**4. Adiponectin and its relationship to endothelial dysfunction**

In vitro experiments revealed the physiological concentrations of adiponectin inhibited TNF alpha induced expression of VCAM 1 and ICAM 1 on the endothelium and exhibited other antiatherogenic effects. In 2008 Vaverková et al. published a study concerning the relationship between adiponectin and serum concentrations of soluble adhesive molecules VCAM 1 and ICAM 1 as well as with markers of insulin resistance and inflammation in patients with cardiovascular disease and in dyslipidemic patients at high risk of cardiovascular disease [28].

The aim of the study was to evaluate the relationship of adiponectin to soluble forms of vascular cell adhesion molecule 1 (VCAM 1) and intercellular cell adhesion molecule 1 (ICAM 1) in patients with cardiovascular disease or dyslipidemia.

The data from experimental research in animals support the hypothesis of antiaterogenic properties of adiponectin. Adiponectin accumulates in the arterial wall of injured arteries [29]. In adenovirus-treated animals the increase of adiponectin significantly reduced progression of atherosclerotic lesions [6]. In vitro experiments revealed the fact that physiological concentrations of adiponectin inhibited TNF alfa induced expression of VCAM 1 and ICAM 1 on the endothelium [29] and exhibited other antiatherogenic effects.

We have investigated the relationship between adiponectin and serum concentrations of VCAM 1 and ICAM 1 as well as with markers of insulin resistance and inflammation in patients with cardiovascular disease and in dyslipidemic patients at high risk of CVD.

#### **4.1. Subjects**

264 patients of Lipid Center at Faculty Hospital Olomouc were included in the study. All patients were examined by a physician and the following information were obtained: medical history, physical examination and NYHA classification. Subjects were tested for secondary hyperlipidemia. Patients were divided into three groups, those with the presence of clinically manifest atherosclerosis (G1), those with dyslipidemia defined according to Sniderman, but without clinically manifest atherosclerosis (G2), and healthy individuals (G3).

#### **4.2. Results**

The characteristics of the three subgroups of the studied cohort are shown in Table 5. Participants with CVD (G1) had comparable lipid, lipoprotein and apolipoprotein profile to the dyslipidemic subjects without CVD (G2) but were more insulin resistant. These differences persisted after adjustment for age, sex and BMI. The G1 had also the highest soluble ICAM 1, the difference in VCAM 1 was not statistically significant. Subjects with dyslipidemia (G2) had significantly lower adiponectin levels and higher levels of ICAM 1 compared with G3. Lower adiponectin levels in patients with CVD did not reach statistical significance, possibly due to a small number of patients. Adiponectin correlated with many lipid and nonlipid markers of insulin resistance. Adiponectin did not correlate with ICAM 1, but there was a strong positive association of adiponectin with VCAM 1. While ICAM 1 and VCAM 1 were strongly intercorrelated, they showed different association pattern with other risk factors. ICAM 1 correlated strongly with many markers of insulin resistance and hsCRP, while VCAM 1 were negatively associated with apo AI and apo B, and positively with adiponectin. Association of adiponectin with VCAM 1 was most prominent in group G1 and G2, but was not significant with G3. Results of multiple backward stepwise regression analysis confirmed these observations. Adiponectin levels were independently positively associated with sex (higher in women), HDL cholesterol and VCAM 1, and negatively with hsCRP. In multiple stewise regression analysis with VCAM 1 as the dependent variable, VCAM 1 was independently associated with ICAM 1 (p < 0.0001), adiponectin (p < 0.0001), HDL cholesterol (p = 0.0208) and triglycerides (p = 0.0091). On the other hand, ICAM 1 was independentely associated with VCAM 1 (p < 0.0001), atherogenic index (p < 0.0001), hsCRP (p = 0.0001) and HOMA (p = 0.0307). (More detailed results are given in lit. [28].)

#### **4.3. Discussion**

Our study confirms the previously described correlations of adiponectin with many lipid and nonlipid markers of IR as well as its relationships with HDL cholesterol, sex and hsCRP [30, 31, 32]. The unexpected finding was the significant independent positive association of adiponectin with VCAM 1 but not with ICAM 1 serum concentrations in patients with or at risk for CVD. Their expression results in adhesion of circulating leukocytes to the endothelial cells and their subsequent transendothelial migration- an important step in initiation and progression of atherosclerosis. VCAM 1 and ICAM 1 have different expression pattern and probably different roles in atherogenesis [33]. Soluble forms of these molecules can be measured in peripheral circulation. The origins of circulating soluble cell adhesion molecules are not entirely clear, but they may derive from shedding or proteolytic cleavage from endothelial cell.


