PDF herunterladen
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   *
1   INSERM Unité Mixte de Recherche–Santé 1176, Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France
,
Jose Javier Lopez   *
1   INSERM Unité Mixte de Recherche–Santé 1176, Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France
2   Departamento de Fisiología, Catedrático de Universidad, Universidad de Extremadura, Cáceres, Spain
,
Muriel Coupaye
3   Service des Explorations Fonctionnelles, Hôpital Louis Mourier, Assistance Publique–Hôpitaux de Paris, Colombes, France
4   Centre Intégré Nord Francilien de prise en charge de l'Obésité (CINFO), Paris, France
,
Kevin Zuber
5   Service de Recherche Clinique, Fondation Ophtalmologique A. de Rothschild, Paris, France
,
Yann Becker
1   INSERM Unité Mixte de Recherche–Santé 1176, Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France
,
Aurélie Kondratieff
1   INSERM Unité Mixte de Recherche–Santé 1176, Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France
,
Christelle Repérant
1   INSERM Unité Mixte de Recherche–Santé 1176, Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France
,
Marion Pépin
1   INSERM Unité Mixte de Recherche–Santé 1176, Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France
,
Laurence Salomon
5   Service de Recherche Clinique, Fondation Ophtalmologique A. de Rothschild, Paris, France
6   Département de Santé Publique, Hôpital Louis Mourier, Assistance Publique–Hôpitaux de Paris, Colombes, France
,
France Teillet
7   Service d'Hématologie et Transfusion, Hôpital Louis Mourier, Assistance Publique–Hôpitaux de Paris, Colombes, France
8   Université Paris Diderot, Sorbonne Paris Cité, Paris, France
,
Simon Msika
8   Université Paris Diderot, Sorbonne Paris Cité, Paris, France
9   Service de Chirurgie Digestive, Hôpital Louis Mourier, Assistance Publique–Hôpitaux de Paris, Colombes, France
,
Cécile V. Denis
1   INSERM Unité Mixte de Recherche–Santé 1176, Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France
,
Dominique de Prost
7   Service d'Hématologie et Transfusion, Hôpital Louis Mourier, Assistance Publique–Hôpitaux de Paris, Colombes, France
8   Université Paris Diderot, Sorbonne Paris Cité, Paris, France
,
Jean-Philippe Rosa
1   INSERM Unité Mixte de Recherche–Santé 1176, Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France
,
Régis Bobe   **
1   INSERM Unité Mixte de Recherche–Santé 1176, Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France
,
Alain Stépanian   **
8   Université Paris Diderot, Sorbonne Paris Cité, Paris, France
10   Service d'Hématologie Biologique, Hôpital Lariboisière, Assistance Publique–Hôpitaux de Paris, Paris, France
11   EA3515 Institut Universitaire d'Hématologie, Hôpital Saint Louis, Paris-Diderot, Paris, France
› Institutsangaben Funding This work was supported by Grant CRC 10018 (Contrat de Recherche Clinique) from Assistance Publique–Hôpitaux de Paris. J.J.L. is supported by contract Juan de la Cierva (Ministerio Economia y Competitividad, Spain) JCI-2012–12934, MINECO (Grants BFU2013–45564-C2–1-P/2-P and BFU2016–74932-C2–1-P/2-P) and Junta de Extremadura-FEDER (Fondo Europeo de Desarrollo Regional Grants IB16046 and GR15029).
Weitere Informationen

Publikationsverlauf

22. August 2018

29. November 2018

Publikationsdatum:
16. Januar 2019 (online)

Auch verfügbar auf
    Lizenzen und Reprints

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

* These authors contributed equally to this work.


** These authors are joint senior authors on this work.


Supplementary Material

 

