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Hypoadiponectinemia Is Closely Linked to Endothelial Dysfunction in Man

Second Department of Internal Medicine (M.S., N.H., T.A., Y.O., N.T.) and Department of Clinical Pharmacology and Therapeutics, Faculty of Medicine (T.T., S.U.), University of the Ryukyus, 903-0215 Okinawa, Japan; and Departments of Medicine and Pathophysiology (I.S.) and Internal Medicine and Molecular Science (T.F., Y.M.), Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan

Address all correspondence and requests for reprints to: Dr. Michio Shimabukuro, Second Department of Internal Medicine, Faculty of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa 903-0215, Japan. E-mail: mshimabukuro-ur{at}umin.ac.jp or me447945{at}members.interq.or.jp.

	Abstract

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Vascular endothelial dysfunction has been demonstrated in overweight or obese patients, but the molecular basis for this link has not been clarified. We asked what the relationship was between adiponectin, an adipose-specific molecule, and endothelial function. Forearm blood flow (FBF) was measured during reactive hyperemia by using strain-gauge plethysmography in 76 Japanese subjects without a history of cardiovascular or cerebrovascular disease, diabetes mellitus, hepatic, or renal disease. The peak FBF and total reactive hyperemic flow [flow debt repayment (FDR)] during reactive hyperemia were correlated with waist circumference (r = -0.418 and -0.414, respectively) and body mass index (r = -0.597 and -0.626, respectively). After correcting for age, gender, and body mass index, the peak FBF was correlated with systolic blood pressure (r = -0.294; P = 0.010), free fatty acid (FFA) (r = -0.331; P = 0.004), and adiponectin in log 10 (r = 0.492; P < 0.001), and FDR was correlated with adiponectin in log 10 (r = 0.462; P = 0.001). In stepwise multiple regression analyses, predictive variables for peak FBF were adiponectin in log 10 (r = 0.468) and FFA (r = -0.292; r² = 0.487; P < 0.0001); and predictive variables for FDR were adiponectin in log 10 (r = 0.474) and FFA (r = -0.275; r² = 0.346, P < 0.0001). Endothelial function was impaired in proportion to the severity of obesity, and the level of severity was closely related to plasma adiponectin levels. Adiponectin may play a protective role against the atherosclerotic vascular change, and loss of effects enhances endothelial dysfunction, as in obese people.

	Introduction

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OBESITY IS ASSOCIATED with increased cardiovascular morbidity and mortality (1, 2). The American Heart Association determined that obesity is a major, modifiable risk factor for coronary heart disease, based on emerging data about the link between adiposity and coronary heart disease (3). Vascular endothelial dysfunction plays a pivotal role in the pathogenesis of atherosclerosis and enhances the risk of future cardiovascular events (4, 5). The presence of vascular endothelial dysfunction has been demonstrated in overweight or obese patients with insulin resistance (6, 7) and visceral obesity (8). However, the molecular basis for the link between obesity and vascular endothelial dysfunction has not been clarified. A newly discovered adipose-specific molecule, adiponectin, was shown to be decreased in obese people (hypoadiponectinemia) (9), as in patients with coronary artery disease (10). Because adiponectin may protect the endothelium from early atherosclerotic events such as the expression of adhesion molecules (10) or the attachment of monocytic cells (11), hypoadiponectinemia could be linked to endothelial damage. The present study questioned the relationship between plasma adiponectin levels and endothelial function in humans.

	Subjects and Methods

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Subjects

This study consisted of 76 Japanese subjects without a history of cardiovascular or cerebrovascular disease, diabetes mellitus, hepatic, or renal disease. The study protocol complied with the Guidelines of the Ethical Committee of the University of the Ryukyus. Informed consent was obtained from all subjects.

