Institute of Biochemistry and Molecular Medicine, and Swiss National Centre of Competence in Research (NCCR) TransCure, University of Bern, Bern, Switzerland.
Physiol Rep. 2023 Aug;11(16):e15783. doi: 10.14814/phy2.15783.
TRPM4 is a calcium-activated, voltage-modulated, nonselective ion channel widely expressed in various cells and tissues. TRPM4 regulates the influx of sodium ions, thus playing a role in regulating the membrane potential. In the heart, TRPM4 is expressed in both cardiomyocytes and cells of the conductive pathways. Clinical studies have linked TRPM4 mutations to several cardiac disorders. While data from experimental studies have demonstrated TRPM4's functional significance in cardiac physiology, its exact roles in the heart have remained unclear. In this study, we investigated the role of TRPM4 in cardiac physiology in a newly generated Trpm4 knockdown mouse model. Male and female Trpm4 knockdown (Trpm4 ) and wild-type mice of different ages (5- to 12- week-old (young) and 24-week-old or more (adult)) were characterized using a multimodal approach, encompassing surface electrocardiograms (ECG), echocardiography recordings, ex vivo ECGs in isolated heart, endocardial mappings, Western blots, and mRNA quantifications. The assessment of cardiac electrophysiology by surface ECGs revealed no significant differences between wild-type and Trpm4 young (5- to 12-week-old) mice of either sex. Above 24 weeks of age, adult male Trpm4 mice showed reduced heart rate and increased heart rate variability. Echocardiography revealed that only adult male Trpm4 mice exhibited slight left ventricular hypertrophic alterations compared to controls, illustrated by alterations of the mitral valve pressure halftime, the mitral valve E/A ratio, the isovolumetric relaxation time, and the mitral valve deceleration. In addition, an assessment of the right ventricular systolic function by scanning the pulmonary valve highlighted an alteration in pulmonary valve peak velocity and pressure in adult male Trpm4 mice. Endocardial mapping recordings showed that applying 5 μM of the new TRPM4 inhibitor NBA triggered a third-degree atrioventricular block on 40% of wild-type hearts. These results confirm the key role of TRPM4 in the proper structure and electrical function of the heart. It also reveals differences between male and female animals that have never been reported. In addition, the investigation of the effects of NBA on heart function confirms the role of TRPM4 in atrioventricular conduction.
瞬时受体电位阳离子通道亚家族 M 成员 4（TRPM4）是一种广泛表达于各种细胞和组织中的钙激活、电压调制、非选择性离子通道。TRPM4 调节钠离子内流，从而在调节膜电位中发挥作用。在心脏中，TRPM4 表达于心肌细胞和传导途径细胞中。临床研究将 TRPM4 突变与多种心脏疾病联系起来。虽然来自实验研究的数据表明了 TRPM4 在心脏生理学中的功能意义，但它在心脏中的确切作用仍不清楚。在这项研究中，我们在新生成的 Trpm4 敲低小鼠模型中研究了 TRPM4 在心脏生理学中的作用。使用多模态方法对不同年龄（5-12 周龄（年轻）和 24 周龄或以上（成年））的雄性和雌性 Trpm4 敲低（Trpm4 -/-）和野生型（WT）小鼠进行了特征描述，该方法包括体表心电图（ECG）、超声心动图记录、离体心脏的体外 ECG、心内膜图、Western 印迹和 mRNA 定量。通过体表 ECG 评估心脏电生理学，发现 WT 和年轻（5-12 周龄）的雄性和雌性 Trpm4 -/-小鼠之间没有显著差异。在 24 周龄以上时，成年雄性 Trpm4 小鼠的心率降低，心率变异性增加。超声心动图显示，只有成年雄性 Trpm4 小鼠与对照组相比表现出轻微的左心室肥厚改变，这表现在二尖瓣压力半衰期、二尖瓣 E/A 比值、等容舒张时间和二尖瓣减速的改变上。此外，通过扫描肺动脉瓣对右心室收缩功能的评估突出显示成年雄性 Trpm4 小鼠的肺动脉瓣峰值速度和压力发生改变。心内膜图记录显示，在 40%的 WT 心脏上施加 5 μM 的新型 TRPM4 抑制剂 NBA 可引发三度房室传导阻滞。这些结果证实了 TRPM4 在心脏的正常结构和电功能中的关键作用。此外，它还揭示了以前从未报道过的雄性和雌性动物之间的差异。此外，对 NBA 对心脏功能的影响的研究证实了 TRPM4 在房室传导中的作用。