**Table 5.** The demographic, clinical and laboratory characteristics of the study population

The expression pattern of adhesion molecules may explain why VCAM 1 is a marker of increased risk for future coronary events only in patients with atherosclerosis [34]. Patients with stable CAD have moderately increased and in several studies even normal levels of soluble VCAM 1 in comparison with healthy controls. The highest level of VCAM 1 was noted in patients with acute myocardial infarction [35]. In another study, VCAM 1 was a useful marker for predicting future ischemic events in the 6 months after presentation with unstable angina pectoris or nonQ myocardial infarction [36]. In our cohort, levels of VCAM 1 in the CVD patients were not significantly higher than in controls. This is in agreement with several other works.

#### **4.4. Conclusions**

690 Lipoproteins – Role in Health and Diseases

(G3).

**4.2. Results** 

**4.3. Discussion** 

from endothelial cell.

medical history, physical examination and NYHA classification. Subjects were tested for secondary hyperlipidemia. Patients were divided into three groups, those with the presence of clinically manifest atherosclerosis (G1), those with dyslipidemia defined according to Sniderman, but without clinically manifest atherosclerosis (G2), and healthy individuals

The characteristics of the three subgroups of the studied cohort are shown in Table 5. Participants with CVD (G1) had comparable lipid, lipoprotein and apolipoprotein profile to the dyslipidemic subjects without CVD (G2) but were more insulin resistant. These differences persisted after adjustment for age, sex and BMI. The G1 had also the highest soluble ICAM 1, the difference in VCAM 1 was not statistically significant. Subjects with dyslipidemia (G2) had significantly lower adiponectin levels and higher levels of ICAM 1 compared with G3. Lower adiponectin levels in patients with CVD did not reach statistical significance, possibly due to a small number of patients. Adiponectin correlated with many lipid and nonlipid markers of insulin resistance. Adiponectin did not correlate with ICAM 1, but there was a strong positive association of adiponectin with VCAM 1. While ICAM 1 and VCAM 1 were strongly intercorrelated, they showed different association pattern with other risk factors. ICAM 1 correlated strongly with many markers of insulin resistance and hsCRP, while VCAM 1 were negatively associated with apo AI and apo B, and positively with adiponectin. Association of adiponectin with VCAM 1 was most prominent in group G1 and G2, but was not significant with G3. Results of multiple backward stepwise regression analysis confirmed these observations. Adiponectin levels were independently positively associated with sex (higher in women), HDL cholesterol and VCAM 1, and negatively with hsCRP. In multiple stewise regression analysis with VCAM 1 as the dependent variable, VCAM 1 was independently associated with ICAM 1 (p < 0.0001), adiponectin (p < 0.0001), HDL cholesterol (p = 0.0208) and triglycerides (p = 0.0091). On the other hand, ICAM 1 was independentely associated with VCAM 1 (p < 0.0001), atherogenic index (p < 0.0001), hsCRP

(p = 0.0001) and HOMA (p = 0.0307). (More detailed results are given in lit. [28].)

Our study confirms the previously described correlations of adiponectin with many lipid and nonlipid markers of IR as well as its relationships with HDL cholesterol, sex and hsCRP [30, 31, 32]. The unexpected finding was the significant independent positive association of adiponectin with VCAM 1 but not with ICAM 1 serum concentrations in patients with or at risk for CVD. Their expression results in adhesion of circulating leukocytes to the endothelial cells and their subsequent transendothelial migration- an important step in initiation and progression of atherosclerosis. VCAM 1 and ICAM 1 have different expression pattern and probably different roles in atherogenesis [33]. Soluble forms of these molecules can be measured in peripheral circulation. The origins of circulating soluble cell adhesion molecules are not entirely clear, but they may derive from shedding or proteolytic cleavage

Many studies, including experiments in vitro, animal models and studies in human, have shown that adiponectin has antiatherogenic and antiinflammatory properties. Low adiponectin levels were found in patients with CAD independently of other risk factors. Therefore, the finding of positive and independent association of adiponectin with the marker of endothelial dysfunction VCAM 1 was suprising. This positive association was present both in patients with CVD and dyslipidemic subjects without CVD, but it was not significant in healthy subjects without dyslipidemia. We hypothesize that adiponectin, which accumulates in the arterial wall only in place of endothelial injury and atherosclerotic plaques (that is the same places where VCAM 1 is expressed) may be involved in shedding of ectodomains of VCAM 1 from endothelial surface. This may represent a mechanism by which VCAM 1 effects on the cell surface can be downregulated. In this way, adiponectin could protect vascular wall from adhesion of leukocytes and thus from progression of atherosclerosis.
