PAC-1 Agonist Maxadilan Reduces Atherosclerotic Lesions in Hypercholesterolemic ApoE Deficient Mice

Recent studies with ApoE knockout (ApoE-/-) mice deficient for PACAP (pituitary adenylate cyclase-activating polypeptide) or its receptor PAC1 provide evidence for a possible involve-ment of immune- and vasoregulatoy PACAP signaling at the PAC1 receptor in atherogenesis and plaque associated vascular inflammation. Therefore, we tested the PAC1 receptor agonist Maxadilan and the PAC1 selective antagonist M65 on plaque development and lumen stenosis in the ApoE-/- atherosclerosis model for possible anti-atherogenic effects. Adult male ApoE-/- mice were fed a cholesterol-enriched diet (CED) or standard chow (SC) treat-ed with Maxadilan, M65 or Sham. Effects of treatment on atherosclerotic plaques, lumen stenosis, apoptosis and pro-inflammatory signatures were analyzed in the brachiocephalic trunk (BT). The percentage of Maxadilan treated mice exhibiting plaques under SC and CED was lower than that of Sham or M65 treatment indicating opposite effects of Maxadilan and M65. Maxadilan ap-plication inhibited lumen stenosis under SC and CED compared to Sham. In spite of significantly increased cholesterol levels, lumen stenosis of Maxadilan-treated mice was similar under CED and SC. In contrast, M65 under SC or CED did not reveal a significant influence on lumen steno-sis. Maxadilan significantly reduced the TNF-α+ area in the plaques under CED, but not under SC. In contrast, the IL-1β+ area was reduced after Maxadilan treatment under SC, but remained unchanged under CED compared to Sham. Maxadilan reduced the caspase-3+ area in the media under both SC and CED without affecting lipid content in plaques. Despite persisting hypercholesterolemia, Maxadilan reduces lumen stenosis, apoptosis and TNF-α driven inflammation. Our data suggest that Maxadilan provides atheroprotection by act-ing downstream of cholesterol-induced vascular inflammation. This implicates the potential of PAC1-specific agonist drugs against atherosclerosis even beyond statins and PCSK-9.