On-off system for PI3-kinase-Akt signaling through S-nitrosylation of phosphatase with sequence homology to tensin (PTEN).

Nitric oxide (NO) physiologically regulates numerous cellular responses through S-nitrosylation of protein cysteine residues. We performed antibody-array screening in conjunction with biotin-switch assays to look for S-nitrosylated proteins. Using this combination of techniques, we found that phosphatase with sequence homology to tensin (PTEN) is selectively S-nitrosylated by low concentrations of NO at a specific cysteine residue (Cys-83). S-nitrosylation of PTEN (forming SNO-PTEN) inhibits enzymatic activity and consequently stimulates the downstream Akt cascade, indicating that Cys-83 is a critical site for redox regulation of PTEN function. In ischemic mouse brain, we observed SNO-PTEN in the core and penumbra regions but found SNO-Akt, which is known to inhibit Akt activity, only in the ischemic core. These findings suggest that low concentrations of NO, as found in the penumbra, preferentially S-nitrosylate PTEN, whereas higher concentrations of NO, known to exist in the ischemic core, also S-nitrosylate Akt. In the penumbra, inhibition of PTEN (but not Akt) activity by S-nitrosylation would be expected to contribute to cell survival by means of enhanced Akt signaling. In contrast, in the ischemic core, SNO-Akt formation would inhibit this neuroprotective pathway. In vitro model systems support this notion. Thus, we identify unique sites of PTEN and Akt regulation by means of S-nitrosylation, resulting in an "on-off" pattern of control of Akt signaling.

Plasma C1q/TNF-Related Protein-9 Levels Are Associated with Atherosclerosis in Patients with Type 2 Diabetes without Renal Dysfunction.

Aim. C1q/tumor necrosis factor-related protein-9 (CTRP9), a paralog of adiponectin, is expressed in adipose tissue. CTRP9 exerts protective effects against obesity and atherosclerosis in rodents. We investigated the association between plasma CTRP9 levels and atherosclerosis in patients with type 2 diabetes. Methods. We included 419 patients with type 2 diabetes, 161 of whom had chronic kidney disease (CKD). Fasting plasma CTRP9 and total adiponectin levels were measured with enzyme-linked immunosorbent assay. The intima-media thickness (IMT) of the common carotid artery was measured with ultrasonography. Results. Plasma CTRP9 levels were higher in the CKD group than in the non-CKD group. Plasma CTRP9 levels were positively correlated with carotid IMT in the non-CKD group. Multivariate analyses revealed that plasma CTRP9 levels were positively associated with carotid IMT in the non-CKD group, independent of age, sex, body mass index, adiponectin, and other cardiovascular risk factors. However, plasma CTRP9 levels were not associated with carotid IMT in the CKD group. Conclusion. Plasma CTRP9 levels are associated with atherosclerosis in diabetic patients without CKD, independently of obesity, adiponectin, and traditional cardiovascular risk factors. This study indicates a potential role of CTRP9 in atherosclerosis progression in human type 2 diabetes.

Visceral Adiposity is Preferentially Associated with Vascular Stiffness Rather than Thickness in Men with Type 2 Diabetes.

AIM: Visceral fat accumulation is known to underlie the clustering of cardiovascular risk factors. However, it is not completely understood how visceral fat accumulation influences the development of cardiovascular disease. In this study, we investigated the clinical impact of visceral adiposity on vascular stiffness and thickness in patients with type 2 diabetes (T2D). METHODS: One hundred and sixty-one patients with T2D, including 92 men and 69 women, were included in this cross-sectional study. Visceral fat area (VFA) and subcutaneous fat area (SFA) were measured by dual bioelectrical impedance analysis. Stiffness parameter ß and intima-media thickness (IMT) of the common carotid artery were measured by ultrasonography. RESULTS: The mean age and duration of diabetes in the study population were 61 years and 13.9 years, respectively. In men, VFA and waist circumference (WC) were positively correlated with stiffness parameter ß, whereas body mass index (BMI), WC, and SFA were negatively correlated with IMT. In contrast, in women, none of the obesity-related indices were significantly correlated with stiffness parameter ß or IMT. In multiple regression analyses, VFA as well as WC, BMI, and SFA were independently associated with stiffness parameter ß after adjustment for age and other potential confounders in men but not in women. None of the obesity-related indices were independently associated with IMT for either sex. CONCLUSION: In men with T2D, visceral adiposity is associated with carotid arterial stiffness but not thickness.