TY - JOUR
T1 - Attenuation of Atherosclerosis with PAR4 Deficiency
T2 - A Potential Role of Hematopoietically Expressed PAR4 in Atherosclerosis - Brief Report
AU - Wadding-Lee, Caris A.
AU - Jay, Megan
AU - Shearer, Shannon M.
AU - Benson, Tyler W.
AU - Spuzzillo, Anthony
AU - Howatt, Deborah A.
AU - Thompson, Joel
AU - Tourdot, Benjamin E.
AU - Daugherty, Alan
AU - Mackman, Nigel
AU - Owens, A. Phillip
N1 - Publisher Copyright:
© 2025 American Heart Association, Inc.
PY - 2025/6/1
Y1 - 2025/6/1
N2 - BACKGROUND: Cardiovascular disease is a significant burden globally and, despite current therapeutics, remains the leading cause of death. PAR (protease-activated receptor) 4 is a receptor highly expressed by hematopoietic cells, strongly activated by thrombin, and plays a vital role in platelet activation and aggregation. However, the role of PAR4 in atherothrombotic disease remains understudied. METHODS: Mice on a low-density lipoprotein receptor-deficient (Ldlr-/-) background were bred with Par4-deficient (Par4-/-) mice to create Ldlr-/-/Par4+/+ and Ldlr-/-/Par4-/- cousin lines. Mice were fed high-fat (42%) and high-cholesterol (0.2%) Western diet for 12 weeks for all studies. Bone marrow transplant studies were conducted by irradiating Ldlr-/-/Par4+/+ and Ldlr-/-/Par4-/- mice with 550 rads (2×, 4 hours apart) and then repopulated with Par4+/+ or Par4-/- bone marrow. To determine whether the effects of thrombin were mediated solely by PAR4, the thrombin inhibitor dabigatran was added to the Western diet. RESULTS: We observed higher abundance of PAR4 in arteries with atherosclerosis in mouse and human lesions versus healthy controls. Using a global deletion of PAR4, we observed an attenuation in atherosclerosis versus Par4+/+ mice. Bone marrow transplant studies demonstrated these effects were due to hematopoietic cells. When observing whether PAR4 activation via thrombin contributes to atherosclerotic development, Ldl-/-/Par4-/- mice given dabigatran did not further decrease their atherosclerotic burden. Differences between apoE-deficient (apoE-/-) and Ldl-/- platelets were assessed for changes in reactivity. PAR4 appeared to be acting independent of PAR1, as there were no changes with the addition of dabigatran to Par4-/- mice. apoE-/- platelets were hyperreactive compared with Ldlr-/- platelets. CONCLUSIONS: We conclude that hematopoietic-derived PAR4 plays a vital role in the development and progression of atherosclerosis. More specifically, we observe thrombin-activated PAR4 contributes to the progression. Specifically, targeting of PAR4 may be a potential therapeutic target for cardiovascular disease.
AB - BACKGROUND: Cardiovascular disease is a significant burden globally and, despite current therapeutics, remains the leading cause of death. PAR (protease-activated receptor) 4 is a receptor highly expressed by hematopoietic cells, strongly activated by thrombin, and plays a vital role in platelet activation and aggregation. However, the role of PAR4 in atherothrombotic disease remains understudied. METHODS: Mice on a low-density lipoprotein receptor-deficient (Ldlr-/-) background were bred with Par4-deficient (Par4-/-) mice to create Ldlr-/-/Par4+/+ and Ldlr-/-/Par4-/- cousin lines. Mice were fed high-fat (42%) and high-cholesterol (0.2%) Western diet for 12 weeks for all studies. Bone marrow transplant studies were conducted by irradiating Ldlr-/-/Par4+/+ and Ldlr-/-/Par4-/- mice with 550 rads (2×, 4 hours apart) and then repopulated with Par4+/+ or Par4-/- bone marrow. To determine whether the effects of thrombin were mediated solely by PAR4, the thrombin inhibitor dabigatran was added to the Western diet. RESULTS: We observed higher abundance of PAR4 in arteries with atherosclerosis in mouse and human lesions versus healthy controls. Using a global deletion of PAR4, we observed an attenuation in atherosclerosis versus Par4+/+ mice. Bone marrow transplant studies demonstrated these effects were due to hematopoietic cells. When observing whether PAR4 activation via thrombin contributes to atherosclerotic development, Ldl-/-/Par4-/- mice given dabigatran did not further decrease their atherosclerotic burden. Differences between apoE-deficient (apoE-/-) and Ldl-/- platelets were assessed for changes in reactivity. PAR4 appeared to be acting independent of PAR1, as there were no changes with the addition of dabigatran to Par4-/- mice. apoE-/- platelets were hyperreactive compared with Ldlr-/- platelets. CONCLUSIONS: We conclude that hematopoietic-derived PAR4 plays a vital role in the development and progression of atherosclerosis. More specifically, we observe thrombin-activated PAR4 contributes to the progression. Specifically, targeting of PAR4 may be a potential therapeutic target for cardiovascular disease.
KW - arteries
KW - atherosclerosis
KW - blood platelets
KW - cause of death
KW - thrombin
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UR - http://www.scopus.com/inward/citedby.url?scp=105003867805&partnerID=8YFLogxK
U2 - 10.1161/ATVBAHA.124.322068
DO - 10.1161/ATVBAHA.124.322068
M3 - Article
AN - SCOPUS:105003867805
SN - 1079-5642
VL - 45
SP - 901
EP - 909
JO - Arteriosclerosis, Thrombosis, and Vascular Biology
JF - Arteriosclerosis, Thrombosis, and Vascular Biology
IS - 6
ER -
