Targeting cardiac fibrosis in aging: role of TRPA1

This work synthesizes current evidence on the transient receptor potential ankyrin 1 (TRPA1) ion channel and its relevance to cardiac fibrosis in aging, situating TRPA1 as a promising focal point for translational research into age-related myocardial remodeling. TRPA1 is a non-selective cation channel permeable to calcium that functions as a versatile sensor of temperature, chemical, and mechanical stimuli and is activated by endogenous inflammatory mediators and reactive oxygen species. Over the past two decades, studies have increasingly documented TRPA1 expression beyond sensory neurons - notably in vascular endothelial cells, vascular smooth muscle cells, cardiomyocytes, and cardiac fibroblasts - implicating the channel in multiple aspects of cardiovascular physiology and pathophysiology. The review highlights TRPA1's structural features and functional properties that are relevant to cardiac biology, including an extensive N-terminal region containing multiple ankyrin repeat domains that mediate protein interactions and confer mechanosensitive and chemically responsive behavior. In the context of myocardial fibrosis, TRPA1's permeability to calcium and sensitivity to oxidative and inflammatory cues position it as a potential regulator of fibroblast activation, extracellular matrix deposition, and cross-talk between inflammatory cells and resident cardiac cells.

The assembled evidence considers TRPA1 involvement in ischemic heart disease and ischemia-reperfusion injury, conditions that commonly provoke fibrotic remodeling, and places myocardial fibrosis within a broader framework of TRPA1-mediated responses to tissue injury and environmental toxins. The review also summarizes data on TRPA1 agonists and antagonists, noting that clinical trials are already evaluating these modulators for neurological and dermatological disorders, which underscores both the translational potential and the pharmacological tractability of targeting TRPA1. Yet the authors emphasize unresolved mechanistic questions and the need for focused research to delineate cell-type specific roles of TRPA1 within the aging heart. Key challenges include clarifying whether TRPA1 activation in cardiac fibroblasts promotes or attenuates fibrotic pathways under different contexts, defining downstream calcium-dependent signaling cascades in aged myocardial tissue, and understanding interactions with reactive oxygen species and inflammatory mediators that are prevalent in aging.

The review calls for integrative approaches combining molecular, cellular, and in vivo studies to evaluate how modulating TRPA1 influences fibroblast phenotype, matrix turnover, and overall cardiac function in aged models. It further highlights opportunities for repurposing or next-generation development of TRPA1 modulators, while cautioning that systemic effects and tissue-specific outcomes must be carefully assessed. By bringing together anatomical, physiological, and pharmacological perspectives, this synthesis positions TRPA1 as an actionable target for interventions aimed at mitigating age-related myocardial fibrosis, and it outlines strategic directions for future research to translate mechanistic insights into therapeutic strategies that could preserve cardiac structure and function in the aging population.