Department of Health Sciences, College of Natural and Health Sciences, Zayed University, Abu Dhabi, United Arab Emirates.
Department of Physiology and Immunology, College of Medicine and Health Sciences, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates.
Front Endocrinol (Lausanne). 2022 Jul 7;13:946313. doi: 10.3389/fendo.2022.946313. eCollection 2022.
The sinoatrial node (SAN) is composed of highly specialized cells that mandate the spontaneous beating of the heart through self-generation of an action potential (AP). Despite this automaticity, the SAN is under the modulation of the autonomic nervous system (ANS). In diabetes mellitus (DM), heart rate variability (HRV) manifests as a hallmark of diabetic cardiomyopathy. This is paralleled by an impaired regulation of the ANS, and by a pathological remodeling of the pacemaker structure and function. The direct effect of diabetes on the molecular signatures underscoring this pathology remains ill-defined. The recent focus on the electrical currents of the SAN in diabetes revealed a repressed firing rate of the AP and an elongation of its tracing, along with conduction abnormalities and contractile failure. These changes are blamed on the decreased expression of ion transporters and cell-cell communication ports at the SAN (i.e., HCN4, calcium and potassium channels, connexins 40, 45, and 46) which further promotes arrhythmias. Molecular analysis crystallized the RGS4 (regulator of potassium currents), mitochondrial thioredoxin-2 (reactive oxygen species; ROS scavenger), and the calcium-dependent calmodulin kinase II (CaMKII) as metabolic culprits of relaying the pathological remodeling of the SAN cells (SANCs) structure and function. A special attention is given to the oxidation of CaMKII and the generation of ROS that induce cell damage and apoptosis of diabetic SANCs. Consequently, the diabetic SAN contains a reduced number of cells with significant infiltration of fibrotic tissues that further delay the conduction of the AP between the SANCs. Failure of a genuine generation of AP and conduction of their derivative waves to the neighboring atrial myocardium may also occur as a result of the anti-diabetic regiment (both acute and/or chronic treatments). All together, these changes pose a challenge in the field of cardiology and call for further investigations to understand the etiology of the structural/functional remodeling of the SANCs in diabetes. Such an understanding may lead to more adequate therapies that can optimize glycemic control and improve health-related outcomes in patients with diabetes.
窦房结（SAN）由高度特化的细胞组成，这些细胞通过自身产生动作电位（AP）来维持心脏的自主跳动。尽管具有这种自动性，但 SAN 仍受自主神经系统（ANS）的调节。在糖尿病（DM）中，心率变异性（HRV）表现为糖尿病心肌病的标志。这与 ANS 调节受损以及起搏结构和功能的病理性重塑相平行。糖尿病对强调这种病理学的分子特征的直接影响仍未明确。最近对糖尿病中 SAN 电流量的关注揭示了 AP 的发射率降低，其迹线拉长，同时伴有传导异常和收缩功能衰竭。这些变化归咎于 SAN 中离子转运体和细胞间通讯口（即 HCN4、钙和钾通道、连接蛋白 40、45 和 46）的表达减少，这进一步促进了心律失常。分子分析使 RGS4（钾电流调节剂）、线粒体硫氧还蛋白-2（活性氧；ROS 清除剂）和钙依赖性钙调蛋白激酶 II（CaMKII）结晶化，成为传递 SAN 细胞（SANCs）结构和功能病理性重塑的代谢罪魁祸首。特别关注 CaMKII 的氧化和 ROS 的产生，这会导致细胞损伤和糖尿病 SANCs 的细胞凋亡。因此，糖尿病 SAN 包含的细胞数量减少，纤维化组织显著浸润，进一步延迟 SANCs 之间 AP 的传导。由于抗糖尿病药物（急性和/或慢性治疗），真正的 AP 产生和其衍生波向邻近的心房心肌传导也可能失败。所有这些变化都对心脏病学领域构成了挑战，并呼吁进一步研究以了解糖尿病中 SANCs 结构/功能重塑的病因。这种理解可能会导致更合适的治疗方法，从而优化糖尿病患者的血糖控制并改善与健康相关的结果。
