Abstract P242: Nicotinic Acetylcholine Receptor Subunit α7 is Protective Against Angiotensin II-induced Aneurysm and Hypertension
Alpha7 nicotinic acetylcholine receptor (α7 nAChR), an integral component of the cholinergic nervous system is known to mediate cholinergic anti-inflammatory activity in various disease models such as sepsis, stroke and neurocognitive disorders. We report for the first time that the α7 nAChR -/- deficient mouse serves as a novel model of hypertension and aneurysm formation. Seven month old male WT and α7 nAChR -/- mice weighing 28-33g were infused with low dose Ang II (350 ng/kg/min) or high dose (700 ng/kg/min) or vehicle for 15 days using mini-osmotic pumps (Alzet, model 2004) implanted subcutaneously. Blood pressure (BP) was recorded on day 0,3,7,10 and 14. Mice were euthanized on day 15. Heart and body weights were measured, histological analysis was performed on the aortas and immune profile of peripheral blood was analyzed by flow cytometry. High dose Ang II resulted in 70% mortality from aneurysm rupture in α7 nAChR -/- mice starting as early as the 4 th day of infusion. While cardiac hypertrophy was not observed, low dose Ang II resulted in a sharp rise in blood pressure in α7 nAChR -/- beginning on the 3 rd day to 167±3.7 mmHg compared to 138±3.3 mmHg in WT treated mice. On day14 of low dose treatment, BP in α7 nAChR -/- rose to 171±4.2 vs.135±3.1 in WT mice. No changes were observed in BP of untreated WT or α7 nAChR -/- animals. Histological analysis revealed high grade aneurysm in aortas of α7 nAChR -/- mice treated with low dose Ang II, demonstrating a prominent germinal center within the false lumen and fibrous desmoplastic stroma. Increased infiltration of CD11B + monocytes, and myeloperoxidase + stained neutrophils were observed in these aortas but not in the aortas of similarly treated WT mice. Flow cytometric analysis showed 27% ± 3.9 CD11B + /CD45 + circulating monocytes and 48% ± 0.8 Ly6G + /CD45 + neutrophils in α7 nAChR -/- vs. 19% ± 3 monocytes and 11.85% ± 2.9 neutrophils in WT mice. No differences in the levels of circulating immune cells were observed in untreated mice of either genotype. These data support a protective role of α7 nAChR in hypertension and aneurysm, potentially acting through its cholinergic anti-inflammatory activity. The α7 nAChR -/- mouse may serve as a new genetic model of aneurysm relevant in studies of the human disease.