Inhibition of pyruvate dehydrogenase complex activity by 3-bromopyruvate affects blood platelets responses in type 2 diabetes
Hyperactivation of blood platelets is an essential factor in the pathomechanism of diabetes-evoked angiopathies. The aim of this work was to investigate whether blood platelets hyperactivation resulting from type 2 diabetic hyperglycaemia-increased pyruvate dehydrogenase complex activity and excessive acetyl-CoA accumulation may be brought to the normal range by the enzyme inhibitors.
Platelets were isolated from the blood of 9 type 2 diabetic patients and 10 healthy donors. Effects of 3-bromopyruvate and 3-nitropropionate on pyruvate dehydrogenase complex (PDHC) and succinate dehydrogenase activities, as well as levels of acetyl-CoA, ATP, thiobarbituric acid reactive species and aggregation were assessed in non-activated and thrombin-activated platelets.
In type 2 diabetic patients fasting plasma glucose and fructosamine levels were 61 and 64% higher, respectively, than in the healthy group (p < 0.001). In non-activated diabetic platelets PDHC activity, PDHC-E2, acetyl-CoA and ATP levels were 66, 70, 68 and 60%, higher, respectively, than in platelets from healthy controls (p < 0.01). 3-bromopyruvate (0.1 mM) decreased pyruvate dehydrogenase activity in healthy and diabetic platelets by 42% and 59%, respectively. Similar inhibitory effects were observed for acetyl-CoA and ATP levels, aggregation and TBARS accumulation rates. Succinate dehydrogenase activity was inhibited by 3-nitropropionate (10 mM) to 38 and 41% of control values in healthy and diabetic platelets, respectively, but affected neither function nor acetyl-CoA metabolism in platelets of both groups.
These data indicate that inhibition of pyruvate dehydrogenase excessive activity in diabetic platelets by 3-bromopyruvate may normalise their functional parameters through adjustment of acetyl-CoA/ATP levels to control values.
Keywords3-Bromopyruvate Acetyl-CoA ATP Blood platelets Pyruvate dehydrogenase complex TBARS Aggregation
Pyruvate dehydrogenase complex
Thiobarbituric acid reactive species
Tricarboxylic acid cycle
This work was supported by Medical University of Gdansk projects, ST-57, MN0116.
AM was responsible for conceptualization, validation, investigation, data curation, formal analysis, writing, supervision and project administration. KG was responsible for investigation and resources. HB was responsible for data curation, validation, and funding acquistation. MZ was resoponsible for statistical analysis. AS was responsible for conceptualization, formal analysis , writing and supervision.
Compliance with ethical standards
Conflict of interest
All the co-authors of the manuscript contributed to the presented manuscript. There are no circumstances that present a potential conflict of interest.
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