ArticleArteriosclerosis, thrombosis, and vascular biology2023
PAR4 Inhibition Reduces Coronary Artery Atherosclerosis and Myocardial Fibrosis in SR-B1/LDLR Double Knockout Mice.
Article in Arteriosclerosis, thrombosis, and vascular biology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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10 citing papers in PubMed, 19 citations in OpenAlex.
- Multi-Omics and Experimental Validation Reveal the Protective Effect of Paeoniflorin Against Coronary Heart Disease in Mice via Inhibiting the C3-Cfd-C3aR Pathway.International journal of molecular sciences · 2026Article
- A neurotensin receptor type 1-derived pepducin acts as a biased allosteric modulator to regulate target receptor function.Acta pharmaceutica Sinica. B · 2026Article
- Protease-activated receptors act as a liaison between metabolism and inflammation.Inflammopharmacology · 2026Review
- Platelets impair the resolution of inflammation in atherosclerotic plaques in insulin-resistant mice after lipid lowering.JCI insight · 2025Article
- Protease-activated receptor 4 deficiency increases mortality, intracranial bleeding, and blood-brain barrier impairment following traumatic brain injury in mice.Research and practice in thrombosis and haemostasis · 2025Article
- Platelets and diseases: signal transduction and advances in targeted therapy.Signal transduction and targeted therapy · 2025Review
- Article
- Macrophages in cardiovascular diseases: molecular mechanisms and therapeutic targets.Signal transduction and targeted therapy · 2024Review
- MicroRNA-26a alleviates tubulointerstitial fibrosis in diabetic kidney disease by targeting PAR4.Journal of cellular and molecular medicine · 2024Article
- Targeting PAR4 to Reduce Atherosclerosis.Arteriosclerosis, thrombosis, and vascular biology · 2023Article
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8 authors at 2 institutions in 1 country.
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Abstract
backgroundSR-B1 (scavenger receptor class B type 1)/LDLR (low-density lipoprotein receptor) double knockout mice fed a high-fat, high-cholesterol diet containing cholate exhibit coronary artery disease characterized by occlusive coronary artery atherosclerosis, platelet accumulation in coronary arteries, and myocardial fibrosis. Platelets are involved in atherosclerosis development, and PAR (protease-activated receptor) 4 has a prominent role in platelet function in mice. However, the role of PAR4 on coronary artery disease in mice has not been tested.
methodsWe tested the effects of a PAR4 inhibitory pepducin (RAG8) on diet-induced aortic sinus and coronary artery atherosclerosis, platelet accumulation in atherosclerotic coronary arteries, and myocardial fibrosis in SR-B1/LDLR double knockout mice. SR-B1/LDLR double knockout mice were fed a high-fat, high-cholesterol diet containing cholate and injected daily with 20 mg/kg of either the RAG8 pepducin or a control reverse-sequence pepducin (SRQ8) for 20 days.
resultsPlatelets from the RAG8-treated mice exhibited reduced thrombin and PAR4 agonist peptide-mediated activation compared with those from control SRQ8-treated mice when tested ex vivo. Although aortic sinus atherosclerosis levels did not differ, RAG8-treated mice exhibited reduced coronary artery atherosclerosis, reduced platelet accumulation in atherosclerotic coronary arteries, and reduced myocardial fibrosis. These protective effects were not accompanied by changes in circulating lipids, inflammatory cytokines, or immune cells. However, RAG8-treated mice exhibited reduced VCAM-1 (vascular cell adhesion molecule 1) protein levels in nonatherosclerotic coronary artery cross sections and reduced leukocyte accumulation in atherosclerotic coronary artery cross sections compared with those from SRQ8-treated mice.
conclusionsThe PAR4 inhibitory RAG8 pepducin reduced coronary artery atherosclerosis and myocardial fibrosis in SR-B1/LDLR double knockout mice fed a high-fat, high-cholesterol diet containing cholate. Furthermore, RAG8 reduced VCAM-1 in nonatherosclerotic coronary arteries and reduced leukocyte and platelet accumulation in atherosclerotic coronary arteries. These findings identify PAR4 as an attractive target in reducing coronary artery disease development, and the use of RAG8 may potentially be beneficial in cardiovascular disease.
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