Hachiro Obata

NF-κB involvement in the activation of primary adult T-cell leukemia cells and its clinical implications

The HTLV-I provirus-encoded Tax protein induces NF-kappaB in Tax-transfected Jurkat T cells or HTLVL-I- infected T cells in vitro. Tax induction of NF-kappaB is presumed to be involved in proliferation and activation of primary leukemia cells in vivo. Recent studies have demonstrated that NF-kappaB activities in human T cells are mediated by at least four c-Rel-related DNA binding proteins - p50, p55, p75 and p85. We examined the significance of NF-kappaB induction in primary adult T cell leukemia cells and the induction kinetics of each of the four NF-kappaB species. Marked NF-kappaB activity was detected using an electrophoretic mobility shift assay (EMSA) in the primary cells of patients with acute disease, but little activity was noted in the cells of chronic patients. NF-kappaB activity was enhanced in a time-dependent manner in acute type cells cultured with mitogen-free medium; there was no induction of activity in chronic type cells. UV crosslinking demonstrated all four species of NFkappaB complex - high levels of p50 and lower levels of p55 and p75, in acute type cells; chronic type cells showed only the p50. As a control, normal resting T cells similarly showed only p50; control cells showed little change in activity when cultured without mitogenic stimulation, analogous to chronic type ATL. Northern blotting revealed enhancement of c-rel (encoding p85) and KBFI (encoding p50 and p55) expression in acute type cells during culture, while there was no significant enhancement of mRNAs in chronic type ATL cells or unstimulated normal T cells. Northern blotting also revealed that Tax is upregulated at the mRNA level in acute- but not chronic-type cells during culture. Expression of c-rel and KBF1 mRNAs in acute type cells appeared to be related to Tax mRNA expression. These results suggest that Tax is capable of inducing nuclear expression of all four NF-kappaB species in primary ATL cells of acute type patients, with marked effects on p55, p75, and p85. Tax induction of NF-kappaB species is regulated, at least in part, at a pretranslational level involving increases in c-rel and KBF1 mRNA.

Angiotensin II type 1 receptor participates in extracellular matrix production in the late stage of remodeling after vascular injury

OBJECTIVE Extracellular matrix (ECM) accumulation is important in restenosis after angioplasty. Underlying molecular mechanisms remain to be elucidated, especially in vivo. We investigated expression of angiotensin II type 1 receptor (ATR1) in a rat model for up to 24 weeks after vascular injury, and also the effect of an ATR1 antagonist on neointimal thickening and ECM production. METHODS AND RESULTS Carotid arteries of rats were injured with a balloon catheter and then removed at 2, 5, and 7 days and 2, 4, 8, 16, and 24 weeks after injury. Although ATR1 immunoreactivity was slightly detectable in smooth muscle cells (SMC) in the media of uninjured arteries, reactivity was strong in neointimal SMC even 24 weeks after injury. Western blotting demonstrated similar results. ATR1 mRNA also was upregulated in neointimal SMC even 24 weeks after injury, as indicated by RT-PCR and by in situ hybridization. Candesartan, an ATR1 antagonist, significantly inhibited histologically evident neointimal thickening and collagen and elastin accumulation at 8 weeks after injury whether given beginning 1 day before injury, 4 days after injury, or 7 days after injury. CONCLUSION ATR1 is upregulated in the late stage of remodeling after vascular injury and is important in ECM production.

A Comparative Study of Olmesartan and Valsartan on Insulin Sensitivity in Hypertensive Patients with Diabetes Mellitus or Impaired Glucose Tolerance (OVIS Study)

Activation of renin angiotensin system is implicated in insulin resistance. In mega trials, it has been suggested that angiotensin receptor blockers may be beneficial on insulin sensitivity in hypertensive patients. We conducted a multicenter, open-label, parallel-group trial to compare the effects of olmesartan and valsartan on insulin sensitivity and adiponectin levels in 206 hypertensive patients with diabetes mellitus or impaired glucose tolerance. Patients were randomly assigned to either olmesartan 20 mg/day or valsartan 80 mg/day treatment for 24 weeks. Blood pressure, fasting glucose, fasting insulin, glycosylated hemoglobin (HbA1c), homeostasis model assessment for insulin resistance (HOMA-IR), and serum adiponectin levels were measured. The efficacy was evaluated in 197 patients (olmesartan, n=98; valsartan, n=99). At baseline, all parameters except for systolic blood pressure (SBP) and serum triglyceride did not differ between the 2 groups. HbA1c decreased slightly after a 24-week treatment with valsartan, but not olmesartan, while the decrease did not significantly differ in the two groups. There was no difference in the change from the baseline between olmesartan and valsartan groups concerning fasting glucose, fasting insulin, HOMA-IR, and adiponectin levels after 24-week treatment. The decrease in SBP tended to be greater in the olmesartan group than in the valsartan group even with adjustment for the baseline difference. In conclusion, there was no significant difference in insulin sensitivity or adiponectin levels between the olmesartan and valsartan groups. In the standard dose, olmesartan significantly decreased SBP as compared with valsartan.