Platelet hyperreactivity contributes significantly to thrombosis in acute myocardial infarction and stroke. While antiplatelet drugs are used, residual ischemic risk remains. Intermittent fasting(IF), a dietary patter...Platelet hyperreactivity contributes significantly to thrombosis in acute myocardial infarction and stroke. While antiplatelet drugs are used, residual ischemic risk remains. Intermittent fasting(IF), a dietary pattern characterized by alternating periods of eating and fasting, has shown cardiovascular benefits, but its effect on platelet activation is unclear. This study demonstrates that IF inhibits platelet activation and thrombosis in both patients with coronary artery disease and apolipoprotein E(Apo E) knockout(Apo E-/-) mice, by enhancing intestinal flora production of indole-3-propionic acid(IPA). Mechanistically, elevated IPA in plasma directly attenuates platelet activation by binding to the platelet pregnane X receptor(PXR) and suppressing downstream signaling pathways, including Src/Lyn/Syk and LAT/PLCγ/PKC/Ca2+. Importantly, IF alleviates myocardial and cerebral ischemia/reperfusion injury in Apo E-/-mice. These findings suggest that IF mitigates platelet activation and thrombosis risk in coronary atherosclerosis by enhancing intestinal flora production of IPA, which subsequently activates the platelet PXR-related signaling pathways.展开更多
基金supported by the grants to J.G. from the National Basic Research Center of China (T2288101)the Shanghai Clinical Research Center for Interventional Medicine (19MC1910300)+7 种基金the Shanghai Municipal Key Clinical Specialty (shslczdzk01701)the State Key Clinical Specialty Construction Project (YW2021-002)the National Natural Science Foundation of China (81970298)the Clinical Research Special Fund of Zhongshan Hospital Fudan University (2020ZSLC57)2021 Clinical Research Navigation Project of Shanghai Medical College of Fudan Universitythe National Natural Science Foundation of China (82100355)the Shanghai Sailing Program (21YF1406000)the Shanghai Science and Technology Innovation Fund (22S31904900)
文摘Platelet hyperreactivity contributes significantly to thrombosis in acute myocardial infarction and stroke. While antiplatelet drugs are used, residual ischemic risk remains. Intermittent fasting(IF), a dietary pattern characterized by alternating periods of eating and fasting, has shown cardiovascular benefits, but its effect on platelet activation is unclear. This study demonstrates that IF inhibits platelet activation and thrombosis in both patients with coronary artery disease and apolipoprotein E(Apo E) knockout(Apo E-/-) mice, by enhancing intestinal flora production of indole-3-propionic acid(IPA). Mechanistically, elevated IPA in plasma directly attenuates platelet activation by binding to the platelet pregnane X receptor(PXR) and suppressing downstream signaling pathways, including Src/Lyn/Syk and LAT/PLCγ/PKC/Ca2+. Importantly, IF alleviates myocardial and cerebral ischemia/reperfusion injury in Apo E-/-mice. These findings suggest that IF mitigates platelet activation and thrombosis risk in coronary atherosclerosis by enhancing intestinal flora production of IPA, which subsequently activates the platelet PXR-related signaling pathways.
