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OBJECTIVE -To assess the prognostic role of ambulatory 24-h pulse pressure (PP) on various vascular events in relatively young type 2 diabetic subjects under 60 years of age.RESEARCH DESIGN AND METHODS -In this prospective study, 237 type 2 diabetic subjects without any history of vascular complications were analyzed. After excluding 9 dropout subjects, 228 subjects (mean age, 46 years; 69% men; mean follow-up period, 100 months) entered the study.RESULTS -Distribution of 24-h PP for all subjects showed left skewed data, indicating that there may be a diabetic subgroup that had a wide PP. Therefore, further analysis was performed by stratifying the diabetic subjects by quartile of 24-h PP. Outcomes for the widest quartile (n ϭ 58; cut point ϭ 53.3 mmHg) was then compared with those from the other narrower quartiles (n ϭ 170). In the diabetic subjects with a wide PP, cardiovascular events occurred more frequently than those in the diabetic subjects with a narrow one (20.7 vs. 4.1%; P Ͻ 0.001), resulting in the significant difference in the cumulative incidence of cardiovascular events (P Ͻ 0.001, log-rank test), but not cerebrovascular events, between the two subgroups. The Cox model revealed that a wide 24-h PP at baseline independently predicted subsequent cardiovascular events but not cerebrovascular events. By contrast, only duration of diabetes was the risk factor for cerebrovascular events.CONCLUSIONS -This study showed that a wide 24-h PP is predictive for cardiovascular events in relatively young diabetic subjects. Diabetes Care 28:102-107, 2005T here is now increasing evidence that wide pulse pressure (PP), which is an indicator of large arterial stiffness, is an independent predictor for cardiovascular disease in elderly subjects with essential hypertension (1,2). A prognostic role for PP has been extended to an unselected general population, including relatively young aged (3,4) and normotensive subjects (5). Furthermore, the Atherosclerosis Risk in Communities study (6) and the Hoorn study (7) demonstrated that type 2 diabetic subjects have stiffer arteries than individuals with normal glucose tolerance, which was confirmed using ambulatory 24-h monitoring of PP by van Dijk et al. (8). Recently, Domanski et al. (9) and Miyagi et al. (10) pointed out that a cardiovascular risk in subjects with a wide PP increased with the presence of diabetes. On the other hand, previous studies suggest that in subjects with essential hypertension, ambulatory PP not only correlates with organ damage (11) but also independently predicts cardiovascular events more precisely than clinic PP does (12,13). However, there is little information concerning PP of relatively young type 2 diabetic subjects, and the predictive value of ambulatory 24-h PP among these subjects has not been previously reported.The aim of this present study was to assess a prognostic role of ambulatory 24-h PP on various vascular events in type 2 diabetic subjects Ͻ60 years of age.RESEARCH DESIGN AND METHODS -The blood pressure (BP) monitoring progra...

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Bim is a member of the pro-apoptotic BH3-only Bcl-2 family of proteins. Bim gene undergoes alternative splicing to produce three predominant splicing variants (BimEL, BimL and BimS). The smallest variant BimS is the most potent inducer of apoptosis. Zinc (Zn 2+ ) has been reported to stimulate apoptosis in various cell types. In this study, we examined whether Zn 2+ affects the expression of Bim in human neuroblastoma SH-SY5Y cells. Zn 2+ triggered alterations in Bim splicing and induced preferential generation of BimS, but not BimEL and BimL, in a dose-and time-dependent manner. Other metals (cadmium, cobalt and copper) and stresses (oxidative, endoplasmic reticulum and genotoxic stresses) had little or no effect on the expression of BimS. To address the mechanism of Zn 2+ -induced preferential generation of BimS, which lacks exon 4, we developed a Bim mini-gene construct. Deletion analysis using the Bim mini-gene revealed that predicted binding sites of the SR protein SRSF6, also known as SRp55, are located in the intronic region adjacent to exon 4. We also found that mutations in the predicted SRSF6-binding sites abolished generation of BimS mRNA from the mutated Bim mini-gene. In addition, a UV cross-linking assay followed by Western blotting showed that SRSF6 directly bound to the predicted binding site and Zn 2+ suppressed this binding. Moreover, Zn 2+ stimulated SRSF6 hyper-phosphorylation. TG003, a cdc2-like kinase inhibitor, partially prevented Zn 2+ -induced generation of BimS and SRSF6 hyper-phosphorylation. Taken together, our findings suggest that Zn 2+ inhibits the activity of SRSF6 and promotes elimination of exon 4, leading to preferential generation of BimS.