sLRP1 (Soluble Low-Density Lipoprotein Receptor-Related Protein 1): A Novel Biomarker for P2Y12 (P2Y Purinoceptor 12) Receptor Expression in Atherosclerotic Plaques.

Abstract

OBJECTIVE:

Recent studies suggest that the P2Y12 (P2Y purinoceptor 12) receptor of vascular smooth muscle cells in atherosclerotic plaques aggravates atherosclerosis, and P2Y12 receptor inhibitors such as CDL (clopidogrel) may effectively treat atherosclerosis. It is imperative to identify an effective biomarker for reflecting the P2Y12 receptor expression on vascular smooth muscle cells in plaques. Approach and Results: We found that there was a positive correlation between the level of circulating sLRP1 (soluble low-density lipoprotein receptor-related protein 1) and the number of LRP1+ α-SMA+ (α-smooth muscle actin), P2Y12+, or P2Y12+ LRP1+ cells in plaques from apoE-/- mice fed a high-fat diet. Furthermore, activation of the P2Y12 receptor increased the expression and shedding of LRP1 in vascular smooth muscle cells by inhibiting cAMP (3'-5'-cyclic adenosine monophosphate)/PKA (protein kinase A)/SREBP-2 (sterol regulatory element binding transcription factor 2). Conversely, genetic knockdown or pharmacological inhibition of the P2Y12 receptor had the opposite effects. Additionally, CDL decreased the number of lesional LRP1+ α-SMA+ cells and the levels of circulating sLRP1 by activating cAMP/PKA/SREBP-2 in apoE-/- mice fed a high-fat diet.

CONCLUSIONS:

Our study suggests that sLRP1 may be a biomarker that reflects the P2Y12 receptor level in plaques and has the potential to be an indicator for administering P2Y12 receptor inhibitors for patients with atherosclerosis.

• Authors: Jiefang Chen, Shulan Pi, Cheng Yu, Hanqing Shi, Yuxiao Liu, Xiaoqing Guo, Lian Zhou, Yuanyuan Li, Hui He, Yuanpeng Xia, Ling Mao, Bo Hu
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 40 Issue 6 Pg. e166-e179 (06 2020) ISSN: 1524-4636 [Electronic] United States
• PMID: 32349534 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Actins
• Apolipoproteins E
• Biomarkers
• Low Density Lipoprotein Receptor-Related Protein-1
• P2ry12 protein, mouse
• Purinergic P2Y Receptor Antagonists
• Receptors, Purinergic P2Y12
• Srebf2 protein, mouse
• Sterol Regulatory Element Binding Protein 2
• alpha-smooth muscle actin, mouse
• Clopidogrel
• Cyclic AMP
• Cyclic AMP-Dependent Protein Kinases

Topics

• Actins (analysis)
• Animals
• Apolipoproteins E (deficiency, genetics, physiology)
• Biomarkers (analysis)
• Clopidogrel (pharmacology)
• Cyclic AMP (metabolism)
• Cyclic AMP-Dependent Protein Kinases (metabolism)
• Diet, High-Fat
• Gene Expression
• Gene Knockdown Techniques
• Low Density Lipoprotein Receptor-Related Protein-1 (analysis, blood)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Muscle, Smooth, Vascular (chemistry, metabolism)
• Plaque, Atherosclerotic (chemistry, metabolism)
• Purinergic P2Y Receptor Antagonists (pharmacology)
• Receptors, Purinergic P2Y12 (drug effects, genetics, physiology)
• Signal Transduction
• Sterol Regulatory Element Binding Protein 2 (metabolism)