Correlation Between Circulating Adhesion Molecules and Resistin ...

Inflammation & Allergy - Drug Targets, 2011, 10, 27-31

27

Correlation Between Circulating Adhesion Molecules and Resistin Levels in Hypertensive Type-2 Diabetic Patients José Juan Lozano-Nuevo1,2, Teresa Estrada-Garcia2, Hilda Vargas-Robles2, Bruno A. Escalante-Acosta2 and Alberto F. Rubio-Guerra*,1 1

Hypertension Clinic, Hospital General de Ticomán, SS DF, México

2

Department of Molecular Biomedicine, Centro de Investigación y Estudios Avanzados del Instituto Politécnico Nacional, México Abstract: Background: Endothelial dysfunction, a common feature among hypertensive and type-2 diabetic patients, has been associated with inflammation and increased concentrations of serum soluble adhesion molecules and resistin, a monocyte-macrophage- and adipocyte-derived cytokine. The Aim of this Study: To determine if there is a correlation between the serum concentrations of ICAM-1, VCAM-1, Eselectin and resistin in hypertensive type-2 diabetic patients. Methods: Thirty hypertensive type-2 diabetic patients were enrolled in the study. Serum ICAM-1, VCAM-1, E-selectin and resistin concentrations were determined by ELISA and correlated with the Spearman correlation coefficient. Results: The patients’ serum resistin concentrations significantly correlated with VCAM-1 (r = 0.31, p = 0.05) concentrations but not with ICAM-1 (r = 0.29, p = >0.05) and E-selectin (r = 0.10, p = 0.24) concentrations. Conclusion: VCAM-1 and resistin may participate in the pathophysiology of vascular damage in hypertensive type-2 diabetic patients. Serum resistin concentrations may be a marker of endothelial dysfunction.

Keywords: Circulating adhesion molecules, resistin, hypertension, type 2 diabetes mellitus, inflammation. High blood pressure increases the risk of macrovascular and microvascular complications in patients with type-2 diabetes. Endothelial dysfunction is a common feature in both type-2 diabetes and hypertension, and is usually present in hypertensive patients with type-2 diabetes mellitus [1, 2]. Reduction of endothelial function stimulates inflammation and atherosclerotic complications. Endothelial dysfunction increases the levels of circulating soluble adhesion molecules (SAM). SAM are expressed by cytokine-activated endothelia [2], mediate leukocyte-endothelial cell adhesion and may play an important role in the development of endothelial dysfunction and atherosclerosis [3]. Leukocytes do not adhere to normal arterial endothelium, but in the presence of endothelial dysfunction, adhesion molecules are expressed on the arterial endothelium [4]. Selectins mediate the rolling of leukocytes on the surface of endothelial cells, whereas intercellular adhesion molecule-1 (ICAM-1), a transmembrane glycoprotein molecule of the immunoglobulin superfamily, and vascular adhesion molecule-1 (VCAM-1), which is also a cell membrane surface sialoglycoprotein and a member of the Ig superfamily, are involved in leukocyte attachment to the vascular wall and penetration into the intimae [2, 3]. Adhesion molecules have been implicated in diabetic macrovascular [4] and microvascular [5] complications, as they facilitate the attachment and migration of leukocytes into the arterial walls. Once there, monocytes can *Address correspondence to this author at the Hypertension Clinic, Hospital General de Ticomán, Motozintla # 30, Col Letran Valle, D.F. C.P. 03600, México; Tel/Fax: (52 555) 55393584; E-mail: [email protected] 1871-5281/11 $58.00+.00

differentiate into foam cells that initiate the atherosclerotic process [6]. In fact, there are interrelations between adhesion molecules and early changes in carotid arteries that may lead to atherosclerotic lesions [3, 4]. Circulating levels of SAM are thought to reflect the increased expression of SAM on the endothelial cell surface [2]. Endothelial dysfunction is also associated with increased levels of resistin. Resistin is a monocyte-macrophage- and adipocyte-derived cytokine that is related to insulin resistance and type-2 diabetes mellitus [7]. In hypertensive type-2 diabetic patients, endothelial dysfunction and inflammation are interrelated events that have been implicated in the metabolic syndrome and in the development of coronary heart disease (Figs. 1, 2) [8]; both resistin and circulating levels of SAM are increased when endothelial dysfunction is present [7]. Serum resistin is markedly elevated in hypertensive type-2 diabetic patients (7). As resistin has a direct proinflammatory systemic effect, as well as an effect on vascular endothelial cells [9]. This study was carried out to evaluate whether circulating levels of SAM are correlated with resistin levels in hypertensive type-2 diabetic patients. MATERIALS AND METHODS A total of 30 hypertensive type-2 diabetic patients who had had diabetes for more than 12 months and who had not received prior treatment with thiazolidinediones, statins, or inhibitors of the renin-angiotensin-aldosterone system (RAAS) were included in this study. © 2011 Bentham Science Publishers Ltd.

