PubMed · 7973778
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1994. Platelet pathophysiology.. https://pubmed.ncbi.nlm.nih.gov/7973778/
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OBJECTIVES: Platelet storage lesion (PSL) severely impairs platelet function during storage, presenting a major hurdle in transfusion medicine; however, the dynamic interplay between global proteomic changes and post-translational modifications (PTMs) underlying these functional deteriorations remains insufficiently characterized. Here, we report the first comprehensive multi-omics analysis integrating global proteomics, acetylomics, and succinylomics to dissect the molecular dynamics during platelet storage. METHODS: We performed quantification of global proteomics, acetylome and succinylome based on TMT-labeled LC-MS/MS analysis, combined with antibody-affinity enrichment and purification. Dynamic molecular changes and functional transformation of platelet were also characterized under proper conditions stored for 1, 3, 5, 7 days, respectively. RESULTS: We systematically characterized 3,609 proteins, 1,308 acetylation sites, and 1,947 succinylation sites across multiple storage time points (D1, D3, D5, D7). We distinct temporal patterns of post-translational modifications, with succinylation showing more extensive coverage than acetylation in platelets. Pathway enrichment analysis revealed extensive metabolic reprogramming involving complement activation, energy metabolism, and cellular detoxification processes. The identification of specific motif patterns provided mechanistic insights into the functional specificity of these modifications. Random forest machine learning identified 20 core regulatory proteins representing critical nodes in PSL development. Furthermore, we employed real - time quantitative polymerase chain reaction (RT - QPCR) to measure the expression levels of key genes related to platelet function and PTM - associated pathways. CONCLUSION: By mapping the interplay between proteomic abundance shifts and PTM dynamics, this study provides a multidimensional understanding of PSL, establishing a foundational framework for optimizing storage protocols and enhancing transfusion safety.
Calcium antagonists represent a chemically and pharmacologically diverse group of agents that function by modulating the transmembrane influx of Ca2+ into contractile cells. These compounds, widely used for the treatment of hypertension and angina, bind in a highly specific and reversible fashion to voltage-sensitive Ca2+ channels in vascular smooth muscle cells. A recent study raised concerns about the safety of certain calcium antagonists for treatment of hypertension in diabetic patients. The safety issue has not been resolved and is the subject of other articles in this supplement. However, a biologic mechanism has been proposed to rationalize the potentially deleterious effects of calcium antagonists in this group of patients. This mechanism is based on an assumption that the biochemical composition of cellular membranes in patients with diabetes is fundamentally different, leading to an abnormal increase in the membrane concentration of calcium antagonists and, hence, adverse pharmacologic effects. In support of this model, original research on the lipid composition of membranes from patients with diabetes was cited, along with our own published findings, showing that accumulation of calcium antagonists in membranes is influenced by the molar ratio of cholesterol to phospholipid (C:P). A careful review of these and other related scientific reports, however, yields no evidence for reproducible changes in the membrane C:P molar ratio of diabetic patients that would lead to adverse pharmacologic effects of calcium antagonists.
The platelet phosphotyrosine phosphatase (PTP) SHP-1 is tyrosine phosphorylated during thrombin-induced activation. Stimulation of platelets by the ionophore A23187 in the presence of CaCl2 induced a calpain dependent cleavage of SHP-1. SHP-1 proteolysis was undetectable during thrombin-induced stimulation. When SHP-1 was tyrosine phosphorylated by thrombin, further addition of A23187 failed to induce its cleavage. In the presence of tyrphostin to inhibit thrombin-induced SHP-1 tyrosine phosphorylation, SHP-1 was cleaved. Thus, only the tyrosine unphosphorylated form of SHP-1 was a substrate for calpain. A23187 induced the disappearance of all platelet phosphotyrosine proteins and a two-fold increase in PTP activity, both inhibited by pervanadate, a PTP inhibitor, but unaffected by calpeptin, a calpain inhibitor. The data show that SHP-1 is either tyrosine phosphorylated or cleaved by calpain, and suggest that SHP-1 cleavage does not contribute to A23187-induced PTP activity.