Abstract
Endothelial function (EnF) is impaired in patients with diabetes mellitus (DM) due in large part to an increase in oxidative stress. Haptoglobin (Hp) is a potent antioxidant protein which is encoded by two different alleles (1 and 2) with the Hp 1 protein being a superior antioxidant to the Hp 2 protein. We hypothesized that DM individuals with the Hp 2-2 genotype would have greater endothelial dysfunction as compared to DM individuals with the Hp 1-1 genotype. We studied EnF in 16 Hp 2-2, 14 Hp 1-1 DM individuals and 14 healthy subjects. DM patients’ groups were matched in terms of age, cardiovascular risk factors and metabolic characteristics. EnF was assessed using post-ischemic reactive hyperemia and strain gauge plethysmography and expressed either as the maximal flow after the ischemic period or as the area under the flow–time curve (AUC). We showed that EnF indices, AUC and maximal flow, were also higher in the healthy and Hp 1-1 groups compared with Hp 2-2 genotype group (615 ± 60 and 600 ± 40 vs. 450 ± 50 ml dl−1, 29 ± 2.6 and 25 ± 3 vs. 14 ± 1.8 ml min−1 dl−1, P < 0.003 and P < 0.05, for AUC and maximal flow, one-way ANOVA, respectively). We concluded that Hp 2-2 diabetic patients had a worse EnF than controls and Hp 1-1 diabetic subjects.
Abbreviations
- EnF:
-
Endothelial function
- Hp:
-
Haptoglobin phenotype
- TOD:
-
Target organ damage
- AUC:
-
Area under the flow–time curve
References
Asleh R, Guetta J, Kalet-Litman S, Miller-Lotan R, Levy AP (2005) Haptoglobin genotype- and diabetes-dependent differences in iron-mediated oxidative stress in vitro and in vivo. Circ Res 96:435–441. doi:10.1161/01.RES.0000156653.05853.b9
Bamm VV, Tsemakhovich VA, Shaklai M, Shaklai N (2004) Haptoglobin phenotypes differ in their ability to inhibit heme transfer from hemoglobin to LDL. Biochemistry 43:3899–3906. doi:10.1021/bi0362626
Casino PR, Kilcoyne CM, Quyyumi AA, Hoeg JM, Panza JA (1993) The role of nitric oxide in endothelium-dependent vasodilation of hypercholesterolemic patients. Circulation 88:2541–2547
Corretti MC, Anderson TJ, Benjamin EJ, Celermajer D, Charbonneau F, Creager MA, Deanfield J, Drexler H, Gerhard-Herman M, Herrington D, Vallance P, Vita J, Vogel R (2002) Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol 39:257–265. doi:10.1016/S0735-1097(01)01746-6
Cosentino F, Hishikawa K, Katusic ZS, Luscher TF (1997) High glucose increases nitric oxide synthase expression and superoxide anion generation in human aortic endothelial cells. Circulation 96:25–28
Gryglewski RJ, Palmer RM, Moncada S (1986) Superoxide anion is involved in the breakdown of endothelium-derived vascular relaxing factor. Nature 320:454–456. doi:10.1038/320454a0
Higashi Y, Yoshizumi M (2003) New methods to evaluate endothelial function: method for assessing endothelial function in humans using a strain-gauge plethysmography: nitric oxide-dependent and -independent vasodilation. J Pharmacol Sci 93:399–404. doi:10.1254/jphs.93.399
Hochberg I, Roguin A, Nikolsky E, Chanderashekhar PV, Cohen S, Levy AP (2002) Haptoglobin phenotype and coronary artery collaterals in diabetic patients. Atherosclerosis 161:441–446. doi:10.1016/S0021-9150(01)00657-8
Howard BV, Magee MF (2000) Diabetes and cardiovascular disease. Curr Atheroscler Rep 2:476–481. doi:10.1007/s11883-000-0046-8
Joannides R, Bellien J, Thuillez C (2006) Clinical methods for the evaluation of endothelial function—a focus on resistance arteries. Fundam Clin Pharmacol 20:311–320. doi:10.1111/j.1472-8206.2006.00406.x
