Kuck Lennart, Griffith Tia A, McNamee Antony P, Peart Jason N, Wilson John H, Sharma Ajay, Sharma Lavanya A, Robertson Kai, Du Toit Eugene F, Simmonds Michael J
Biorheology Research Laboratory, Griffith University, Gold Coast, Australia.
School of Pharmacy and Medical Science, Griffith University, Gold Coast, Australia.
FEBS J. 2025 Jun 8. doi: 10.1111/febs.70157.
Circulatory deficits are common and pathophysiologically relevant in type 2 diabetes mellitus (T2DM). Perturbed red blood cell (RBC) homeostasis and diminished nitric oxide (NO) availability contribute to endothelial dysfunction, a hallmark of cardiometabolic disorders; however, underlying pathophysiological mechanisms remain elusive. Here, we investigated RBC signaling pathways in a murine model of metabolic disease, focused on NO. T2DM-RBCs had elevated levels of cytosolic NO, intracellular calcium ions (Ca), and reactive oxygen species. Acute stimulation with exogenous insulin had no effect on NO content. Whereas insulin exposure caused Ca entry into healthy RBCs, T2DM-RBCs were insensitive. Using RBCs isolated from human blood, we confirmed that insulin had no effect on RBC-NO, despite prompting Ca uptake. Ca uptake with insulin exposure was sensitive to inhibition of mechanosensitive ion channels, as well as Ca chelation. Furthermore, co-incubation of RBCs with the piezo-type mechanosensitive ion channel component 1 (Piezo1) channel agonist Yoda1 and insulin did not produce compounded Ca uptake, raising the possibility of crosstalk between insulin and Piezo1. The hyperinsulinemia associated with T2DM may exacerbate normal Piezo1-dependent Ca uptake into RBCs, contributing to RBC dysfunction and circulatory complications in T2DM. The significance of RBC signaling in the pathophysiology of cardiometabolic disorders is still emerging. Individuals carrying mutations in the PIEZO1 gene exhibit hematological aberrations and hereditary anemia, supporting the importance of Piezo1 in RBC homeostasis. Furthermore, a shift in RBC-NO metabolism favoring nitrosative stress may contribute to circulatory complications observed in metabolic diseases such as T2DM. Collectively, the emerging relevance of RBC signaling pathways may provide novel avenues for targeted drug development.
循环系统缺陷在2型糖尿病（T2DM）中很常见且具有病理生理学相关性。红细胞（RBC）内环境稳态紊乱和一氧化氮（NO）可用性降低会导致内皮功能障碍，这是心脏代谢紊乱的一个标志；然而，潜在的病理生理机制仍不清楚。在这里，我们在代谢性疾病的小鼠模型中研究了RBC信号通路，重点是NO。T2DM-RBC的细胞溶质NO、细胞内钙离子（Ca）和活性氧水平升高。外源性胰岛素的急性刺激对NO含量没有影响。虽然胰岛素暴露会导致Ca进入健康的RBC，但T2DM-RBC不敏感。使用从人血中分离的RBC，我们证实胰岛素对RBC-NO没有影响，尽管它能促使Ca摄取。胰岛素暴露引起的Ca摄取对机械敏感离子通道的抑制以及Ca螯合敏感。此外，将RBC与压电型机械敏感离子通道成分1（Piezo1）通道激动剂Yoda1和胰岛素共同孵育不会产生复合的Ca摄取，这增加了胰岛素和Piezo1之间存在相互作用的可能性。与T2DM相关的高胰岛素血症可能会加剧正常的Piezo1依赖性Ca摄取进入RBC，导致T2DM中的RBC功能障碍和循环系统并发症。RBC信号在心脏代谢紊乱病理生理学中的重要性仍在显现。携带PIEZO1基因突变的个体表现出血液学异常和遗传性贫血，这支持了Piezo1在RBC内环境稳态中的重要性。此外，RBC-NO代谢向有利于亚硝化应激的方向转变可能导致在T2DM等代谢性疾病中观察到的循环系统并发症。总的来说，RBC信号通路新出现的相关性可能为靶向药物开发提供新途径。