  • References

  • 1 Van Gaal LF, Mertens IL, De Block CE. Mechanisms linking obesity with cardiovascular disease. Nature 2006; 444 (7121): 875-880
    Suche in Google Scholar
  • 2 World Health Organization. Obesity: preventing and managing the global epidemic. Report of a WHO Consultation; 2000. WHO Technical Report Series 894
    PubMed
  • 3 World Health Organization Fact Sheet N311. Obesity and overweight; 2018
    PubMed
  • 4 Wolk R, Berger P, Lennon RJ, Brilakis ES, Somers VK. Body mass index: a risk factor for unstable angina and myocardial infarction in patients with angiographically confirmed coronary artery disease. Circulation 2003; 108 (18) 2206-2211
    CrossrefPubMedSuche in Google Scholar
  • 5 Yusuf S, Hawken S, Ounpuu S. , et al; INTERHEART Study Investigators. Obesity and the risk of myocardial infarction in 27,000 participants from 52 countries: a case-control study. Lancet 2005; 366 (9497): 1640-1649
    CrossrefPubMedSuche in Google Scholar
  • 6 Rexrode KM, Hennekens CH, Willett WC. , et al. A prospective study of body mass index, weight change, and risk of stroke in women. JAMA 1997; 277 (19) 1539-1545
    CrossrefPubMedSuche in Google Scholar
  • 7 Suk SH, Sacco RL, Boden-Albala B. , et al; Northern Manhattan Stroke Study. Abdominal obesity and risk of ischemic stroke: the Northern Manhattan Stroke Study. Stroke 2003; 34 (07) 1586-1592
    CrossrefPubMedSuche in Google Scholar
  • 8 Stein PD, Beemath A, Olson RE. Obesity as a risk factor in venous thromboembolism. Am J Med 2005; 118 (09) 978-980
    CrossrefPubMedSuche in Google Scholar
  • 9 Parkin L, Sweetland S, Balkwill A, Green J, Reeves G, Beral V. ; Million Women Study Collaborators. Body mass index, surgery, and risk of venous thromboembolism in middle-aged women: a cohort study. Circulation 2012; 125 (15) 1897-1904
    CrossrefPubMedSuche in Google Scholar
  • 10 Blokhin IO, Lentz SR. Mechanisms of thrombosis in obesity. Curr Opin Hematol 2013; 20 (05) 437-444
    CrossrefPubMedSuche in Google Scholar
  • 11 Anfossi G, Russo I, Trovati M. Platelet dysfunction in central obesity. Nutr Metab Cardiovasc Dis 2009; 19 (06) 440-449
    CrossrefPubMedSuche in Google Scholar
  • 12 Santilli F, Vazzana N, Liani R, Guagnano MT, Davì G. Platelet activation in obesity and metabolic syndrome. Obes Rev 2012; 13 (01) 27-42
    CrossrefPubMedSuche in Google Scholar
  • 13 Santilli F, Simeone P, Liani R, Davì G. Platelets and diabetes mellitus. Prostaglandins Other Lipid Mediat 2015; 120: 28-39
    PubMedSuche in Google Scholar
  • 14 Papp B, Enyedi A, Pászty K. , et al. Simultaneous presence of two distinct endoplasmic-reticulum-type calcium-pump isoforms in human cells. Characterization by radio-immunoblotting and inhibition by 2,5-di-(t-butyl)-1,4-benzohydroquinone. Biochem J 1992; 288 (Pt 1): 297-302
    CrossrefPubMedSuche in Google Scholar
  • 15 Brini M, Carafoli E. Calcium pumps in health and disease. Physiol Rev 2009; 89 (04) 1341-1378
    CrossrefPubMedSuche in Google Scholar
  • 16 Elaïb Z, Adam F, Berrou E. , et al. Full activation of mouse platelets requires ADP secretion regulated by SERCA3 ATPase-dependent calcium stores. Blood 2016; 128 (08) 1129-1138
    CrossrefPubMedSuche in Google Scholar
  • 17 López JJ, Redondo PC, Salido GM, Pariente JA, Rosado JA. Two distinct Ca2+ compartments show differential sensitivity to thrombin, ADP and vasopressin in human platelets. Cell Signal 2006; 18 (03) 373-381
    CrossrefPubMedSuche in Google Scholar
  • 18 López JJ, Camello-Almaraz C, Pariente JA, Salido GM, Rosado JA. Ca2+ accumulation into acidic organelles mediated by Ca2+- and vacuolar H+-ATPases in human platelets. Biochem J 2005; 390 (Pt 1): 243-252
    CrossrefPubMedSuche in Google Scholar
  • 19 Angiolillo DJ, Fernández-Ortiz A, Bernardo E. , et al. Platelet aggregation according to body mass index in patients undergoing coronary stenting: should clopidogrel loading-dose be weight adjusted?. J Invasive Cardiol 2004; 16 (04) 169-174
    PubMedSuche in Google Scholar
