Abstract
Previously, we reported that phospholipase D1 (PLD1) and PLD2 inhibition by selective PLD1 and PLD2 inhibitors could prevent platelet aggregation in humans, but not in mice. Moreover, only the PLD1 inhibitor, but not PLD2 inhibitor, could effectively prevent thrombus formation in mice, indicating that PLD might play different roles in platelet function in humans and mice. Although PLD1 and PLD2 were reported to be implicated in thrombotic events, the role of PLD in mice remains not completely clear. Here, we investigated the role of PLD1 and PLD2 in acute pulmonary thrombosis and transient middle cerebral artery occlusion-induced brain injury in mice. The data revealed that inhibition of PLD1, but not of PLD2, could partially prevent pulmonary thrombosis-induced death. Moreover, concurrent PLD1 and PLD2 inhibition could considerably increase survival rate. Likewise, inhibition of PLD1, but not PLD2, partially improved ischemic stroke and concurrent inhibition of PLD1, and PLD2 exhibited a relatively better protection against ischemic stroke, as evidenced by the infarct size, brain edema, modified neurological severity score, rotarod test, and the open field test. In conclusion, PLD1 might play a more important role than PLD2, and both PLD1 and PLD2 could act synergistically or have partially redundant functions in regulating thrombosis-relevant events.
Highlights
Nowadays, a number of researchers or scientists are dedicated to discover a novel drug or new therapeutic strategy that prevents thrombosis-relevant events, such as stroke and heart attack, and has minimal bleeding effect
We previously demonstrated that the phospholipase D1 (PLD1) inhibitor VU1 (2.7 mg/kg), but not the PLD2 inhibitor VU2 (2.5 mg/kg), can significantly prolong occlusion time [9]
We further investigated the role of PLD1 and PLD2 in acute pulmonary thrombosis and transient MCAO-induced brain injury in mice
Summary
A number of researchers or scientists are dedicated to discover a novel drug or new therapeutic strategy that prevents thrombosis-relevant events, such as stroke and heart attack, and has minimal bleeding effect. Thielmann et al [7] reported that these two isoforms have partially redundant functions in thrombus formation and that Pld1−/−/Pld2−/− mice display reduced granule release and enhanced integrin activation. Stegner et al reported that pharmacological inhibition of both PLD1 and PLD2 by 5-fluoro-2-indolyl des-chlorohalopemide (FIPI) can diminish granule release as well [8]. These reports showed that platelets from PLD1 or PLD2 knockout mice or FIPI-treated platelets did not show impairment of platelet aggregation. Our previous study revealed that 5 μM PLD1 inhibitor (VU0155069; VU1) or PLD2 inhibitor (VU0364739; VU2) led to a complete inhibition of platelet aggregation induced by collagen in humans, but not in mice, suggesting that PLD plays differential regulatory roles between mouse and human platelets [9]
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