Abstract-The pathological hallmark of Alzheimer disease is deposition of amyloid-␤ protein (A␤) in the brain.Telmisartan is a unique angiotensin II receptor blocker with peroxisome proliferator-activated receptor-␥ (PPAR-␥)-stimulating activity. Activation of PPAR-␥ is expected to prevent inflammation and A␤ accumulation in the brain. We

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Angiotensin II (Ang II) type 2 (AT2) receptors are abundantly expressed not only in the fetal brain where they probably contribute to brain development, but also in pathological conditions to protect the brain against stroke; however, the detailed mechanisms are unclear. Here, we demonstrated that AT2 receptor signaling induced neural differentiation via an increase in MMS2, one of the ubiquitin-conjugating enzyme variants. The AT2 receptor, MMS2, Src homology 2 domain-containing protein-tyrosine phosphatase 1 (SHP-1), and newly cloned AT2 receptor-interacting protein (ATIP) were highly expressed in fetal rat neurons and declined after birth. Ang II induced MMS2 expression in a dose-dependent manner, reaching a peak after 4 h of stimulation, and this effect was enhanced with AT1 receptor blocker, valsartan, but inhibited by AT2 receptor blocker PD123319. Moreover, we observed that an AT2 receptor agonist, CGP42112A, alone enhanced MMS2 expression. Neurons treated with small interfering RNA of MMS2 failed to exhibit neurite outgrowth and synapse formation. Moreover, the increase in AT2 receptor-induced MMS2 mRNA expression was enhanced by overexpression of ATIP but inhibited by small interfering RNA of SHP-1 and overexpression of catalytically dominant-negative SHP-1 or a tyrosine phosphatase inhibitor, sodium orthovanadate. After AT2 receptor stimulation, ATIP and SHP-1 were translocated into the nucleus after formation of their complex. Furthermore, increased MMS2 expression mediates the inhibitor of DNA binding 1 proteolysis and promotes DNA repair. These results provide a new insight into the contribution of AT2 receptor stimulation to neural differentiation via transactivation of MMS2 expression involving the association of ATIP and SHP-1.

Abstract-The molecular mechanisms of the contribution of angiotensin II type-1 receptor blockers to neuronal protection are still unclear. Here, we investigated the effect of angiotensin II type-2 (AT 2 ) receptor stimulation on neurons and cognitive function involving a new neuroprotective factor, methyl methanesulfonate sensitive 2 (MMS2

Objective: Our aim was to examine the possible cross-talk of angiotensin II (Ang II) and aldosterone (Aldo) in the regulation of vascular cell senescence in cultured vascular smooth muscle cells (VSMC). Methods: VSMC were prepared from thoracic aorta of adult male Sprague-Dawley rats. Cellular senescence was evaluated by senescenceassociated β-galactosidase (SA-β-gal) staining and expression of p21, p53, p16, and p27. Oxidative stress was determined by measuring NADPH oxidase activity and superoxide production. Signal transduction was examined by immunoblot analysis with or without RNA interference methods. Results: Persistent Ang II (100 nM) stimulation increased SA-β-gal-stained VSMC and enhanced expression of p21, p53, p16, p27 and Kiras2A. These effects of Ang II were markedly inhibited by treatment with a selective AT 1 receptor blocker, valsartan, but partially attenuated by a mineralocorticoid receptor antagonist, spironolactone. The culture medium of VSMC treated with Ang II (100 nM) showed a timedependent increase in Aldo concentration, which increased senescent VSMC. Antioxidant, N-acetyl-L-cysteine or superoxide dismutase attenuated Ang II-or Aldo-induced VSMC senescence and Ki-ras2A expression. A lower dose combination of Ang II (100 pM) and Aldo (1 pM) significantly enhanced SA-β-gal-stained VSMC with increases in expression of p21, p53, p16, p27 and Ki-ras2A, oxidative stress, and activity of transcription factors such as NF-κB, AP-1, whereas Ang II or Aldo alone at these doses did not affect these parameters. Kiras2A-siRNA treatment attenuated senescent VSMC, expression of p21, p53, p16 and p27, oxidative stress induced by Ang II or a lower dose combination of Ang II and Aldo. Conclusion: These results suggest that Ang II and Aldo exert cross-talk in VSMC senescence with involvement of oxidative stress and Kiras2A, and could provide a therapeutic benefit for age-related vascular disorders by blockade of both Ang II and Aldo.