Endothelial function

Forearm blood flow (FBF) was measured using a mercury-filled SILASTIC strain-gauge plethysmograph (EC-5R, D. E. Hokanson, Inc., Issaquah, WA), as previously described (12, 13). The strain gauge was attached to the upper arm, held above the right atrium, and connected to a plethysmographic device. A wrist cuff was inflated to a pressure of 200 mm Hg to exclude the hand circulation from the measurements 1 min before each measurement and throughout the measurement of FBF. The upper arm cuff was inflated to 40 mm Hg for 7 sec in each 15-sec cycle to occlude venous outflow from the arm, using a rapid cuff inflator (EC-20, D. E. Hokanson, Inc.). The FBF output signal was transmitted to a recorder (U-228, Advance Co., Nagoya, Japan). FBF was expressed as milliliters per minute per 100 ml of forearm tissue. The FBF was then calculated by two independent observers who had no knowledge of the subjects’ profiles; the interobserver coefficient of variation was 3.0 ± 1.3%.

Study protocol

The study began at 0900 h, after the subjects fasted for at least 12 h. The subjects were kept in a supine position, in a quiet, dark, air-conditioned room (constant temperature of 25 C) throughout the study. After 30 min in the supine position, the basal FBF was measured. Then the effect of reactive hyperemia (RH) and sublingual nitroglycerin (NTG) on FBF was measured, as described, with modifications (14, 15). To induce RH, FBF was occluded by inflating the cuff on the right upper arm to a pressure of 200 mm Hg for 5 min. After releasing the cuff, FBF was measured for 180 sec. Subjects were then given 0.3 mg of NTG sublingually, and FBF was measured for 5 min. The end of the response to RH or sublingual NTG was followed by a 15-min recovery period. Baseline blood samples were obtained after 30 min at rest. The peak FBF response (12) and total reactive hyperemic flow [flow debt repayment (FDR)] (16) during RH were used to assess the resistance of vessel endothelial function. FDR was defined as the curve under the area flow vs. time during RH above baseline flow (16). Because FDR, but not peak FBF, was significantly decreased by intraarterial infusion of N^G-monomethyl-L-arginine (4 µmol/min), a blocker of nitric oxide (NO) synthesis, we used FDR as a relatively NO-dependent marker (16). In the preliminary study, we confirmed the reproducibility of RH and sublingual NTG-induced vasodilation on two separate occasions in 28 healthy male subjects (mean age, 27 ± 5 yr). The coefficients of variation were 4.3% and 2.8%, respectively.

Biochemical measurements

Venous blood samples were obtained in tubes containing EDTA-sodium (1 mg/ml) and polystyrene tubes without an anticoagulant. The EDTA-containing tubes were promptly chilled. Plasma was immediately separated by centrifugation at 3000 rpm at 4 C for 10 min, and serum was separated by centrifugation at 1000 rpm at room temperature for 10 min. Samples were stored at -80 C until assayed. Routine chemical methods were used to determine the serum concentrations of total cholesterol, high-density lipoprotein cholesterol, triglycerides, creatinine, glucose, and electrolytes. The serum concentration of low-density lipoprotein was estimated using Friedewald’s method (17). The plasma adiponectin concentration was measured by sandwich ELISA, as previously described (9). Homeostasis model assessment of insulin resistance (HOMA-IR), an insulin resistance index, was calculated as described (18).

Statistical analysis

Values are expressed as the mean ± SD. Comparisons of time-course curves of FBF during RH were analyzed by two-way ANOVA for repeated measures on one factor, followed by Fisher’s protected least significant difference for multiple-paired comparisons. The repeated factor was time of RH, and the nonrepeated factor was one group vs. the other group. Multigroup comparisons of variables were made by one-way ANOVA followed by Fisher’s protected least significant difference for multiple-paired comparisons. Probabilities less than 0.05 were considered to be significant. The data were processed using StatView J-5.0 software (SAS Institute Inc., Cary, NC).

