ANGIOTENSIN II AND AMYLOID-beta SYNERGISTICALLY INDUCE BRAIN VASCULAR SMOOTH MUSCLE CELL SENESCENCE

BACKGROUNDAmyloid-beta (A beta) induces cerebrovascular damage and is reported to stimulate endothelial cell senescence. We previously demonstrated that angiotensin II (Ang II)-promoted vascular senescence. We examined the possible cross-talk between Ang II and A beta in regulating brain vascular smooth muscle cell (BVSMC) senescence.METHODSBVSMCs were prepared from adult male mice and stimulated with Ang II (0, 0.1, 1, 10, and 100 nmol/l) and/or A beta 1-40 (0, 0.1, 0.3, 0.5, 1, 3, and 5 mu mol/l) for the indicated times. Cellular senescence was evaluated by senescence-associated beta-galactosidase staining.RESULTSTreatment with Ang II (100 nmol/l) or A beta (1 mu mol/l) at a higher dose increased senescent cells compared with control at 6 days. Treatment with Ang II (10 nmol/l) or A beta (0.5 mu mol/l) at a lower dose had no effect on senescence whereas a combined treatment with lower doses of Ang II and A beta significantly enhanced senescent cells. This senescence enhanced by lower dose combination was markedly blocked by valsartan (Ang II type 1 receptor inhibitor) or TAK-242 (A beta receptor TLR4 inhibitor) treatment. Moreover, lower dose combination caused increases in superoxide anion levels and p-ERK expression for 2 days, NF-kappa B activity, p-I kappa B, p-IKK alpha/beta, p16 and p53 expression for 4 days, and an obvious decrease in pRb expression. These changes by lower dose combination, except in p-I kappa B expression and NF-kappa B activity, were significantly inhibited by pretreatment with U0126 (ERK inhibitor).CONCLUSIONSAng II and A beta synergistically promoted BVSMC senescence at least due to enhancement of the p-ERK-p16-pRb signaling pathway, oxidative stress, and NF-kappa B/I kappa B activity.