  • 20 Sowers JR. Obesity as a cardiovascular risk factor. Am J Med 2003; 115 (Suppl 8A): 37S-41S
    CrossrefPubMedSuche in Google Scholar
  • 21 Beavers CJ, Heron P, Smyth SS, Bain JA, Macaulay TE. Obesity and antiplatelets-does one size fit all?. Thromb Res 2015; 136 (04) 712-716
    CrossrefPubMedSuche in Google Scholar
  • 22 Stepanian A, Bourguignat L, Hennou S. , et al. Microparticle increase in severe obesity: not related to metabolic syndrome and unchanged after massive weight loss. Obesity (Silver Spring) 2013; 21 (11) 2236-2243
    CrossrefPubMedSuche in Google Scholar
  • 23 Dellas C, Schäfer K, Rohm I. , et al. Absence of leptin resistance in platelets from morbidly obese individuals may contribute to the increased thrombosis risk in obesity. Thromb Haemost 2008; 100 (06) 1123-1129
    Thieme ConnectPubMedSuche in Google Scholar
  • 24 Varadi A, Lebel L, Hashim Y, Mehta Z, Ashcroft SJ, Turner R. Sequence variants of the sarco(endo)plasmic reticulum Ca(2+)-transport ATPase 3 gene (SERCA3) in Caucasian type II diabetic patients (UK Prospective Diabetes Study 48). Diabetologia 1999; 42 (10) 1240-1243
    CrossrefPubMedSuche in Google Scholar
  • 25 Hotamisligil GS. Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell 2010; 140 (06) 900-917
    CrossrefPubMedSuche in Google Scholar
  • 26 Fu S, Yang L, Li P. , et al. Aberrant lipid metabolism disrupts calcium homeostasis causing liver endoplasmic reticulum stress in obesity. Nature 2011; 473 (7348): 528-531
    PubMedSuche in Google Scholar
  • 27 Li SY, Yang X, Ceylan-Isik AF, Du M, Sreejayan N, Ren J. Cardiac contractile dysfunction in Lep/Lep obesity is accompanied by NADPH oxidase activation, oxidative modification of sarco(endo)plasmic reticulum Ca2+-ATPase and myosin heavy chain isozyme switch. Diabetologia 2006; 49 (06) 1434-1446
    CrossrefPubMedSuche in Google Scholar
  • 28 Wu ZK, Wang JJ, Wang T. , et al. Clopidogrel resistance response in patients with coronary artery disease and metabolic syndrome: the role of hyperglycemia and obesity. J Geriatr Cardiol 2015; 12 (04) 378-382
    PubMedSuche in Google Scholar
  • 29 Darlington A, Tello-Montoliu A, Rollini F. , et al. Pharmacodynamic effects of standard dose prasugrel versus high dose clopidogrel in non-diabetic obese patients with coronary artery disease. Thromb Haemost 2014; 111 (02) 258-265
    Thieme ConnectPubMedSuche in Google Scholar
  • 30 Norgard NB, Monte SV. Obesity and inflammation and altered clopidogrel pharmacokinetics and pharmacodynamics. Drug Metab Lett 2017; 11 (01) 3-13
    PubMedSuche in Google Scholar
  • 31 Haas S, Hansson J, Klimmeck D. , et al. Inflammation-induced emergency megakaryopoiesis driven by hematopoietic stem cell-like megakaryocyte progenitors. Cell Stem Cell 2015; 17 (04) 422-434
    CrossrefPubMedSuche in Google Scholar
  • 32 Nurden P, Debili N, Vainchenker W. , et al. Impaired megakaryocytopoiesis in type 2B von Willebrand disease with severe thrombocytopenia. Blood 2006; 108 (08) 2587-2595
    CrossrefPubMedSuche in Google Scholar
  • 33 Mountian I, Manolopoulos VG, De Smedt H, Parys JB, Missiaen L, Wuytack F. Expression patterns of sarco/endoplasmic reticulum Ca(2+)-ATPase and inositol 1,4,5-trisphosphate receptor isoforms in vascular endothelial cells. Cell Calcium 1999; 25 (05) 371-380
    CrossrefPubMedSuche in Google Scholar
  • 34 Lipskaia L, Hulot JS, Lompré AM. Role of sarco/endoplasmic reticulum calcium content and calcium ATPase activity in the control of cell growth and proliferation. Pflugers Arch 2009; 457 (03) 673-685
    CrossrefPubMedSuche in Google Scholar
  • 35 Raoux L, Moszkowicz D, Vychnevskaia K. , et al. Effect of bariatric surgery-induced weight loss on platelet count and mean platelet volume: a 12-month follow-up study. Obes Surg 2017; 27 (02) 387-393
    CrossrefPubMedSuche in Google Scholar
  • 36 Angiolillo DJ, Fernandez-Ortiz A, Bernardo E. , et al. Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives. J Am Coll Cardiol 2007; 49 (14) 1505-1516
    CrossrefPubMedSuche in Google Scholar