Obesity with insulin resistance increase thrombosis in wild-type and bone marrow-transplanted Zucker fatty rats

 

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Summary

Obesity induces metabolic and inflammatory alterations that contribute to the presentation of cardiovascular events. Although obesity is a risk factor for atherosclerosis and vascular disease, its role on thrombosis has not been directly explored. Therefore, we aimed to investigate the mechanisms by which obesity affects thrombosis. Thrombus formation was monitored by real-time intravital microscopy in Zucker Fatty rats (ZF) and lean controls (ZC). Crossed bone marrow (BM) transplants between ZF and ZC were performed. Intravital microscopy showed that ZF had significantly shorter occlusion times (OTs) than ZC, reflecting a three-fold higher thrombotic risk. Transplantation of ZC-BM to ZF recipients significantly reduced thrombosis, reducing their thrombotic risk to one third of that observed in non-transplanted ZF. Wild-type ZF showed increased platelet counts and increased platelet size compared to wild-type ZC and platelet number remained unaltered after transplantation. However, ZF-BM produced a significant increase in platelet size in ZC recipients. Thrombotic risk was found to be inversely correlated with both weight and insulin levels and directly correlated to HOMA-IR, while platelet number and size were directly correlated with weight. Thus, our data shows that obesity with insulin resistance significantly increases thrombosis and that alterations in BM-derived cells significantly contribute to this prothrombotic behaviour. Importantly, the reduction of insulin resistance was associated with reduced thrombotic risk even in the presence of obesity.

