Effects of obesity and smoking on mental stress-induced blood pressure and augmentation index responses in normotensive young males: the J-SHIPP study.

Exaggerated blood pressure (BP) response to mental stress has been known to be a prognostic factor for cardiovascular disease. It has been argued that such unusual vascular reactivity to mental stress may arise from insulin resistance. To examine the vascular responses to mental stress, we evaluated the stress-related changes in BP and the augmentation index (AI), an index of arterial stiffness, in normotensive young males. Changes in late systolic BP (SBP2) representing central aortic pressure were also examined. Subjects were 86 males (21+/-2 years), 13 of whom were classified as obese (>or=25 kg/m(2)). AI was obtained from the radial arterial waveform as a ratio of the height of the late systolic peak to that of the first peak. Blood pressure and AI measurements were taken before, during and after a simple mental arithmetic test (MAT) lasting 3 min. Systolic BP (baseline 125+/-13, during MAT 133+/-13, post-MAT 124+/-11 mmHg; p<0.001) and heart rate (74+/-12, 81+/-13, 74+/-11 beats/min; p<0.001) were significantly increased during the MAT, whereas AI showed a slight reduction. In a separate analysis, the opposite response was observed between obese subjects showing increased AI (54+/-11, 56+/-13, 52+/-11%) and non-obese subjects who showed reduced AI (54+/-12, 51+/-12, 53+/-12%; p=0.032). The responses in SBP and SBP2 (obese 103+/-14, 117+/-12, 104+/-12; non-obese 98+/-13, 104+/-12, 97+/-12 mmHg; p=0.007) were also larger in the obese subjects. Stress-related transient increases in arterial stiffness may be involved in the exaggerated responses in aortic pressure in obese subjects.

An intermediary role of proHB-EGF shedding in growth factor-induced c-Myc gene expression.

Activation of growth factor receptors by ligand binding leads to an increased expression of c-Myc, a transcriptional regulator for cell proliferation. The activation of transcriptional factors via the activated receptors is thought to be the main role of c-Myc gene expression. We demonstrate here that epidermal growth factor receptor (EGFR)- and fibroblast growth factor receptor (FGFR)-mediated c-Myc induction and cell cycle progression in primary cultured mouse embryonic fibroblasts (MEFs) are abrogated by knockout of the heparin-binding EGF-like growth factor (Hb-egf) gene, or by a metalloproteinase inhibitor, although molecules downstream of the receptors are activated. Induction of c-Myc expression by EGF or basic FGF is recovered in Hb-egf-depleted MEFs by overexpression of wild-type proHB-EGF, but no recovery was observed with an uncleavable mutant of proHB-EGF. The uncleavable mutant also inhibited EGF-induced acetylation of histone H3 at the mouse c-Myc first intron region, which could negatively affect transcriptional activation. We conclude that signal transduction initiated by generation of the carboxyl-terminal fragment of proHB-EGF (HB-EGF-CTF) in the shedding event plays an important intermediary role between growth factor receptor activation and c-Myc gene induction.