Novel Approaches to Fine-Tune Therapeutic Targeting of Platelets in Atherosclerosis: A Critical Appraisal

Abstract

The pathogenesis of atherosclerotic vascular disease is driven by a multitude of risk factors intertwining metabolic and inflammatory pathways. Increasing knowledge about platelet biology sheds light on how platelets take part in these processes from early to later stages of plaque development. Recent insights from experimental studies and mouse models substantiate platelets as initiators and amplifiers in atherogenic leukocyte recruitment. These studies are complemented by results from genetics studies shedding light on novel molecular mechanisms which provide an interesting prospect as novel targets. For instance, experimental studies provide further details how platelet-decorated von Willebrand factor tethered to activated endothelial cells plays a role in atherogenic monocyte recruitment. Novel aspects of platelets as atherogenic inductors of neutrophil extracellular traps and particularities in signaling pathways such as cyclic guanosine monophosphate and the inhibitory adaptor molecule SHB23/LNK associating platelets with atherogenesis are shared. In summary, it was our intention to balance insights from recent experimental data that support a plausible role for platelets in atherogenesis against a paucity of clinical evidence needed to validate this concept in humans.

The Emerging Role of Neutrophil Extracellular Traps in Arterial, Venous and Cancer-Associated Thrombosis

“…NETs have been detected in patients with atherosclerosis and in animal models, and NETs are related to various pathogeneses of atherosclerosis. NETs play a role in all stages of atherosclerosis, from early endothelial dysfunction to atherosclerotic plaque rupture and atherosclerotic thrombosis ( 25 , 26 ). As a scaffold for cells and various coagulation factors, NETs not only exist in plaques and thrombi but also induce oxidative stress, induce the activation of endothelial cells, antigen-presenting cells and platelets, increase the expression of coagulation factors, and lead to proinflammatory reactions ( Figure 2A ).…”

The multifaceted contribution of platelets in the emergence and aftermath of acute cardiovascular events

“…Although there is a large body of data from animal models in the different stages of plaque development [91,92], this is yet incompletely translated to humans. The evidence for a role of platelets in atherogenesis in humans is limited and largely indirect, which might be attributed to the fact that experimental options are far more abundant in animal models.…”

Identification of novel proteins for lacunar stroke by integrating genome-wide association data and human brain proteomes

“…According to our findings, CAND2 is decreased, predominantly in GABAergic neurons in the brains of lacunar stroke patients, indicating its role in the etiology of lacunar stroke. Both ALDH2 and MRVI1 are involved in platelet adhesion [ 47 ] and vascular inflammation [ 48 , 49 ]. Previous research has linked increased blood-brain barrier permeability to an inflammatory process involving activated monocytes/macrophages in individuals with cerebral small vessel disease [ 50 , 51 ].…”