28

Inflammation & Allergy - Drug Targets, 2011, Vol. 10, No. 1

Lozano-Nuevo et al.

Fig. (1). Correlation between circulating SAM Levels and resistin.

The diagnosis of type-2 diabetes was performed according to the American Diabetes Association criteria [10], and the diagnosis of hypertension was made according to the JNC 7 criteria [11]. In all patients, serum levels of resistin, VCAM-1, ICAM1 and E-selectin were measured in duplicate using commercial ELISA kits (R&D Systems, Minneapolis, Minn., USA). All venous samples were collected in the morning after a 12-hour overnight fast. The intra-assay variation was 3.1 for VCAM-1, 4.1 for ICAM-1, and 3.8 for E-selectin,

whereas the inter-assay variation was 7 for VCAM-1, 7.3 for E-selectin and 7.4 for ICAM-1. Fasting glycemia (glycose oxidase) and HbA1c were also measured in all patient samples. Patients with any of the following diagnoses were excluded from the study: decompensated diabetes mellitus (fasting blood glucose >250 mg/dl); heart, hepatic, or renal failure; evidence of valvular heart disease; heart block or cardiac arrhythmia; acute coronary syndrome or cerebrovascular disease six months before initiation of the study; autoimmune disease; pregnancy; urinary tract

Circulating Adhesion Molecules and Resistin


29

Fig. (2). Pathways that lead to endothelial dysfunction, inflammation and hyperresistinemia.

infection; fever; or history of alcohol and/or psychotropic drug abuse. The study was conducted with the approval of the Research and Medical Ethics Committee of our hospital (Reg. No. 2080100504), in accordance with the Helsinki Declaration. Participants gave written informed consent before their inclusion in the study. Statistical Analysis: Data are presented as the mean ± standard deviation, the correlation between SAM levels and resistin was assesed with the Spearman rank correlation coefficient test, and alpha error (p 0.05) was considered to be significant. RESULTS Basal characteristics of the patients are shown in Table 1.

The circulating levels of SAM in our patients were as follows: VCAM-1 861.3±45 ng/mL; ICAM-1 316.6±17 ng/mL; and E-selectin 71±4 ng/mL. The circulating level of resistin was 25.5±13 ng/ml. Table 1.

Basal Characteristics of Patients

Age (Years)

60 ± 9

Sex (Male/Female)

16/14

Glycemia (mg/dl) LDL (mg/dl) HbA1c (%) Blood Pressure (mm Hg)

133.3 ± 29 125± 29 6.0 175/93

Body Mass Index (Kg/m2)

30.4 ± 5.1

History of DM2

8.36 years

30


Lozano-Nuevo et al.

Fig. (3). Illustrated model of adipocyte-macrophage-endothelial cells interactions that lead to hyperresistinemia and inflammation.

When circulating SAM levels were correlated with serum levels of resistin, the Spearman correlation coefficient analysis did not show any relationship between resistin and ICAM-1 (r = 0.29, p > 0.05) or E-selectin (r = 0.10, p > 0.24). However, we found a significant positive correlation (r = 0.31; p = 0.05) between VCAM-1 and resistin (Fig. 1). DISCUSSION In this study, we found that the circulating levels of VCAM-1 correlated with serum resistin levels in hypertensive type-2 diabetic patients; the circulating levels of ICAM-1 and E-selectin did not have a significant correlation with serum resistin. It is important to note that in our work the circulating levels of SAM were measured in duplicate; thus, intra-individual variation was taken into account when the statistical analyses were performed. It is also relevant to say that our patients were thiazolindinedione-naïve, statin-naïve, and inhibitors of the RAAS-naïve, because all of these drugs have shown to reduce circulating levels of SAM [2]. Qatani et al. generated mice that express human resistin, but lack adipocyte-derived mouse resistin, and they placed these mice on a high-fat diet. Mice developed white adipose tissue inflammation, increased lipolysis and increased serum free fatty acids. The mice accumulated diacylglycerols in the muscle tissue, and increased serine phosphorylation of IRS-1 was observed. They concluded that human resistin

exacerbates white adipose tissue contributes to insulin resistance [9].

