Platelet Functions are Decreased in Obesity and Restored after Weight Loss: Evidence for a Role of the SERCA3-Dependent ADP Secretion Pathway

Ziane Elaïb; Jose Javier Lopez; Muriel Coupaye; Kevin Zuber; Yann Becker; Aurélie Kondratieff; Christelle Repérant; Marion Pépin; Laurence Salomon; France Teillet; Simon Msika; Cécile V. Denis; Dominique de Prost; Jean-Philippe Rosa; Régis Bobe; Alain Stépanian

doi:10.1055/s-0038-1677033

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2019; 119(03): 384-396
DOI: 10.1055/s-0038-1677033

Cellular Haemostasis and Platelets

Georg Thieme Verlag KG Stuttgart · New York

Platelet Functions are Decreased in Obesity and Restored after Weight Loss: Evidence for a Role of the SERCA3-Dependent ADP Secretion Pathway

Ziane Elaïb^*

¹INSERM Unité Mixte de Recherche–Santé 1176, Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France

,

Jose Javier Lopez^*

¹INSERM Unité Mixte de Recherche–Santé 1176, Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France

²Departamento de Fisiología, Catedrático de Universidad, Universidad de Extremadura, Cáceres, Spain

,

Muriel Coupaye

³Service des Explorations Fonctionnelles, Hôpital Louis Mourier, Assistance Publique–Hôpitaux de Paris, Colombes, France

⁴Centre Intégré Nord Francilien de prise en charge de l'Obésité (CINFO), Paris, France

,

Kevin Zuber

⁵Service de Recherche Clinique, Fondation Ophtalmologique A. de Rothschild, Paris, France

,

Yann Becker

¹INSERM Unité Mixte de Recherche–Santé 1176, Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France

,

Aurélie Kondratieff

¹INSERM Unité Mixte de Recherche–Santé 1176, Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France

,

Christelle Repérant

¹INSERM Unité Mixte de Recherche–Santé 1176, Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France

,

Marion Pépin

¹INSERM Unité Mixte de Recherche–Santé 1176, Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France

,

Laurence Salomon

⁵Service de Recherche Clinique, Fondation Ophtalmologique A. de Rothschild, Paris, France

⁶Département de Santé Publique, Hôpital Louis Mourier, Assistance Publique–Hôpitaux de Paris, Colombes, France

,

France Teillet

⁷Service d'Hématologie et Transfusion, Hôpital Louis Mourier, Assistance Publique–Hôpitaux de Paris, Colombes, France

⁸Université Paris Diderot, Sorbonne Paris Cité, Paris, France

,

Simon Msika

⁸Université Paris Diderot, Sorbonne Paris Cité, Paris, France

⁹Service de Chirurgie Digestive, Hôpital Louis Mourier, Assistance Publique–Hôpitaux de Paris, Colombes, France

,

Cécile V. Denis

¹INSERM Unité Mixte de Recherche–Santé 1176, Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France

,

Dominique de Prost

⁷Service d'Hématologie et Transfusion, Hôpital Louis Mourier, Assistance Publique–Hôpitaux de Paris, Colombes, France

⁸Université Paris Diderot, Sorbonne Paris Cité, Paris, France

,

Jean-Philippe Rosa

¹INSERM Unité Mixte de Recherche–Santé 1176, Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France

,

Régis Bobe^**

¹INSERM Unité Mixte de Recherche–Santé 1176, Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France

,

Alain Stépanian^**

⁸Université Paris Diderot, Sorbonne Paris Cité, Paris, France

¹⁰Service d'Hématologie Biologique, Hôpital Lariboisière, Assistance Publique–Hôpitaux de Paris, Paris, France

¹¹EA3515 Institut Universitaire d'Hématologie, Hôpital Saint Louis, Paris-Diderot, Paris, France

› Author Affiliations

Abstract

In obesity, platelets are described as hyperactive, mainly based on increased platelet size and presence of pro-thrombotic plasmatic molecules. We explored platelet functions, including calcium signalling in obesity, and the effect of weight loss. We included 40 obese patients (women with body mass index [BMI] of ≥ 35 kg/m²) who were to undergo gastric bypass surgery and 40 healthy lean subjects (women with BMI of < 25 kg/m²) as a control group. Approximately 1 year after surgery, the obese patients lost weight (75% had a BMI < 35 kg/m²). They were explored a second time with the same healthy control for the same platelet experiments. Compared with controls, obese patients' platelets displayed reduced sensitivity to thrombin (aggregation EC₅₀ increased by 1.9 ± 0.3-fold, p = 0.005) and a lower Ca²⁺ response (70 ± 7% decrease, p < 10⁻⁴). In 17 pairs of patients, we performed additional experiments: in obese patients' platelets, thrombin-induced αIIbβ3 activation was significantly lower (p = 0.003) and sarco-endoplasmic reticulum Ca²⁺ATPase (SERCA3) expression was decreased (48 ± 6% decrease, p < 10⁻⁴). These differences were abolished after weight loss. Interestingly, pharmacological inhibition of SERCA3 activity in control group's platelets mimicked similar alterations than in obese patients' platelets and was associated with defective adenosine diphosphate (ADP) secretion. Addition of ADP to agonist restored platelet functions in obese patients and in SERCA3-inhibited control platelets (five experiments) confirming the direct involvement of the SERCA3-dependent ADP secretion pathway. This is the first study demonstrating that platelets from obese patients are hypo-reactive, due to a deficiency of SERCA3-dependent ADP secretion. Weight loss restores SERCA3 activity and subsequent calcium signalling, αIIbβ3 activation, platelet aggregation and ADP secretion.

Keywords

platelets - obesity - SERCA3 - bariatric surgery - calcium

Full Text

References

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Supplementary Material

Supplementary Material