SIRT1 prevents pulmonary thrombus formation induced by arachidonic acid via downregulation of PAF receptor expression in platelets.
SIRT1, a class III histone deacetylase, is critically involved in cellular response to stress and modulates cardiovascular risk factors. However, its role in thrombus formation is largely unknown. Thus, this study investigated the effect of SIRT1 on pulmonary thrombus formation, and then identified its role in the modulation of platelet aggregation. In isolated human platelets, cell aggregation was increased by various platelet activators, such as platelet activating factor (PAF), arachidonic acid (AA), ADP, and thrombin. AA- and PAF-mediated platelet aggregations were suppressed by WEB2086, a PAF receptor (PAFR) antagonist. Pulmonary thrombus formation induced by PAF or AA was also attenuated by WEB2086, suggesting that PAFR plays a key role in AA-induced platelet aggregation. In platelets isolated from SIRT1-TG mice as well as in platelets treated with resveratrol or reSIRT1, PAFR expression was decreased, whereas this expressional downregulation by SIRT1 activators was inhibited in platelets treated with MG132 (a proteasome inhibitor) or NH4Cl (a lysosome inhibitor). Furthermore, platelet aggregation induced by AA was markedly attenuated by resveratrol and reSIRT1. Likewise, the increased pulmonary thrombus formation in mice treated with AA was also attenuated by SIRT1 activators. In line with these results, pulmonary thrombus formation was markedly attenuated in SIRT1-TG mice. Taken together, this study showed that SIRT1 downregulates PAFR expression on platelets via proteasomal and lysosomal pathways, and that this downregulation inhibits platelet aggregation in vitro and pulmonary thrombus formation in vivo.
a Department of Pharmacology, School of Medicine , Pusan National University , Yangsan , Gyeongnam , Republic of Korea.
Yun Hak
YH
Kim
a Department of Pharmacology, School of Medicine , Pusan National University , Yangsan , Gyeongnam , Republic of Korea.
Jin Ung
JU
Bae
b Department of Laboratory Medicine , Pusan National University School of Medicine and Pusan National University Yangsan Hospital , Yangsan , Gyeongnam , Republic of Korea.
In Suk
IS
Kim
b Department of Laboratory Medicine , Pusan National University School of Medicine and Pusan National University Yangsan Hospital , Yangsan , Gyeongnam , Republic of Korea.
Chulhun L
CL
Chang
c Department of Anatomy , School of Medicine, Pusan National University , Yangsan , Gyeongnam , Republic of Korea.
Sae Ock
SO
Oh
a Department of Pharmacology, School of Medicine , Pusan National University , Yangsan , Gyeongnam , Republic of Korea.
Chi Dae
CD
Kim
D000818:Animals; D016718:Arachidonic Acid / Q000009:adverse effects*; D001792:Blood Platelets / Q000378:metabolism*; D015536:Down-Regulation; D005786:Gene Expression Regulation; D006801:Humans; D008171:Lung Diseases / Q000097:blood / Q000175:diagnosis / Q000209:etiology*; D051379:Mice; D010974:Platelet Aggregation / Q000187:drug effects / Q000235:genetics; D010979:Platelet Function Tests; D010980:Platelet Membrane Glycoproteins / Q000235:genetics*; D011651:Pulmonary Artery / Q000473:pathology; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D056564:Sirtuin 1 / Q000235:genetics*; D013927:Thrombosis / Q000097:blood / Q000175:diagnosis / Q000209:etiology*
D010980:Platelet Membrane Glycoproteins; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor; D016718:Arachidonic Acid; D056564:Sirtuin 1
Arachidonic acid; PAF receptor; SIRT1; platelet aggregation; pulmonary embolism