Dept. of Internal Medicine/Cardiology, Rush University Medical Center, 1750 W. Harrison St., Chicago, IL 60612, USA; Biological Science Center, Department of Physiology, Av. Cel Francisco H. dos Santos 100, 19031 Centro Politécnico-Curitiba, Brazil.
Dept. of Physiology & Biophysics, The Ohio State University, 5018 Graves Hall, 333 W.10th Ave., Columbus, OH 4321, USA.
J Mol Cell Cardiol. 2023 Jun;179:90-101. doi: 10.1016/j.yjmcc.2023.04.004. Epub 2023 Apr 20.
Sinoatrial node (SAN) dysfunction (SND) and atrial arrhythmia frequently occur simultaneously with a hazard ratio of 4.2 for new onset atrial fibrillation (AF) in SND patients. In the atrial muscle attenuated activity of p21-activated kinase 1 (Pak1) increases the risk for AF by enhancing NADPH oxidase 2 dependent production of reactive oxygen species (ROS). However, the role of Pak1 dependent ROS regulation in SAN function has not yet been determined. We hypothesize that Pak1 activity maintains SAN activity by regulating the expression of the hyperpolarization activated cyclic nucleotide gated cation channel (HCN). To determine Pak1 dependent changes in heart rate (HR) regulation we quantified the intrinsic sinus rhythm in wild type (WT) and Pak1 deficient (Pak1) mice of both sexes in vivo and in isolated Langendorff perfused hearts. Pak1 hearts displayed an attenuated HR in vivo after autonomic blockage and in isolated hearts. The contribution of the Ca clock to pacemaker activity remained unchanged, but Ivabradine (3 μM), a blocker of HCN channels that are a membrane clock component, eliminated the differences in SAN activity between WT and Pak1 hearts. Reduced HCN4 expression was confirmed in Pak1 right atria. The reduced HCN activity in Pak1 could be rescued by class II HDAC inhibition (LMK235), ROS scavenging (TEMPOL) or attenuation of Extracellular Signal-Regulated Kinase (ERK) 1/2 activity (SCH772984). No sex specific differences in Pak1 dependent SAN regulation were determined. Our results establish Pak1 as a class II HDAC regulator and a potential therapeutic target to attenuate SAN bradycardia and AF susceptibility.
窦房结（SAN）功能障碍（SND）和房性心律失常常同时发生，SND 患者新发心房颤动（AF）的危险比为 4.2。在心房肌中，p21 激活激酶 1（Pak1）的活性降低会增加 AF 的风险，这是通过增强 NADPH 氧化酶 2 依赖性活性氧物种（ROS）的产生来实现的。然而，Pak1 依赖性 ROS 调节在 SAN 功能中的作用尚未确定。我们假设 Pak1 活性通过调节超极化激活环核苷酸门控阳离子通道（HCN）的表达来维持 SAN 活性。为了确定 Pak1 依赖性心率（HR）调节变化，我们在体内和离体 Langendorff 灌流心脏中定量测定了野生型（WT）和 Pak1 缺陷型（Pak1）小鼠的固有窦性节律。Pak1 心脏在自主阻断后和离体心脏中显示出 HR 降低。钙时钟对起搏活动的贡献保持不变，但 HCN 通道阻滞剂 Ivabradine（3 μM）消除了 WT 和 Pak1 心脏之间 SAN 活性的差异。在 Pak1 右心房中证实了 HCN4 表达减少。Pak1 中减少的 HCN 活性可以通过 II 类组蛋白去乙酰化酶抑制（LMK235）、ROS 清除（TEMPOL）或 ERK1/2 活性衰减（SCH772984）来挽救。未确定 Pak1 依赖性 SAN 调节中的性别特异性差异。我们的研究结果确立了 Pak1 作为 II 类组蛋白去乙酰化酶调节剂和潜在的治疗靶点，可减轻 SAN 心动过缓和 AF 易感性。