• References

• 1 Fontaine KR, Redden DT, Wang C. et al. Years of life lost due to obesity. J Am Med Assoc 2003; 289: 187-193.
  CrossrefPubMedGoogle Scholar
• 2 Hu FB, Willett WC, Li T. et al. Adiposity as Compared with Physical Activity in Predicting Mortality among Women. N Engl J Med 2004; 351: 2694-2703.
  CrossrefPubMedGoogle Scholar
• 3 Poirier P, Giles TD, Bray GA. et al. Obesity and Cardiovascular Disease: Pathophysiology, Evaluation, and Effect of Weight Loss. Circulation 2006; 113: 898-918.
  CrossrefPubMedGoogle Scholar
• 4 Yusuf S, Hawken S, Ounpuu S. et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 2004; 364: 937-952.
  CrossrefPubMedGoogle Scholar
• 5 Darvall KA, Sam RC, Silverman SH. et al. Obesity and thrombosis. Eur J Vasc Endovasc Surg 2007; 33: 223-233.
  CrossrefPubMedGoogle Scholar
• 6 Lavie CJ, Milani RV, Ventura HO. Obesity and cardiovascular disease: risk factor, paradox, and impact of weight loss. J Am Coll Cardiol 2009; 53: 1925-1932.
  CrossrefPubMedGoogle Scholar
• 7 Alberti KG, Eckel RH, Grundy SM. et al. Harmonising the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 2009; 120: 1640-1645.
  CrossrefPubMedGoogle Scholar
• 8 Mottillo S, Filion KB, Genest J. et al. The metabolic syndrome and cardiovascular risk a systematic review and meta-analysis. J Am Coll Cardiol 2010; 56: 1113-1132.
  CrossrefPubMedGoogle Scholar
• 9 Onat A. Metabolic syndrome: nature, therapeutic solutions and options. Expert Opin Pharmacother 2011; 12: 1887-1900.
  CrossrefPubMedGoogle Scholar
• 10 Ford ES, Li C, Sattar N. Metabolic syndrome and incident diabetes: current state of the evidence. Diabetes Care 2008; 31: 1898-1904.
  CrossrefPubMedGoogle Scholar
• 11 Konstantinides S, Schafer K, Koschnick S. et al. Leptin-dependent platelet aggregation and arterial thrombosis suggests a mechanism for atherothrombotic disease in obesity. J Clin Invest 2001; 108: 1533-1540.
  CrossrefPubMedGoogle Scholar
• 12 Nakata M, Yada T, Soejima N. et al. Leptin promotes aggregation of human platelets via the long form of its receptor. Diabetes 1999; 48: 426-429.
  CrossrefPubMedGoogle Scholar
• 13 Alessi MC, Lijnen HR, Bastelica D. et al. Adipose tissue and atherothrombosis. Pathophysiol Haemost Thromb 2003; 33: 290-297.
  CrossrefPubMedGoogle Scholar
• 14 McDermott MM, Green D, Greenland P. et al. Relation of levels of haemostatic factors and inflammatory markers to the ankle brachial index. Am J Cardiol 2003; 92: 194-199.
  PubMedGoogle Scholar
• 15 Reiner AP, Siscovick DS, Rosendaal FR. Haemostatic risk factors and arterial thrombotic disease. Thromb Haemost 2001; 85: 584-595.
  Article in Thieme ConnectPubMedGoogle Scholar
• 16 Shimomura I, Funahashi T, Takahashi M. et al. Enhanced expression of PAI-1 in visceral fat: possible contributor to vascular disease in obesity. Nat Med 1996; 02: 800-803.
  CrossrefPubMedGoogle Scholar
• 17 Berg AH, Scherer PE. Adipose tissue, inflammation, and cardiovascular disease. Circ Res 2005; 96: 939-949.
  CrossrefPubMedGoogle Scholar
• 18 Furukawa S, Fujita T, Shimabukuro M. et al. Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest 2004; 114: 1752-1761.
  CrossrefPubMedGoogle Scholar
• 19 Higdon JV, Frei B. Obesity and oxidative stress: a direct link to CVD?. Arterioscler Thromb Vasc Biol 2003; 23: 365-367.
  CrossrefPubMedGoogle Scholar
• 20 Oáate B, Vilahur G, Ferrer-Lorente R. et al. The subcutaneous adipose tissue reservoir of functionally active stem cells is reduced in obese patients. FASEB J 2012; 26: 4327-4336.
  CrossrefPubMedGoogle Scholar
• 21 Nilsson C, Raun K, Yan F-F. , et al. Laboratory animals as surrogate models of human obesity. Acta Pharmacol Sin 2012; 33: 173-181.
  CrossrefPubMedGoogle Scholar
• 22 Phillips MS, Liu Q, Hammond HA. et al. Leptin receptor missense mutation in the fatty Zucker rat. Nat Genet 1996; 13: 18-19.
  CrossrefPubMedGoogle Scholar
• 23 White BD, Martin RJ. Evidence for a central mechanism of obesity in the Zucker rat: role of neuropeptide Y and leptin. Proc Soc Exp Biol Med 1997; 214: 222-232.
  CrossrefPubMedGoogle Scholar
• 24 Hajer GR, van Haeften TW, Visseren FL. Adipose tissue dysfunction in obesity, diabetes, and vascular diseases. Eur Heart J 2008; 29: 2959-2971.
  CrossrefPubMedGoogle Scholar
• 25 Hernández Vera R, Vilahur G, Ferrer-Lorente R. et al. Platelets derived from the bone marrow of diabetic animals show dysregulated endoplasmic reticulum stress proteins that contribute to increased thrombosis. Arterioscler Thromb Vasc Biol 2012; 32: 2141-2148.
  CrossrefPubMedGoogle Scholar
• 26 Bath PM, Butterworth RJ. Platelet size: measurement, physiology and vascular disease. Blood Coagul Fibrinolysis 1996; 07: 157-161.
  CrossrefPubMedGoogle Scholar
• 27 Greisenegger S, Endler G, Hsieh K. et al. Is elevated mean platelet volume associated with a worse outcome in patients with acute ischemic cerebrovascular events?. Stroke 2004; 35: 1688-1691.
  CrossrefPubMedGoogle Scholar
• 28 Martin JF, Trowbridge EA, Salmon G. et al. The biological significance of platelet volume: its relationship to bleeding time, platelet thromboxane B2 production and megakaryocyte nuclear DNA concentration. Thromb Res 1983; 32: 443-460.
  CrossrefPubMedGoogle Scholar
• 29 Bavbek N, Kargili A, Kaftan O. et al. Elevated concentrations of soluble adhesion molecules and large platelets in diabetic patients: are they markers of vascular disease and diabetic nephropathy?. Clin Appl Thromb Haemost 2007; 13: 391-397.
  CrossrefPubMedGoogle Scholar
• 30 Watala C, Boncler M, Gresner P. Blood platelet abnormalities and pharmacological modulation of platelet reactivity in patients with diabetes mellitus. Pharmacol Rep 2005; 57 Suppl 42-58.
  PubMedGoogle Scholar
• 31 Gasparyan AY, Ayvazyan L, Mikhailidis DP. et al. Mean platelet volume: a link between thrombosis and inflammation?. Curr Pharm Des 2011; 17: 47-58.
  CrossrefPubMedGoogle Scholar
• 32 Ishibashi T, Kimura H, Uchida T. et al. Human interleukin 6 is a direct promoter of maturation of megakaryocytes in vitro. Proc Natl Acad Sci USA 1989; 86: 5953-5957.
  CrossrefPubMedGoogle Scholar
• 33 Kaushansky K. The molecular mechanisms that control thrombopoiesis. J Clin Invest 2005; 115: 3339-3347.
  CrossrefPubMedGoogle Scholar
• 34 Yudkin JS, Kumari M, Humphries SE. et al. Inflammation, obesity, stress and coronary heart disease: is interleukin-6 the link?. Atherosclerosis 2000; 148: 209-214.
  CrossrefPubMedGoogle Scholar
• 35 Heilbronn LK, Noakes M, Clifton PM. Energy restriction and weight loss on very-low-fat diets reduce C-reactive protein concentrations in obese, healthy women. Arterioscler Thromb Vasc Biol 2001; 21: 968-970.
  CrossrefPubMedGoogle Scholar
• 36 Nicoletti G, Giugliano G, Pontillo A. et al. Effect of a multidisciplinary program of weight reduction on endothelial functions in obese women. J Endocrinol Invest 2003; 26: RC5-8.
  CrossrefPubMedGoogle Scholar
• 37 Kaser A, Brandacher G, Steurer W. et al. Interleukin-6 stimulates thrombopoiesis through thrombopoietin: role in inflammatory thrombocytosis. Blood 2001; 98: 2720-2725.
  CrossrefPubMedGoogle Scholar
• 38 van der Loo B, Martin JF. A role for changes in platelet production in the cause of acute coronary syndromes. Arterioscler Thromb Vasc Biol 1999; 19: 672-679.
  CrossrefPubMedGoogle Scholar
• 39 Grant PJ. Diabetes mellitus as a prothrombotic condition. J Intern Med 2007; 262: 157-172.
  CrossrefPubMedGoogle Scholar
• 40 Hess K, Grant PJ. Inflammation and thrombosis in diabetes. Thromb Haemost 2011; 105 (Suppl. 01) S43-54
  Article in Thieme ConnectPubMedGoogle Scholar
• 41 Vazzana N, Ranalli P, Cuccurullo C. et al. Diabetes mellitus and thrombosis. Thromb Res 2012; 129: 371-377.
  CrossrefPubMedGoogle Scholar