	Results

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The mean values (range) of basal FBF, peak FBF, and the maximal flow after NTG administration (in milliliters per minute per 100 ml) were 3.27 ± 1.43 (1.37–6.19), 18.45 ± 6.76 (4.05–35.3), and 4.26 ± 1.64 (2.35–6.88) in all 76 subjects. Single correlation analyses showed that the peak FBF was negatively correlated with waist circumference, body mass index (BMI), systolic blood pressure, free fatty acid (FFA), and leptin, and was positively correlated with adiponectin (Fig. 1 and Table 1). FDR correlated negatively with waist circumference, BMI, HOMA-IR, FFA, and leptin, and positively with adiponectin. The maximal flow after NTG did not correlate with any metabolic and anthropometric variables. After correcting for age, gender, and BMI, the peak FBF was correlated only with systolic blood pressure, FFA, and adiponectin, and FDR was correlated with adiponectin. In stepwise multiple regression analyses, predictive variables for peak FBF were adiponectin in log 10 (r = 0.468) and FFA (r = -0.292; r² = 0.487; P < 0.0001), and predictive variables for FDR were adiponectin in log 10 (r = 0.474) and FFA (r = -0.275; r² = 0.346; P < 0.0001) (Table 2, model 1). When BMI was included in the model (Table 2, model 2), predictive variables for peak FBF and FDR were adiponectin in log 10 (r = 0.439 and 0.388, respectively) and BMI (r = -0.498 and -0.516, respectively). Serum adiponectin in log 10 (micrograms per milliliter) was negatively correlated with waist circumference (r = -0.334; P = 0.020), BMI (r = -0.365; P = 0.007), HOMA-IR (r = -302; P = 0.034), and FFA (r = -0.271; P = 0.052).

View larger version (31K): [in this window] [in a new window]   FIG. 1. Correlation between peak FBF (upper panels) and FDR (lower panels) during RH, BMI, waist circumference, and serum adiponectin levels in all 76 subjects. Pearson’s correlation coefficients are shown.

	Discussion

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Serum adiponectin and endothelial function

Measurements of FBF during intraarterial infusion of acetylcholine are used to investigate endothelium-dependent vasodilatation (12, 13). However, this technique is invasive and time consuming and cannot be used routinely. We measured FBF during RH using strain-gauge plethysmography. With this noninvasive method, resistant vessel endothelial function can be assessed physiologically with a high reproducibility (14, 15). Higashi et al. (15) reported that peak FBF during RH was well correlated with FBF to maximal acetylcholine dose (30 µg/min; r = 0.91; P < 001), indicating that this noninvasive method is a useful alternative for assessing resistance vessel endothelial function. Because the contribution of NO may be different at the RH phase, we used peak FBF as a combination marker of shear stress and local metabolic factors at an early phase of RH, and FDR as a relatively NO-dependent marker at the mid-to-late phase of RH (16).

The peak FBF and FDR were correlated negatively with waist circumference, BMI, FFA, systolic blood pressure (peak FBF), HOMA-IR (FDR), and leptin, and correlated positively with adiponectin. After correcting for age, gender, and BMI, the endothelial function indices were correlated positively with adiponectin and negatively with FFA. NTG-induced FBF changes were not correlated with any metabolic and anthropometric variables, indicating that endothelium-dependent function was predominantly affected by hypoadiponectinemia. It is suggested that, in humans, the plasma level of adiponectin may be directly linked to endothelial function.

Mechanisms for a link between hypoadiponectinemia and endothelial dysfunction

Two possible mechanisms by which hypoadiponectinemia decreases endothelial function are postulated.