Koch W, Latz W, Eichinger M, Roguin A, Levy AP, Schomig A, Kastrati A (2002) Genotyping of the common haptoglobin Hp 1/2 polymorphism based on PCR. Clin Chem 48:1377–1382
Kuvin JT, Karas RH (2003) Clinical utility of endothelial function testing: ready for prime time? Circulation 107:3243–3247. doi:10.1161/01.CIR.0000075928.54461.33
Langlois MR, Delanghe JR (1996) Biological and clinical significance of haptoglobin polymorphism in humans. Clin Chem 42:1589–1600
Lavi S, Gaitini D, Milloul V, Jacob G (2006) Impaired cerebral CO2 vasoreactivity: association with endothelial dysfunction. Am J Physiol Heart Circ Physiol 291:H1856–H1861. doi:10.1152/ajpheart.00014.2006
Levy AP (2004) Haptoglobin: a major susceptibility gene for diabetic cardiovascular disease. Isr Med Assoc J 6:308–310
Levy AP, Roguin A, Hochberg I, Herer P, Marsh S, Nakhoul FM, Skorecki K (2000) Haptoglobin phenotype and vascular complications in patients with diabetes. N Engl J Med 343:969–970. doi:10.1056/NEJM200009283431313
Levy AP, Hochberg I, Jablonski K, Resnick HE, Lee ET, Best L, Howard BV (2002) Haptoglobin phenotype is an independent risk factor for cardiovascular disease in individuals with diabetes: the Strong Heart Study. J Am Coll Cardiol 40:1984–1990. doi:10.1016/S0735-1097(02)02534-2
Melamed-Frank M, Lache O, Enav BI, Szafranek T, Levy NS, Ricklis RM, Levy AP (2001) Structure–function analysis of the antioxidant properties of haptoglobin. Blood 98:3693–3698. doi:10.1182/blood.V98.13.3693
Miller YI, Altamentova SM, Shaklai N (1997) Oxidation of low-density lipoprotein by hemoglobin stems from a heme-initiated globin radical: antioxidant role of haptoglobin. Biochemistry 36:12189–12198. doi:10.1021/bi970258a
Nakhoul FM, Marsh S, Hochberg I, Leibu R, Miller BP, Levy AP (2000) Haptoglobin genotype as a risk factor for diabetic retinopathy. JAMA 284:1244–1245. doi:10.1001/jama.284.10.1244-a
Peters AL, Schriger DL (1998) The new diagnostic criteria for diabetes: the impact on management of diabetes and macrovascular risk factors. Am J Med 105:15S–19S. doi:10.1016/S0002-9343(98)00206-X
Rother RP, Bell L, Hillmen P, Gladwin MT (2005) The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: a novel mechanism of human disease. JAMA 293:1653–1662. doi:10.1001/jama.293.13.1653
Suleiman M, Aronson D, Asleh R, Kapeliovich MR, Roguin A, Meisel SR, Shochat M, Sulieman A, Reisner SA, Markiewicz W, Hammerman H, Lotan R, Levy NS, Levy AP (2005) Haptoglobin polymorphism predicts 30-day mortality and heart failure in patients with diabetes and acute myocardial infarction. Diabetes 54:2802–2806. doi:10.2337/diabetes.54.9.2802
The Diabetes Control and Complications Trial Research Group (1993) The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 329:977–986. doi:10.1056/NEJM199309303291401
The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group (2000) Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. N Engl J Med 342:381–389. doi:10.1056/NEJM200002103420603
Acknowledgment
This investigation was supported in part by grants from Israel Diabetes Association (ISDA) and the San-Francisco Diabetes Research Fund.
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Dayan, L., Levy, A.P., Blum, S. et al. Haptoglobin genotype and endothelial function in diabetes mellitus: a pilot study. Eur J Appl Physiol 106, 639–644 (2009). https://doi.org/10.1007/s00421-009-1048-z
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DOI: https://doi.org/10.1007/s00421-009-1048-z