Platelet Sarcoplasmic Endoplasmic Reticulum Ca
            <sup>2+</sup>
            -ATPase and μ-Calpain Activity Are Altered in Type 2 Diabetes Mellitus and Restored by Rosiglitazone

Randriamboavonjy, Voahanginirina; Pistrosch, Frank; Bölck, Birgit; Schwinger, Robert H. G.; Dixit, Madhulika; Badenhoop, Klaus; Cohen, Richard A.; Busse, Rudi; Fleming, Ingrid

doi:10.1161/circulationaha.107.719807

Cited by 95 publications

(76 citation statements)

References 41 publications

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“…Because platelet agonists alone are poor activators of the protease, calpains were activated via the Ca 2ϩ -sensing receptor by increasing the extracellular concentration of Ca 2ϩ as described previously 12 or using the combination of Ca 2ϩ and ionomycin. The 2 approaches were also used to differentiate between -and m-calpain activation, both of which are expressed in platelets.…”

Section: Proteomic Analysis Of Platelets From Patients With and Withomentioning

confidence: 99%

“…This leads to the limited proteolysis of target proteins without eliciting full-blown platelet activation. 12 Several platelet proteins are known to be calpain substrates, including spectrin, adducin, talin, CD31, the myosin light-chain kinase, and N-ethylmaleimide-sensitivefactor attachment receptor (SNARE) proteins such as SNAP-23 and vesicle-associated membrane protein 3 (VAMP-3). 13 However, the spectrum of proteins that serve as pathophysiologically relevant targets of calpain in diabetic humans and their eventual role in the accelerated development of cardiovascular disease is unknown.…”

Section: Introductionmentioning

confidence: 99%

“…To determine which platelet proteins could be affected by calpain activation/inhibition in diabetic humans, we made use of the fact that peroxisome proliferator-activated receptor (PPAR)␥ agonist therapy increases SERCA-2 expression, normalizes platelet Ca 2ϩ , attenuates calpain activation, and prevents substrate cleavage. 12 …”

Section: Introductionmentioning

confidence: 99%

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Calpain inhibition stabilizes the platelet proteome and reactivity in diabetes

Randriamboavonjy

Isaak

Elgheznawy

et al. 2012

Blood

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Platelets from patients with diabetes are hyperreactive and demonstrate increased adhesiveness, aggregation, degranulation, and thrombus formation, processes that contribute to the accelerated development of vascular disease. Part of the problem seems to be dysregulated platelet Ca 2؉ signaling and the activation of calpains, which are Ca 2؉ -activated proteases that result in the limited proteolysis of substrate proteins and subsequent alterations in signaling. In the present study, we report that the activation of -and m-calpain in patients with type 2 diabetes has profound effects on the platelet proteome and have identified septin-5 and the integrin-linked kinase (ILK) as novel calpain substrates. The calpain-dependent cleavage of septin-5 disturbed its association with syntaxin-4 and promoted the secretion of ␣-granule contents, including TGF-␤ and CCL5. Calpain was also released by platelets and cleaved CCL5 to generate a variant with enhanced activity. Calpain activation also disrupted the ILK-PINCH-Parvin complex and altered platelet adhesion and spreading. In diabetic mice, calpain inhibition reversed the effects of diabetes on platelet protein cleavage, decreased circulating CCL5 levels, reduced plateletleukocyte aggregate formation, and improved platelet function. The results of the present study indicate that diabetesinduced platelet dysfunction is mediated largely by calpain activation and suggest that calpain inhibition may be an effective way of preserving platelet function and eventually decelerating atherothrombosis development. (Blood. 2012;120(2): 415-423) IntroductionCalpains are Ca 2ϩ -regulated cysteine proteases that are responsible for the limited proteolysis of target proteins, resulting in their modification (eg, activation, inhibition, or altered sensitivity to intracellular signals) rather than in their degradation. 1 In contrast to promiscuous degradative proteases, calpains cleave a relatively restricted set of protein substrates and use complex substrate recognition mechanisms involving primary and secondary structural features of target proteins to alter protein function and cellular signaling. 2 Platelets express -calpain (calpain 1) and m-calpain (calpain 2); named for the micro-and millimolar Ca 2ϩ concentrations, respectively, that are required to activate them in vitro. 3 Although Ca 2ϩ is the main regulator of calpain activity, protease activation does not simply occur in response to any stimuli that increases platelet Ca 2ϩ . Indeed, the regulation of proteolytic activity is complex and involves the association of calpain with a regulatory subunit, the endogenous inhibitor calpastatin, 4 other interacting proteins, 5 and binding to phospholipids. 6,7 Genetic deletion of m-calpain results in embryonic lethality, 8,9 but -calpain Ϫ/Ϫ mice are viable and demonstrate attenuated aggregation and clot retraction but normal bleeding times. 10 Mechanistically, the latter effects were attributed to the tyrosine dephosphorylation of platelet proteins because -calpain Ϫ/Ϫ platelets exh...

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Section: Proteomic Analysis Of Platelets From Patients With and Withomentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Calpain inhibition stabilizes the platelet proteome and reactivity in diabetes

Randriamboavonjy

Isaak

Elgheznawy

et al. 2012

Blood

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“…In a related development, Randriamboavonjy et al, (2008) also demonstrated that treatment of megakaryocytes and platelets with rosiglitazone upregulates SERCA2b.…”

Section: Rosiglitazone and Calcium Homeostasismentioning

confidence: 89%

Rosiglitazone and Cardiovascular Risk – A Review

Isa¹

2012

Bayero J. Pure App. Sci.

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The thiazolidinediones (TZDs) are a class of oral drugs used for the management of type 2 diabetes mellitus and act as ligands for the transcription factor Peroxisome Proliferator-Activated Receptor gamma (PPARγ). Rosiglitazone, an example of TZD, is an anti-diabetic agent acting as a potent insulin sensitizer and is used clinically to enhance insulin-stimulated glucose uptake in tissues. However, in spite of the beneficial effects of TZDs in management of type 2 diabetes, the safety of rosiglitazone has recently been called into question. The debate about the risks associated with rosiglitazone therapy heightened in 2007, when it was reported that rosiglitazone was associated with an increase risk of myocardial infarction and death from cardiovascular causes. The cardiovascular risk associated with rosiglitazone use remains to be further elucidated, but there are several reasonable hypotheses.

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“…La sobreexpresión de SERCA revirtió el efecto del ácido palmítico sobre la señaliza-ción de la insulina, indicando que la reducción de su expresión y de su actividad sería la causa de que el ácido palmítico induzca un estado de resistencia en las células endoteliales 71 . El tratamiento de las personas diabéticas con rosiglitazona, un fármaco antidiabético, incrementó la expresión de SERCA, restaurando la reducción de la expresión de la bomba observada en pacientes diabéticos con hiperglucemia alterada 72 . El empleo de la chaperona química TUDCA restaura la expresión y la actividad de la bomba SERCA en ratones obesos (ob/ ob) 73 .…”

Section: Papel De Los áCidos Grasos En El Estrés Del Retículo Endopláunclassified