inflammation

and

Additionally, Shetty et al. found a negative correlation between resistin and HDL and a positive correlation between resistin and C-reactive protein (CRP) in a cross-sectional study, and they concluded that there is an association between resistin and inflammatory markers that is independent of the body mass index (BMI) [12]. These results agree with our findings and support a correlation between resistin and inflammatory markers (Fig. 3). Indeed, inflammation has a role in the development endothelial dysfunction [6], and both VCAM-1 and ICAM-1 are responsible for leukocyte infiltration into the vessel intima [4], causing secondary tissue damage from leukocyte proteases [2, 3]. Previous reports have shown that macrophages accumulate within the arterial intima of patients with diabetes and hypertension. The concentrations of ICAM-1, VCAM-1 and E-Selectin are elevated in patients with type-1 and type-2 diabetes mellitus. Therefore, it is not surprising that, in our study, circulating levels of VCAM-1 correlated with the serum levels of resistin in type-2 diabetic hypertensive patients. As far as we know, this paper is the first study that correlates circulating levels of SAM with serum resistin. In type-2 diabetes mellitus patients with hypertension, this correlation is independent of blood pressure values and supports the association of inflammation with endothelial dysfunction. The correlation may be due to diabetes-associated endothelial dysfunction, which facilitates both resistin and increased SAM expression [2], and to the

Circulating Adhesion Molecules and Resistin


initiation of the inflammatory process, but this association requires further evaluation.

[5]

It has been shown that statins [13], angiotensinconverting enzyme inhibitors [14] and calcium channel blockers [15, 16] decrease circulating levels of VCAM-1. If VCAM-1 is associated with resistin, as shown in our study, the vasoprotective effect of these drugs in diabetic hypertensive patients may be explained, at least in part, by their decreased effects on inflammation mediated by SAM and resistin levels. This theory warrants experimental confirmation.

[6]

In conclusion, our study has shown that circulating SAM levels were significant and positively correlated with serum resistin levels in hypertensive type-2 diabetic patients and that the levels of VCAM-1 were specifically correlated with resistin in these patients. These findings may have preventive implications through lifestyle changes and the use of drugs that act on SAM and resistin levels for the reduction of macrovascular and microvascular diabetic damage [17]. Our results suggest that VCAM-1 could interact with resistin in the pathophysiology of endothelial dysfunction in type-2 diabetic hypertensive patients. Many questions remain; however, resistin may be an important link between adhesion molecules and insulin resistance as part of an increased and abnormal inflammatory reaction [18]. Our findings support the role of resistin as a proinflammatory substance acting on vascular endothelial cells; our results also support the possibility that resistin determines the inflammatory status of the vasculature as part of the metabolic syndrome and the progression of atherosclerosis [19, 20].

[7]

[8] [9]

[10] [11] [12]

[13]

[14]

[15]

[16]

REFERENCES [1]

[2]

[3] [4]

Afsar, B.; Sezer, S.; Elsurer, R.; Ozdemir, F.N. Is HOMA index a predictor of nocturnal nondipping in hypertensives with newly diagnosed type 2 diabetes mellitus? Blood Press. Monit., 2008, 13(1), 63-64. Rubio, A.F.; Vargas, H.; Lozano, J.J. Escalante BA. Corrrelation between circulating adhesión molecules levels and albuminuria in type 2 diabetic hypertensive patients. Kidney Blood Press. Res., 2009, 32(4), 106-109. Woolard, K.J.; Chin-Dusting, J. Therapeutic targeting of P-selectin in atherosclerosis. Inflamm. Allergy-Drug Targets, 2006, 6, 69-74. Rizzoni, D.; Muiesan, M.L.; Porteri, E.; Castellano, M.; Salvetti, M.; Monteduro, C.; De Ciuceis, C.; Boari, G.; Valentini, U.; Cimino, A.; Sleiman, I.; Agabiti-Rosei, E. Circulating adhesion molecules and carotid artery structural changes in patients with non-insulin-dependent diabetes mellitus. J. Hum. Hypertens., 2003, 17(7), 463-470.

