Ion channels in macrophages: dynamic regulation in cardiovascular and cerebrovascular diseases and therapeutic potential

Abstract

Background: Cardiovascular and cerebrovascular diseases (CCVDs) have surpassed cancer as a significant global health challenge. As essential responders of the immune system, macrophages play a critical role in maintaining and remodeling CCVD homeostasis. They are involved in various functions, including the clearance of apoptotic cells, regulation of inflammatory responses, enhancement of electrical conduction, and facilitation of tissue development and repair. Ion channels not only participate in the electrophysiological activities of macrophages but also directly influence tissue immune responses and inflammatory processes. The regulatory role of ion channels in macrophage function in CCVDs has attracted considerable attention.

Aim: of Review: This review aims to systematically elucidate the specific expression and functional regulation of macrophage ion channels within the cardiovascular and cerebrovascular systems and analyzes the functional heterogeneity of these channels across distinct tissue-specific macrophage subsets. It further explores their mechanistic roles in the progression and repair of CCVDs. Key Scientific Concepts of Review: This review elucidates the fundamental functions and electrophysiological basis of macrophages in the heart, vasculature, and brain, including parenchymal resident macrophages (microglia) of the brain. It further discusses the variation in ion channel expression across macrophages of different tissue origins and polarization states and how this heterogeneity dictates their specific functional roles. Additionally, this review summarizes the pathophysiological contributions of macrophage ion channels to major cardiovascular and cerebrovascular disorders, as well as the underlying molecular mechanisms. Furthermore, it provides an in-depth analysis of the functional mechanisms of key ion channels, critically discusses existing controversies and limitations in current research, and offers our perspectives along with feasible solutions. Finally, this review explores future research directions and emerging trends in this field, along with the clinical potential of targeting macrophage ion channels as a novel therapeutic strategy for CCVDs.

Keywords: Cardiovascular and cerebrovascular diseases; Inflammation; Ion channels; Macrophages.