PAR4 Inhibition Reduces Coronary Artery Atherosclerosis and Myocardial Fibrosis in SR-B1/LDLR Double Knockout Mice-Reference-Cited by-同舟云学术

PAR4 Inhibition Reduces Coronary Artery Atherosclerosis and Myocardial Fibrosis in SR-B1/LDLR Double Knockout Mice

Published:2023-11 Issue:11 Volume:43 Page:2165-2178
ISSN:1079-5642
Container-title:Arteriosclerosis, Thrombosis, and Vascular Biology
language:en
Short-container-title:ATVB

Author:

Lee Samuel K.¹²³,Malik Rida A.¹⁴²^ORCID,Zhou Ji¹⁴²^ORCID,Wang Wei¹²³^ORCID,Gross Peter L.¹⁴²^ORCID,Weitz Jeffrey I.¹⁴²³^ORCID,Ramachandran Rithwik⁵^ORCID,Trigatti Bernardo L.¹²³^ORCID

Affiliation:

1. Thrombosis and Atherosclerosis Research Institute (S.K.L., R.A.M., J.Z., W.W., P.L.G., J.I.W., B.L.T.), McMaster University, Hamilton, Ontario, Canada.

2. Hamilton Health Sciences, Ontario, Canada (S.K.L., R.A.M., J.Z., W.W., P.L.G., J.I.W., B.L.T.).

3. Department of Biochemistry and Biomedical Sciences McMaster University, Hamilton, Ontario, Canada (S.K.L., W.W., J.I.W., B.L.T.).

4. Department of Medicine (R.A.M., J.Z., P.L.G., J.I.W.), McMaster University, Hamilton, Ontario, Canada.

5. Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada (R.R.).

Abstract

BACKGROUND: SR-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. METHODS: We 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. RESULTS: Platelets 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. CONCLUSIONS: The 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.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine

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