Received: August 18, 2010

[17]

[18] [19]

[20]

31

Mallika, V.; Goswami, B.; Rajappa, M. Atherosclerosis pathophysiology and the role of novel risk factors: A clinicobiochemical perspective. Angiology, 2007, 58(5), 513-522. Hansson, G.K. Inflammation, atherosclerosis and coronary artery disease. N. Engl. J. Med., 2005, 352(16), 1685-1695. Tokuyama, Y.; Osawa, H.; Ishizuka, T.; Onuma, H.; Matsui, K.; Egashira, T.; Makino, H.; Kanatsuka, A.. Serum resistin level is associated with insulin sensitivity in Japanese patients with type 2 diabetes mellitus. Metabolism, 2007, 56(5), 693-698. Libby, P.; Ridker, P.M.; Maseri, A. Inflammation and atherosclerosis. Circulation, 2002, 105(9), 1135-1143 Qatani, M.; Szwergold, N.R.; Greaves D.R.; Ahima, R.S.; Lazar, M.A. Macrophage-derived human resistin exacerbates adipose tissue inflammation and insulin resistance in mice. J. Clin. Invest., 2009, 119, 531-539. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care, 2006, 29(Suppl. 1), S43-S48. The seven report of the joint national committee on detection, evaluation, and treatment of high blood pressure. JNC 7. Complete version. Hypertension, 2003, 42, 1206-1252. Shety, G.K.; Economides, P.A.; Horton, E.S.; Mantzoros, Cs.; Veves, A. Circulating adiponectin and resistin levels in relation to metabolic factors, inflammatory markers and vascular reactivity in diabetic patients and subjects at risk for diabetes. Diabetes Care, 2004, 27(10), 2450-2457. Ghittoni, R.; Lazzerini, P.E.; Pasini, F.L.; Baldari, C.T. T lymphocytes as targets of statins: Molecular mechanisms and therapeutic perspectives. Inflamm. Allergy - Drug Targets, 2006, 6(1), 3-16. Gasic, S.; Wagner, O.; Fasching, P.; Ludwig, C.; Veitl, M.; Kapiotis, S.; Jilma, B. Fosinopril decreases levels of soluble vascular cell adhesion molecule-1 in borderline hypertensive type-2 diabetic patients with microalbuminuria. Am. J. Hypertens., 1999, 12(2 Pt. 1), 217-222. Zanchetti, A.; Bond, M.G.; Hennig, M.; Neiss, A.; Mancia, G.; Dal Palù, C.; Hansson, L.; Magnani, B.; Rahn, K.H.; Reid, J.L.; Rodicio, J.; Safar, M.; Eckes, L.; Rizzini, P.; European Lacidipine Study on Atherosclerosis investigators. Calcium antagonist lacidipine slows down progression of asymptomatic carotid atherosclerosis. Circulation, 2002, 106(19), 2422-2427. Yamaguchi, M.; Suwa, H.; Miyasaka, M.; Kumada, K. Selective inhibition of vascular cell adhesion molecule-1 expression by verapamil in human vascular endothelial cells. Transplantation, 1997, 63(5), 759-764. Rubio-Guerra, A.F.; Vargas-Robles, H.; Vargas-Ayala, G.; Rodriguez-Lopez, L.; Escalante-Acosta, B.A. The effect of trandolapril and its fixed-dose combination with verapamil on circulating adhesion molecules levels in hypertensive patients with type 2 diabetes. Clin. Exp. Hypertens., 2008, 30(7), 682-688. Steppan, C.M.; Bailey, S.T.; Bhat, S.; Brown, E.J.; Banerjee, R.R.; Wright, C.M.; Patel, H.R.; Ahima, R.S.; Lazar, M.A. The hormone resistin links obesity to diabetes. Nature, 2001, 409(6818), 307-312 Kim, J.; Montagnani, M.; Koh, K.K.; Quon, M.J. Reciprocal relationship between insulin resistance and endothelial dysfunction. Circulation, 2006, 113(15), 1888-1904. Rubio, A.F.; Vargas, H.; Maceda, A.; Vargas, G.; Rodriguez, L.; Escalante, B.A. Correlation between the levels of circulating adhesion molecules and atherosclerosis in hypertensive type-2 diabetic patients. Clin. Exp. Hypertens., 2010, 32(5), 308-310.

Revised: October 19, 2010

Accepted: October 25, 2010