Abstract 19968: Nicotinic Acetylcholine Receptor Signaling is Associated With RV Dysfunction in PAH
Introduction: Limited therapeutic options are available for RV failure associated with Pulmonary Arterial Hypertension (PAH). In this study, we investigated the role of cholinergic pathway and nAChR activation in a rat model of PAH and RV dysfunction as well as isolated cardiac fibroblasts.
Methods: Rats were exposed to Sugen/Hypoxia for 3 wks (PAH), followed by 2 and 4 wks of normoxia. Vehicle/normoxia animals served as controls (Con). After the 7 wk protocol, echocardiography was performed and tissue harvested for analysis of hypertrophy and cholinergic proteins. Rat hearts were enzymatically digested and cardiac fibroblasts (CF) isolated for in vitro studies. Quiesced CF were exposed to either acetylcholine or nicotine with or without α-bungarotoxin (α-BTX) or mecamylamine (nAChR blockers) followed by proliferation (cell counts) or collagen production (Sircol) measurement. In additional experiments cells were exposed to TGF-β or Ang II with or without α-BTX or α7 nAChR siRNA.
Results: PAH caused RV dysfunction (increased RV and RA pressures, decreased TAPSE, PAT as determined by echocardiography, p<.05 vs Con), increased RV collagen content and RV hypertrophy (RV/LV+S, p<.05). RV dysfunction was associated with increased expression of acetylcholine synthetic/signaling proteins (Choline Transporter (ChT), Choline acetyltransferase (ChAT), and nAChR (p<.05vs Con, n=3-4 ) in the RV but not LV. nAChR agonists (ACh, nicotine) applied to isolated cardiac fibroblasts significantly increased proliferation and collagen content which was blocked by the nAChR antagonists α-BTX and mecamylamine (n=3-7, p<.05) . Interestingly, nAChR blockade (α-BTX, α7 nAChR siRNA) had no effect on TGF-β-induced fibrosis but blocked Ang II-induced proliferation and collagen production (n=3-7, p<.05).
Conclusions: RV hypertrophy and dysfunction in PAH associated with increased expression of ACh synthetic enzymes and nAChR. In addition, nAChR activation can directly increase proliferation and collagen production of CF and is required for Ang II-induced CF proliferation. Therefore, CF nAChR signaling may be an important therapeutic target to limit RV dysfunction.
Author Disclosures: A. Vang: None. R. Clements: Research Grant; Significant; Novartis. A. Allawzi: None. R. Kue: None. G. Choudhary: Research Grant; Significant; Novartis.
- © 2016 by American Heart Association, Inc.