First, adiponectin level can be linked to whole-body insulin sensitivity, and hypoadiponectinemia can cause endothelial dysfunction by decreasing insulin sensitivity. Because the plasma adiponectin level was decreased in the prediabetic insulin-resistant phase in rhesus monkeys (Macaca mulatta), hypoadiponectinemia might play a causative role in the development of insulin resistance (19). We confirmed this concept by showing that experimental ablation of the adiponectin gene in mice reduces insulin sensitivity, and adenovirus-mediated supplementation of plasma adiponectin can recover the sensitivity (20). There is a close correlation between whole-body insulin sensitivity and endothelium-dependent vasodilatation (6, 7). We previously reported that endothelial NO production (21) and vasodilatation induced by local intraarterial infusion of insulin/glucose (22) were both closely linked to whole-body insulin sensitivity (21). In the current study, FDR was negatively correlated with HOMA-IR (Table 1), indicating a link between FDR and insulin sensitivity. But this correlation was abolished after correcting for age, gender, and BMI, probably by a strong confounding effect of BMI on insulin sensitivity. In multiple regression analysis, endothelial function was negatively correlated with FFA and positively correlated with adiponectin (Table 2, model 1). When BMI was included in the model as an independent variable, the power of FFA, but not of adiponectin, was abolished (Table 2, model 2). HOMA-IR, a casual marker for insulin resistance (18), was not selected as a predictor for endothelial function. Serum adiponectin levels were reported to be closely linked to insulin sensitivity in human subjects (19, 23), and the current study showed that adiponectin levels were correlated negatively with waist circumference, BMI, and HOMA-IR, indicating a close link between hypoadiponectinemia and insulin resistance. Adiponectin might eliminate the predictive power of HOMA-IR, which is a relatively weaker predictor for insulin sensitivity than other markers, such as an M-value by the hyperinsulinemic euglycemic clamp (23). It was also reported that FFA can directly impair endothelial function in humans by decreasing insulin sensitivity (6, 7). Adiponectin (19 , 29,23) and FFA (6, 7), which are both secreted from adipocytes, may independently and bidirectionally regulate endothelial function through modulation of insulin sensitivity in the whole body and vascular beds.

Second, hypoadiponectinemia may be directly linked to early atherosclerotic vascular damage and a subsequent endothelial dysfunction. Experimentally, Ouchi et al. (10) showed that adiponectin inhibited TNF--induced expression of endothelial adhesion molecules in endothelial cells and that adiponectin reduced atherogenic transformation of macrophage to foam cells by suppressing scavenger receptor expression (11). It was also evident that plasma adiponectin levels were decreased in patients with atherosclerotic risk factors such as obesity, impaired glucose tolerance, diabetes mellitus, or previous coronary heart disease (10). Loss of plasma adiponectin may accelerate early atherosclerotic vascular damage and reduce various physiological roles of endothelial cells, including NO synthesis and supply, which may be linked to decreases in the peak FBF and FDR, in the current study.

Study limitation

The current study cannot determine which of the following is plausible: 1) hypoadiponectinemia impairs endothelial function by impairment of insulin sensitivity in the whole body and vascular beds; 2) hypoadiponectinemia first accelerates vascular damage and then impairs NO supply from endothelium; or 3) hypoadiponectinemia first impairs NO synthesis and supply and then accelerates vascular damage (3). Direct actions of adiponectin on vascular function should be observed in future studies.

Conclusions

The current study showed that endothelial function was impaired in proportion to the severity of obesity and that endothelial function was closely related to plasma adiponectin levels. Adiponectin may play a protective role directly against the atherosclerotic vascular change and/or indirectly through improving insulin sensitivity. The loss of adiponectin effects enhances endothelial dysfunction and may be associated with future cardiovascular events.

	Footnotes

 
This work was supported by grants from the Takeda Science Foundation and from the Japanese Society for the Promotion of Science (11770645).

Abbreviations: BMI, Body mass index; FBF, Forearm blood flow; FDR, flow debt repayment; FFA, free fatty acid; HOMA-IR, homeostasis model assessment of insulin resistance; NO, nitric oxide; NTG, nitroglycerin; RH, reactive hyperemia.

Received November 30, 2002.

Accepted March 14, 2003.

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				G. F. Mitchell, J. A. Vita, M. G. Larson, H. Parise, M. J. Keyes, E. Warner, R. S. Vasan, D. Levy, and E. J. Benjamin Cross-Sectional Relations of Peripheral Microvascular Function, Cardiovascular Disease Risk Factors, and Aortic Stiffness: The Framingham Heart Study Circulation, December 13, 2005; 112(24): 3722 - 3728. [Abstract] [Full Text] [PDF]

