Platelet PMCA- and SERCA-type Ca2+ -ATPase expression in diabetes: a novel signature of abnormal megakaryocytopoiesis.
BACKGROUND
Previous studies have shown platelet Ca(2+) abnormalities in diabetes mellitus and some reports suggest abnormal platelet production. Platelet Ca(2+) homeostasis is controlled by a multi-Ca(2+)-ATPase system that includes two plasma membrane Ca(2+)-ATPase (PMCA) and seven sarco/endoplasmic reticulum Ca(2+)-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].


OBJECTIVE
To analyze the expression of major platelet Ca(2+)-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.
Chaabane
C
C
U689 INSERM, CRCIL, Hôpital Lariboisière, Paris Cedex 10, France.
Dally
S
S
Corvazier
E
E
Bredoux
R
R
Bobe
R
R
Ftouhi
B
B
Raies
A
A
Enouf
J
J
D000328:Adult; D000368:Aged; D001792:Blood Platelets / Q000378:metabolism*; D000252:Calcium-Transporting ATPases / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000097:blood* / Q000378:metabolism*; D005260:Female; D005343:Fibrinolytic Agents / Q000494:pharmacology; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D008533:Megakaryocytes / Q000378:metabolism; D008875:Middle Aged; D010865:Pilot Projects; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D034061:Thrombopoiesis
D005343:Fibrinolytic Agents; C507517:ATP2B4 protein, human; D053499:Plasma Membrane Calcium-Transporting ATPases; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506949:ATP2A3 protein, human; D000252:Calcium-Transporting ATPases