Key ion channels in mechanical stress-induced cardiac remodeling: from mechanotransduction to therapeutic targets

Abstract

Mechanical stress—including pressure overload and volume overload—is a core pathophysiological stimulus driving cardiac remodeling, and Ca²⁺ signaling is the central common pathway mediating this process. Traditional research has primarily focused on L-type Ca²⁺ channels (LTCC) and the renin-angiotensin-aldosterone system, whereas the synergistic contributions of mechanosensitive channels (transient receptor potential (TRP), Piezo), canonical excitation-contraction coupling channels [voltage-gated Na⁺ channels, LTCC, the sarcoplasmic reticulum Ca²⁺ release channel type 2 ryanodine receptor (RyR2), and the Na⁺/Ca²⁺ exchanger (NCX)], non-canonical Ca²⁺ channels (NMDAR), and the mechanosensitive angiotensin II type 1 receptor are increasingly being recognized. This review systematically integrates the mechanisms by which these distinct ion channel families transduce mechanical stimuli into intracellular Ca²⁺ signals and cooperatively regulate cardiac remodeling, with particular emphasis on their cell-type-specific distribution and function in cardiomyocytes, endothelial cells, vascular smooth muscle cells, cardiac fibroblasts, and perivascular sensory neurons and macrophages. We highlight the Ca²⁺-Na⁺-reactive oxygen species (ROS) signaling triad, which forms a self-reinforcing vicious cycle that drives cardiomyocyte hypertrophy, fibrosis, and electrical remodeling, and we elucidate how the relevant channels are differentially regulated under pressure overload versus volume overload. Key findings include the direct mechanosensor function of Piezo1, the multimodal sensing capacity of TRP channels, the non-canonical cardiac expression of NMDAR and its proarrhythmic effects, the paradoxical hypertrophic response triggered by reduced LTCC activity, and the pivotal role of RyR2 as a disease-modifying node. From a therapeutic perspective, we review classical calcium channel blockers and emerging strategies—including mechanosensitive channel modulators, NMDAR antagonists, RyR2 stabilizers, NCX modulation, and ROS-targeted interventions—stratified by disease context and level of evidence. This integrated mechano-calcium signaling framework provides a new theoretical basis and potential therapeutic targets for cardiac remodeling-related diseases.

Keywords

Cardiac remodeling / mechanotransduction / mechanosensitive ion channels / calcium signaling / cardiac hypertrophy / cell-type specificity / reactive oxygen species / therapeutic targets

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