Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta (H.J.J., M. Mackasey, Y.L., J.K., A.W.K., R.A.R.), Cumming School of Medicine, University of Calgary, Alberta.
Department of Physiology and Pharmacology (H.J.J., M. Mackasey, Y.L., J.K., A.W.K., R.A.R.), Cumming School of Medicine, University of Calgary, Alberta.
Circ Arrhythm Electrophysiol. 2019 Jan;12(1):e006863. doi: 10.1161/CIRCEP.118.006863.
Atrial fibrillation (AF) commonly occurs in hypertension and in association with elevated Ang II (angiotensin II) levels. The specific mechanisms underlying Ang II-mediated AF are unclear, and interventions to prevent the effects of Ang II are lacking. NPs (natriuretic peptides), which elicit their effects through specific NP receptors, including NPR-C (natriuretic peptide receptor-C), are cardioprotective hormones that affect cardiac structure and function.
This study used wild-type and NPR-C knockout (NPR-C) mice to investigate the effects of Ang II (3 mg/kg per day for 3 weeks) on AF susceptibility and atrial function using in vivo electrophysiology, high-resolution optical mapping, patch clamping, and molecular biology. In some experiments, wild-type mice were cotreated with Ang II and the NPR-C agonist cANF (0.07-0.14 mg/kg per day) for 3 weeks.
In wild-type mice, Ang II increased susceptibility to AF in association with a prolongation of P-wave duration, increased atrial refractory period, and slowed atrial conduction. These effects were exacerbated in Ang II-treated NPR-C mice. Ang II prolonged action potential duration and reduced action potential upstroke velocity (V). These effects were greater in left atrial myocytes from Ang II-treated NPR-C mice. Ang II also increased fibrosis in both atria in wild-type mice, whereas Ang II-treated NPR-C mice exhibited substantially higher fibrosis throughout the atria. Fibrotic responses were associated with changes in expression of profibrotic genes, including TGFβ and TIMP1. Cotreating wild-type mice with Ang II and the NPR-C agonist cANF dose dependently reduced AF inducibility by preventing some of the Ang II-induced changes in atrial myocyte electrophysiology and preventing fibrosis throughout the atria.
NPR-C may represent a new target for the prevention of Ang II-induced AF via protective effects on atrial electrical and structural remodeling.
心房颤动（AF）常发生于高血压患者，与血管紧张素 II（Ang II）水平升高有关。Ang II 介导的 AF 的具体机制尚不清楚，缺乏预防 Ang II 作用的干预措施。NPs（利钠肽）通过包括 NPR-C（利钠肽受体-C）在内的特定 NP 受体发挥作用，是影响心脏结构和功能的心脏保护性激素。
本研究使用野生型和 NPR-C 敲除（NPR-C）小鼠，通过体内电生理学、高分辨率光学映射、膜片钳和分子生物学方法，研究 Ang II（3 毫克/千克/天，持续 3 周）对 AF 易感性和心房功能的影响。在一些实验中，野生型小鼠同时接受 Ang II 和 NPR-C 激动剂 cANF（0.07-0.14 毫克/千克/天）治疗 3 周。
在野生型小鼠中，Ang II 增加了 AF 的易感性，同时延长了 P 波持续时间，增加了心房不应期，并减慢了心房传导。在 Ang II 处理的 NPR-C 小鼠中，这些作用加剧。Ang II 延长了动作电位持续时间并降低了动作电位上升速度（V）。在 Ang II 处理的 NPR-C 小鼠的左心房心肌细胞中，这些作用更大。Ang II 还增加了野生型小鼠左右心房的纤维化，而 Ang II 处理的 NPR-C 小鼠的整个心房纤维化程度明显更高。纤维化反应与包括 TGFβ 和 TIMP1 在内的促纤维化基因的表达变化有关。用 Ang II 和 NPR-C 激动剂 cANF 共同处理野生型小鼠可剂量依赖性地降低 AF 的诱导性，通过防止心房肌细胞电生理学中某些 Ang II 诱导的变化，并防止整个心房的纤维化。
NPR-C 可能通过对心房电重构和结构重构的保护作用，成为预防 Ang II 诱导的 AF 的新靶点。
