Introduction and hypothesis: Brain renin–angiotensin system plays a role in ischemic brain damage after stroke. It is known that stimulation of angiotensin II type 2 (AT2) receptor has a protective role in ischemic brain injury. We demonstrated that AT2 receptor stimulation by compound 21 (C21), direct AT2 receptor agonist, inhibited vascular intimal proliferation with activation of peroxisome proliferator-activated receptor-gamma (PPAR-γ). Agents with PPAR-γ agonistic effect have been demonstrated to be neuroprotective in brain ischemia. However, whether direct AT2 receptor stimulation has a protective effect on ischemic brain injury via PPAR-γ activation is still unknown. Thus, we investigated the beneficial effect of C21 on ischemic brain damage by AT2 receptor stimulation via PPAR-γ activation.
Methods: Eight-week-old male C57BL/6J and human renin and human angiotensinogen double-transgenic (hRN/hANG-Tg) mice were subjected to middle cerebral artery (MCA) occlusion. Before MCA occlusion, they were administered C21 with or without GW9662, a PPAR-γ antagonist, for 2 weeks. Ischemic size, inflammation and oxidative stress were assessed 24 hours after MCA occlusion. Cerebral blood flow was measured in the core and periphery of the MCA territory before, immediately after, 1 hour and 24 hours after MCA occlusion.
Results: Administration of C21 with or without GW9662 had no significant effect on blood pressure. Ischemic brain area at 24 hours after MCA occlusion was significantly enlarged in hRN/hANG-Tg mice, compared with C57BL/6J mice. Treatment with C21 decreased the ischemic area compared with the no-treatment group, with an increase in cerebral blood flow, both in C57BL/6J and hRN/hANG-Tg mice. Co-administration of GW9662 partially attenuated the protective effect of C21 on ischemic size, via an increment in the expression of inflammatory cytokines and superoxide production, although GW9662 treatment alone had no significant effect on ischemic size.
Conclusions: These results suggest that direct AT2 receptor stimulation has a beneficial effect on stroke partly due to activation of PPAR-γ.