Platelet-Derived Microparticles From Obese Individuals: Characterization of Number, Size, Proteomics, and Crosstalk With Cancer and Endothelial Cells

Abstract

Rationale: Obesity is a risk factor for atherothrombosis and various cancers. However, the mechanisms are not yet completely clarified.Objectives: We aimed to verify whether the microparticles (MPs) released from thrombin-activated platelets differed in obese and non-obese women for number, size, and proteomics cargo and the capacity to modulate in vitro the expression of (i) genes related to the epithelial to mesenchymal transition (EMT) and the endothelial to mesenchymal transition (EndMT), and (ii) cyclooxygenase (COX)-2 involved in the production of angiogenic and inflammatory mediators.Methods and Results: MPs were obtained from thrombin activated platelets of four obese and their matched non-obese women. MPs were analyzed by cytofluorimeter and protein content by liquid chromatography-mass spectrometry. MPs from obese women were not different in number but showed increased heterogeneity in size. In obese individuals, MPs containing mitochondria (mitoMPs) expressed lower CD41 levels and increased phosphatidylserine associated with enhanced Factor V representing a signature of a prothrombotic state. Proteomics analysis identified 44 proteins downregulated and three upregulated in MPs obtained from obese vs. non-obese women. A reduction in the proteins of the α-granular membrane and those involved in mitophagy and antioxidant defenses-granular membrane was detected in the MPs of obese individuals. MPs released from platelets of obese individuals were more prone to induce the expression of marker genes of EMT and EndMT when incubated with human colorectal cancer cells (HT29) and human cardiac microvascular endothelial cells (HCMEC), respectively. A protein, highly enhanced in obese MPs, was the pro-platelet basic protein with pro-inflammatory and tumorigenic actions. Exclusively MPs from obese women induced COX-2 in HCMEC.Conclusion: Platelet-derived MPs of obese women showed higher heterogeneity in size and contained different levels of proteins relevant to thrombosis and tumorigenesis. MPs from obese individuals presented enhanced capacity to cause changes in the expression of EMT and EndMT marker genes and to induce COX-2. These effects might contribute to the increased risk for the development of thrombosis and multiple malignancies in obesity.Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT01581801.

Influence of Cardiometabolic Risk Factors on Platelet Function

“…Weight reduction, by calorie restriction with or without exercise [106] or after gastrectomy, reduces PMP production. Interestingly, another study has recently shown that PMPs from obese subjects were not different in number if compared with non-obese subjects but, as supported by proteomics data, they showed greater heterogeneity in size and distribution with different levels of proteins relevant to thrombosis and tumorigenesis [107].…”

Extracellular Vesicles as Signaling Mediators and Disease Biomarkers across Biological Barriers

“…Due to their substantial stability, EVs circulate systemically and have been detected in basically all body fluids, including blood, urine, cerebrospinal fluid, saliva, milk, and tears [16,[42][43][44][45][46][47][48]. Moreover, there is clear indication that EVs can cross multiple biological barriers, as demonstrated by the finding of glial/neuronal EVs in the cerebrospinal fluid, blood, tears, and urine [44].…”

Aspirin Mitigated Tumor Growth in Obese Mice Involving Metabolic Inhibition

“…Evidence indicates that statins, metformin, and sodium-glucose cotransporter-2 inhibitors slow tumor growth and reverse the obesity-driven aggressiveness of cancer [1,2,4,5]. Additionally, platelet numbers, platelet activation, and platelet-derived microparticles are positively associated with obese individuals [6][7][8]. Pre-diagnostic high platelet counts indicate a poor prognosis for cancer patients, and play a role in the responsiveness to targeted therapy, radiotherapy, and chemotherapy [9][10][11][12][13][14].…”