Platelet PMCA‐ and SERCA‐type Ca2+‐ATPase expression in diabetes: a novel signature of abnormal megakaryocytopoiesis

Abstract

Summary. Background: Previous studies have shown platelet Ca2+ abnormalities in diabetes mellitus and some reports suggest abnormal platelet production. Platelet Ca2+ homeostasis is controlled by a multi‐Ca2+‐ATPase system that includes two plasma membrane Ca2+‐ATPase (PMCA) and seven sarco/endoplasmic reticulum Ca2+‐ATPase (SERCA) isoforms. In addition, we recently found that the expression of PMCA4b and SERCA3 isoforms may serve as new markers of abnormal megakaryocytopoiesis [Nurden P et al. Impaired megakaryocytopoiesis in type 2B von Willebrand disease with severe thrombocytopenia. Blood 2006; 108: 2587–95]. Aim: To analyze the expression of major platelet Ca2+‐ATPases in 27 patients with type 1 or type 2 diabetes (T1D or T2D) compared with normal donors. Methods: Investigation of protein and mRNA expressions of PMCA1b and PMCA4b, and SERCA2b, SERCA3a and SERCA3b, using specific Western blotting and reverse transcriptase‐polymerase chain reaction, respectively. Results: Remarkably, all patients with T1D were found to present a higher expression of PMCA4b protein (212% ± 28%; n = 10) and PMCA4b mRNA (155% ± 16%; n = 17), coupled with a higher expression of SERCA3b mRNA (165% ± 9%) in some cases. Patients with T2D (n = 10) were also studied for protein expression and were found to present similar major upregulation of the expression of PMCA4b protein (180% ± 28%; n = 10). Lastly, five of 10 patients with T1D were studied for PMCA4b expression after insulin treatment, with four of five recovering normal expression (96% ± 15%; n = 5). Conclusions: Compared with the expression of PMCA4b upon platelet maturation, platelets from diabetic patients exhibit similarities with immature megakaryocytes. Thus, this study reinforces the idea that abnormal megakaryocytopoiesis can provide additional insights into diabetes and could represent a novel therapeutic target for antithrombotic drugs.

Potential regulatory role of calsequestrin in platelet Ca2+ homeostasis and its association with platelet hyperactivity in diabetes mellitus

“…Next, we evaluated the Ca 2+ release response in Ca 2+ ‐free medium and Ca 2+ influx following the addition of 1 m m Ca 2+ induced by thrombin or ADP. As previously reported [4–7], both of the Ca 2+ signaling processes were significantly augmented in diabetic platelets (Fig. 3C,D).…”

The recovery of platelet cyclooxygenase activity explains interindividual variability in responsiveness to low‐dose aspirin in patients with and without diabetes

“…[15]. In the present study, MPV was the strongest predictor of the TXB 2 recovery slope in patients with diabetes, suggesting that the diabetic milieu may account for faster de novo synthesis of COX‐1 in the bone marrow progenitors or their accelerated turn‐over [31–33], as seen in essential thrombocythemia [14,15].…”

Endoplasmic-Reticulum Calcium Depletion and Disease

“…The direct stimulatory interaction of STIM1 with SERCA3 is impaired in type-2 diabetes (Lopez et al 2008), which can explain the increased plasma-membrane Ca 2þ entry, and the higher [Ca 2þ ] cyt at rest and during thrombin stimulation (Saavedra et al 2004). SERCA3b was upregulated in type-1 diabetes (Chaabane et al 2007). This isoform is involved in cell adhesion (Chaabane et al 2006) and its up-regulation can thus explain the increased adhesiveness in diabetic patients.…”