Apocynin Prevents Abnormal Megakaryopoiesis and Platelet Activation Induced by Chronic Stress

Abstract

Environmental chronic stress (ECS) has been identified as a trigger of acute coronary syndromes (ACS). Changes in redox balance, enhanced reactive oxygen species (ROS) production, and platelet hyperreactivity were detected in both ECS and ACS. However, the mechanisms by which ECS predisposes to thrombosis are not fully understood. Here, we investigated the impact of ECS on platelet activation and megakaryopoiesis in mice and the effect of Apocynin in this experimental setting. ECS induced by 4 days of forced swimming stress (FSS) treatment predisposed to arterial thrombosis and increased oxidative stress (e.g., plasma malondialdehyde levels). Interestingly, Apocynin treatment prevented these alterations. In addition, FSS induced abnormal megakaryopoiesis increasing the number and the maturation state of bone marrow megakaryocytes (MKs) and affecting circulating platelets. In particular, a higher number of large and reticulated platelets with marked functional activation were detected after FSS. Apocynin decreased the total MK number and prevented their ability to generate ROS without affecting the percentage of CD42d+ cells, and it reduced the platelet hyperactivation in stressed mice. In conclusion, Apocynin restores the physiological megakaryopoiesis and platelet behavior, preventing the detrimental effect of chronic stress on thrombosis, suggesting its potential use in the occurrence of thrombosis associated with ECS.

Fenretinide treatment accelerates atherosclerosis development in apoE‐deficient mice in spite of beneficial metabolic effects

“…Twenty microlitres of whole blood were stimulated at RT for 5 min with 5 μM ADP, then 200 μl of cell blood lysis buffer (BD Biosciences) were added for 15 min, and then samples were stained with saturating concentrations of anti‐CD45 (leukocytes), anti‐CD41 (platelets), and anti‐CD14 (monocytes) or anti‐Lys6G (neutrophils) or isotype controls at RT for 30 min in the dark. Aggregates were counted by flow FACS “Novocyte3000.” A minimum of 5,000 events was collected in the CD14+ or Lys6G+ gate as previously described (Sandrini et al, ).…”

Sub-Chronic Stress Exacerbates the Pro-Thrombotic Phenotype in BDNFVal/Met Mice: Gene-Environment Interaction in the Modulation of Arterial Thrombosis

“…In the CNS, they affect the expression of different genes and molecules involved in brain plasticity such as neurotrophins [ 3 ]. Moreover, in the periphery they stimulate megakaryo- and thrombo-poiesis, induce platelet activation [ 4 , 5 ] and endothelial dysfunction, enhance coagulation pathway activation and reduce fibrinolysis [ 6 ] predisposing to onset and progression of CVD [ 7 ] and arterial thrombosis [ 8 ]. However, stressors do not affect everyone in the same way.…”

Depression and Cardiovascular Disease: The Viewpoint of Platelets

“…These events have been recently associated with increased coagulation factor binding and enhanced thrombin and fibrin generation, favoring a pro-coagulant phenotype of platelets [ 284 ]. Activated platelets, via NOX, cyclooxygenases, eNOS, XO, and mitochondrial respiration [ 285 , 286 ], are able to generate per se ROS, that in turn re-activate platelets [ 287 , 288 ], especially in older patients [ 289 ]. As consequence, intra-platelets ROS support platelet activation promoting α-granule exocytosis [ 290 ], increasing the sensitivity of platelets receptor like GPIIb/IIIa, GPIbα and GPVI [ 291 , 292 ].…”

“…PGF2α can in turn activates TX receptor beyond supporting platelet activation [ 295 , 296 , 297 ]. Finally, the redox imbalance is furtherly fed by a vicious cycle of ROS production due to activation of NOX enzyme [ 285 , 286 , 287 , 288 , 289 ] and to alteration of platelet mitochondrial function [ 298 , 299 ]. ROS: Reactive Oxygen Species; GP: glycoprotein; CD40L: CD40 Ligand; Ca 2+ : Calcium; NOX: NADPH oxidase; PLA 2 : Phospholipase A 2 ; AA: Arachidonic Acid; TX: Thromboxane.…”