 signaling

IGFBP-4:

Insulin-like growth factor-binding protein-4

JNK:

C-Jun N-terminal kinase

LDL-C:

Low-density lipoprotein cholesterol

LDLRAP1:

LDLR-adapter protein 1

LDLRs:

Low-density lipoprotein receptors

LRP:

Low-density lipoprotein receptor-related protein

mTORC1:

Rapamycin complex 1

mTORC2:

Rapamycin complex 2

Non-canonical Wnt/PCP:

Non-canonical Wnt/planar cell polarity

OFT:

Outflow tract

PPPSP motif:

Pro-Pro-Pro-Ser-Pro motif

P1427Q:

Distinctive cyclic structure of the proline’s side chain at P1427

R611C:

An arginine to cysteine mutation at residue 611

SNP:

Single-nucleotide polymorphism

Sp1:

Specificity protein 1

TCF-4:

T-cell factor 4

TCF7L2:

Transcription factor 7-like 2

TCF/LEF:

N-terminus of T-cell factor/lymphoid-enhancing factors

TG:

Triglyceride

VSD:

Ventricular septal defect

VSMCs:

Vascular smooth muscle cells

Wnt/STOP signaling:

Wnt/β-catenin-independent de-repression

Wnt/TOR signaling:

Wnt/mTOR pathway

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Acknowledgements

We sincerely appreciate those researchers in Key Laboratory of Arrhythmias of the Ministry of Education of China who provided important data in favor of our work. This work was supported in part by a Project of National Natural Science Foundation of China (81870247, to S. K.), Key Disciplines Group Construction Project of Pudong Health Bureau of Shanghai (Grant No. PWZxq 2017-05), and Top-level Clinical Discipline Project of Shanghai Pudong District (Grant No. PWYgf 2018-02).

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  1. Department of Cardiology, Shanghai East Hospital, Tongji University, Jimo Road 150, Shanghai, 200120, China

    Sheng Kang

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Kang, S. Low-density lipoprotein receptor-related protein 6-mediated signaling pathways and associated cardiovascular diseases: diagnostic and therapeutic opportunities. Hum Genet 139, 447–459 (2020). https://doi.org/10.1007/s00439-020-02124-8

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