				S. Watanabe, T. Tagawa, K. Yamakawa, M. Shimabukuro, and S. Ueda Inhibition of the Renin-Angiotensin System Prevents Free Fatty Acid-Induced Acute Endothelial Dysfunction in Humans Arterioscler. Thromb. Vasc. Biol., November 1, 2005; 25(11): 2376 - 2380. [Abstract] [Full Text] [PDF]

				M. Galisteo, M. Sanchez, R. Vera, M. Gonzalez, A. Anguera, J. Duarte, and A. Zarzuelo A Diet Supplemented with Husks of Plantago ovata Reduces the Development of Endothelial Dysfunction, Hypertension, and Obesity by Affecting Adiponectin and TNF-{alpha} in Obese Zucker Rats J. Nutr., October 1, 2005; 135(10): 2399 - 2404. [Abstract] [Full Text] [PDF]

				E. Kajantie, R. Kaaja, O. Ylikorkala, S. Andersson, and H. Laivouri Adiponectin Concentrations in Maternal Serum: Elevated in Preeclampsis But Unrelated to Insulin Sensitivity Reproductive Sciences, September 1, 2005; 12(6): 433 - 439. [Abstract] [PDF]

				D. Rothenbacher, H. Brenner, W. Marz, and W. Koenig Adiponectin, risk of coronary heart disease and correlations with cardiovascular risk markers Eur. Heart J., August 2, 2005; 26(16): 1640 - 1646. [Abstract] [Full Text] [PDF]

				A. Singhal, N. Jamieson, M. Fewtrell, J. Deanfield, A. Lucas, and N. Sattar Adiponectin Predicts Insulin Resistance But Not Endothelial Function in Young, Healthy Adolescents J. Clin. Endocrinol. Metab., August 1, 2005; 90(8): 4615 - 4621. [Abstract] [Full Text] [PDF]

				S. Pilz, R. Horejsi, R. Moller, G. Almer, H. Scharnagl, T. Stojakovic, R. Dimitrova, G. Weihrauch, M. Borkenstein, W. Maerz, et al. Early Atherosclerosis in Obese Juveniles Is Associated with Low Serum Levels of Adiponectin J. Clin. Endocrinol. Metab., August 1, 2005; 90(8): 4792 - 4796. [Abstract] [Full Text] [PDF]

				M.-P. Chen, J. C.-R. Tsai, F.-M. Chung, S.-S. Yang, L.-L. Hsing, S.-J. Shin, and Y.-J. Lee Hypoadiponectinemia Is Associated With Ischemic Cerebrovascular Disease Arterioscler. Thromb. Vasc. Biol., April 1, 2005; 25(4): 821 - 826. [Abstract] [Full Text] [PDF]

				J. K. Olijhoek, J. Koerselman, P. P.Th. de Jaegere, M. C. Verhaar, D. E. Grobbee, Y. van der Graaf, F. L.J. Visseren, and for the SMART Study Group Presence of the Metabolic Syndrome Does Not Impair Coronary Collateral Vessel Formation in Patients With Documented Coronary Artery Disease Diabetes Care, March 1, 2005; 28(3): 683 - 689. [Abstract] [Full Text] [PDF]

				J. Miller, A. Rosenbloom, and J. Silverstein Childhood Obesity J. Clin. Endocrinol. Metab., September 1, 2004; 89(9): 4211 - 4218. [Full Text] [PDF]

				J. Malyszko, J. S. Malyszko, S. Brzosko, S. Wolczynski, and M. Mysliwiec Adiponectin Is Related to CD146, a Novel Marker of Endothelial Cell Activation/Injury in Chronic Renal Failure and Peritoneally Dialyzed Patients J. Clin. Endocrinol. Metab., September 1, 2004; 89(9): 4620 - 4627. [Abstract] [Full Text] [PDF]

				B. B. Duncan, M. I. Schmidt, J. S. Pankow, H. Bang, D. Couper, C. M. Ballantyne, R. C. Hoogeveen, and G. Heiss Adiponectin and the Development of Type 2 Diabetes: The Atherosclerosis Risk in Communities Study Diabetes, September 1, 2004; 53(9): 2473 - 2478. [Abstract] [Full Text] [PDF]