Volume 5 Issue 4 - August 1, 2008
Increased Rho Kinase Activity in a Taiwanese Population with Metabolic Syndrome
Ping-Yen Liu1, 2, 3*, Jyh-Hong Chen1, 2, Li-Jen Lin1, 2 and James K. Liao3

1Division of Cardiology, Internal Medicine, National Cheng Kung University, Tainan, Taiwan, 2Cardiovascular Research Center, National Cheng Kung University, Tainan, Taiwan, 3Vascular Medicine Research Unit, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts.
Email: larry@mail.ncku.edu.tw

J Am Coll Cardiol 2007; 49:1619-24

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Background
Metabolic syndrome (MetS) is a cluster of atherosclerotic cardiovascular disease risk factors and is closely associated with insulin resistance and obesity. The precise diagnosis of MetS, however, is still somewhat controversial, and no serological markers are available for its detection. Nevertheless, according to the criteria of National Cholesterol Educational Program Adult Treatment Panel (ATP)-III, the prevalence of MetS in U.S. adults who are older than 20 years of age is approximately 24%. Metabolic syndrome is a growing problem worldwide, particularly in the Asian population. The World Health Organization Expert Consultation recommended a lower cut-off point of body mass index (expressed as body weight (kg) over square value of body height (m)) for observed risk in Asian populations than that for non-Asian populations, varying from 22 to 25 kg/m2. Some studies on migrants from Asian countries to Western countries also indicated that Asian populations might be more susceptible to the Western diet and lifestyle than white ones in developing the MetS. Patients with MetS have twice the incidence of developing new-onset diabetes compared with those without MetS. Metabolic syndrome, therefore, is associated with increasing risk of developing diabetes and cardiovascular disease.

Several inflammatory mediators and adipocytokines, including tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, high-sensitivity C-reactive protein (hs-CRP), and adiponectin are associated with the development of insulin resistance and MetS. Despite these associations, the pathogenesis of MetS remains unknown. We recently reported that Rho kinase (ROCK) mediates the expression of plasminogen activator inhibitor-1 under hyperglycemic conditions. Furthermore, ROCK is up-regulated under inflammatory conditions and may be involved in adipocyte differentiation. Thus, growing evidence suggest that ROCK may contribute to the pathogenesis of MetS. However, clinical studies are lacking, which definitively link ROCK activity with MetS.

Rho kinase is a serine/threonine kinase that mediates the downstream signaling of the small guanosine triphosphate–binding protein, Rho, on the actin cytoskeleton. ROCK consists of 2 isoforms, ROCK1 and ROCK2. In mostly animal models, the inhibition of ROCK ameliorates many cardiovascular conditions, including hypertension, atherosclerosis, myocardial fibrosis, and stroke. Furthermore, ROCK also could regulate insulin signaling and glucose metabolism through direct phosphorylation of the insulin receptor substrate (IRS)-1. Thus, it is likely that ROCK plays an important role in the pathogenesis of MetS and diabetes. However, evidence is lacking showing that ROCK activity is increased in human subjects with MetS. In the current study, we measured ROCK activity in Taiwanese population with MetS and determined whether ROCK activity is an independent marker of MetS and whether it correlates with other components and risk markers of MetS. We sought to determine whether Rho kinase (ROCK) activity is increased in a Taiwanese population with metabolic syndrome (MetS).
Table 1. Clinical Manifestations of Metabolic Syndrome and Control Subjects
Values are expressed as mean ± SD or n (%).
BMI = body mass index; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; MetS = metabolic syndrome; TG = triglycerides.

Methods
We studied 40 Taiwanese subjects (60% men, mean age 55.5 ± 5.6 years) who were diagnosed with MetS with National Cholesterol Educational Program Adult Treatment Panel III criteria and 40 age- and gender-matched control subjects. Subject demographics were recorded, and blood samples were obtained. (Table 1)
Figure 2. ROC Analysis to Determine the Cutoff Value to Differentiate MetS
The best cutoff value for Rho kinase activity to differentiate the presence of metabolic syndrome (MetS) was 0.39; both sensitivity and specificity rates were 70%. The area under the curve = 0.76 ± 0.07, p = 0.001. ROC = receiver-operating characteristic.
Figure 1.ROCK Activity Is Greater Among Asian Subjects With MetS
(A) Baseline protein expression of Rho kinase (ROCK)1 by immunoblotting method; (B) baseline protein expression of ROCK2 by immunoblotting method; (C) phosphorylation levels of MBS (pMBS) and total MBS (tMBS) were determined by immunoblotting methods; (D) ROCK activity, expressed as pMBS/MBS, between metabolic syndrome (MetS) patients and controls. Three repeated experiments were performed in duplicate.


Results
Compared with control subjects, ROCK activity, as determined by phosphorylation of myosin binding subunit (MBS) in leukocytes, was greater in MetS subjects (mean phospho-MBS/MBS ratio 0.46 vs. 0.35, p = 0.002). (Figure 1) A cutoff value for ROCK activity of 0.39 predicted the presence of MetS with specificity and sensitivity rates of 70%. (Figure 2) Plasma high-sensitivity C-reactive protein was greater (5.5 mg/l, 95% confidence interval [CI] 3.1 to 7.2 mg/l vs. 2.8 mg/l, 95% CI 1.1 to 3.9 mg/l, p = 0.01) and adiponectin was lower (4.9 μg/ml, 95% CI 3.2 to 6.1 μg/ml vs. 5.9 μg/ml, 95% CI 4.2 to 7.5 μg/ml, p = 0.01) in MetS subjects compared with control subjects, but plasma levels of interleukin-6 and tumor necrosis factor-alpha were not different (p > 0.05 for both). (Table 2) Body mass index, waist circumference, fasting glucose, high-sensitivity C-reactive protein, and triglyceride levels were associated with increased levels of ROCK activity. (Table 3) The risk of increased ROCK activity increased with the number of MetS components (p for trend <0.001). (Table 4)
Table 2. Baseline Inflammatory Markers of Metabolic Syndrome Subjects and Control Subjects
Values are expressed as geometric means with corresponding 95% confidence intervals (in parentheses).
hs-CRP = high-sensitivity C-reactive protein; IL = interleukin; TNF = tumor necrosis factor.
Table 3. Partial Correlation Coefficient Adjusted for Smoking Status Between Clinical and Biochemical Parameters With Rho Kinase Activity Among Metabolic Syndrome Subjects
Table 4. Adjusted Odds Ratios of Greater ROCK Activity With the Number of MetS Components
CI = confidence interval; MBS = myosin binding subunit; ROCK = Rho kinase.
Risks are compared with subjects without any risk factor component of metabolic syndrome (MetS) and adjusted for age and smoking status.
‡p < 0.01 †p < 0.001.

Conclusions
Rho kinase activity is increased in Taiwanese subjects with MetS and is associated with each component of MetS and markers of inflammation. These findings suggest that ROCK activity may be a novel serological marker of MetS.
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