Sirtuin inhibition induces apoptosis-like changes in platelets and thrombocytopenia

Sirtuins are evolutionarily conserved NAD+-dependent acetyl-lysine deacetylases that belong to class III type of histone deacetylases. In humans, seven sirtuin isoforms (Sirt1 to Sirt7) have been identified. Sirtinol, a cell permeable lactone ring derived from naphthol, is a dual Sirt1/Sirt2 inhibitor of low potency whereas EX-527 is a potent and selective Sirt1 inhibitor. Here we have demonstrated that Sirt1, Sirt2 and Sirt3 are expressed in enucleate platelets. Both sirtinol or EX-527 induced apoptosis-like changes in platelets as revealed from enhanced annexin V binding, ROS production and drop in mitochondrial transmembrane potential. Above changes were associated with increased phagocytic clearance of the platelets by macrophages. Expression of acetylated p53 and the conformationally active form of Bax were found to be significantly higher in both sirtinol- as well as EX-527-treated platelets, thus implicating p53-Bax axis in apoptosis induced by sirtuin inhibitors. Administration of either sirtinol or EX-527 in mice led to reduction in both platelet count and number of reticulated platelets. Our results, for the first time, implicate sirtuins as a central player in determination of platelet aging. Since sirtuin inhibitors are being evaluated for their anti-tumor activity, this study rekindles attention to potential side effect of sirtuin inhibition in delimiting platelet life span and management of thrombosis

Anti-apoptotic role of sonic hedgehog on blood platelets

Sonic hedgehog (Shh) is an essential morphogen involved in vertebrate organogenesis. Perturbation of Hh signaling is associated with pathological consequences like tumor formation and chronic lung fibrosis. Platelets are highly sensitive circulating blood cells responsible for hemostasis, while hyperactivity of these cells lead to morbidities like ischemic heart diseases and stroke. Despite being terminally differentiated cells with life span of 10-12 days, platelets have recently been shown to respond to Wnt ligand, another developmental signal similar to Shh. In this study, we demonstrate that components of Shh signaling, Patched and Gli3, are expressed in human platelets consistent with existence of functional Hedgehog signaling in these cells. Shh had potent inhibitory effect on platelet apoptosis induced by ABT-737 or thrombin through attenuation of caspase-3 activity. The Shh-mediated pathway may thus represent a novel endogenous mechanism for regulating platelet activity and life span

Plasma fibrinogen is a natural deterrent to amyloid β-induced platelet activation and neuronal toxicity

Alzheimer's disease (AD) is a devastating neurodegenerative disorder, characterized by extensive loss of neurons and deposition of amyloid β (Aβ) in the form of extracellular plaques. Aβ is considered to have a critical role in synaptic loss and neuronal death underlying cognitive decline. Platelets contribute to 95% of circulating amyloid precursor protein that releases Aβ into circulation. We have recently demonstrated that the Aβ active fragment containing amino acid sequence 25–35 (Aβ<SUB>25–35</SUB>) is highly thrombogenic in nature and elicits strong aggregation of washed human platelets in a RhoA-dependent manner. In this study, we evaluated the influence of fibrinogen on Aβ-induced platelet activation. Intriguingly, Aβ failed to induce aggregation of platelets suspended in plasma but not in buffer. Fibrinogen brought about dose-dependent decline in aggregatory response of washed human platelets elicited by Aβ<SUB>25–35</SUB>, which could be reversed by increasing doses of Aβ. Fibrinogen also attenuated Aβ-induced platelet responses such as secretion, clot retraction, rise in cytosolic Ca<SUP>+2</SUP> and reactive oxygen species. Fibrinogen prevented intracellular accumulation of full-length Aβ peptide (Aβ<SUB>42</SUB>) in platelets as well as neuronal cells. We conclude that fibrinogen serves as a physiological check against the adverse effects of Aβ by preventing its interaction with cells