Platelet sarcoplasmic endoplasmic reticulum Ca2+-ATPase and mu-calpain activity are altered in type 2 diabetes mellitus and restored by rosiglitazone.
BACKGROUND
Platelets from patients with type 2 diabetes mellitus display hyperaggregability and increased thrombogenic potential.


RESULTS
In platelets from patients with type 2 diabetes mellitus, we found enhanced tyrosine nitration and inactivation of the sarcoplasmic endoplasmic reticulum Ca2+-ATPase (SERCA-2), elevated platelet [Ca2+]i, and activation of mu-calpain. The tyrosine nitration of SERCA-2 and the activation of mu-calpain in vitro in platelets from healthy volunteers could be evoked in vitro by peroxynitrite. Platelet endothelial cell adhesion molecule-1 was identified as a mu-calpain substrate; its in vitro degradation was stimulated by peroxynitrite and prevented by calpain inhibitors. Calpain activation also was linked to hyperresponsiveness to thrombin and the loss of platelet sensitivity to nitric oxide synthase inhibitors. Platelets from patients with type 2 diabetes mellitus (hemoglobin A1c >6.6%) contained little or no intact platelet endothelial cell adhesion molecule-1, whereas degradation products were detectable. The peroxisome proliferator-activated receptor-gamma agonist rosiglitazone increased SERCA-2 expression in megakaryocytes, and treating patients with type 2 diabetes mellitus with rosiglitazone for 12 weeks increased platelet SERCA-2 expression and Ca2+-ATPase activity, decreased SERCA-2 tyrosine nitration, and normalized platelet [Ca2+]i. Rosiglitazone also reduced mu-calpain activity, normalized platelet endothelial cell adhesion molecule-1 levels, and partially restored platelet sensitivity to nitric oxide synthase inhibition.


CONCLUSIONS
These data identify megakaryocytes/platelets as additional cellular targets for peroxisome proliferator-activated receptor-gamma agonists and highlight potential benefits of rosiglitazone therapy in cardiovascular diseases.
Randriamboavonjy
Voahanginirina
V
Vascular Signaling Group, and Institut für Kardiovaskuläre Physiologie, Johann Wolfgang Goethe-Universität, Frankfurt, Germany.
Pistrosch
Frank
F
Bölck
Birgit
B
Schwinger
Robert H G
RH
Dixit
Madhulika
M
Badenhoop
Klaus
K
Cohen
Richard A
RA
Busse
Rudi
R
Fleming
Ingrid
I
D000328:Adult; D000368:Aged; D001792:Blood Platelets / Q000378:metabolism* / Q000473:pathology; D002154:Calpain / Q000378:metabolism*; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000188:drug therapy*; D005260:Female; D006801:Humans; D008297:Male; D008533:Megakaryocytes / Q000187:drug effects / Q000201:enzymology; D008875:Middle Aged; D009574:Nitro Compounds; D047495:PPAR gamma / Q000819:agonists; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D000077154:Rosiglitazone; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism*; D045162:Thiazolidinediones / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use
D009574:Nitro Compounds; D047495:PPAR gamma; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D002154:Calpain; C449002:mu-calpain; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases