Vitamin D in cardiac fibroblasts: new evidence for a TRP-mediated non-genomic pathway

Abstract Background/Introduction Vitamin D’s (VD) role transcends phosphocalcic metabolism to affect different systems, notably the cardiovascular system in health and diseases. Beyond its genomic effect, VD act through non-genomic calcium (Ca2+) signaling pathways, hinting at a broader spectrum of physiological impacts. Despite the established interactions with cardiomyocytes via the Vitamin D Receptor (VDR), little is known about VD and cardiac fibroblast, a pivotal cell player in cardiac function and disease. Purpose This research aims to reveal Vitamin D's role in modulating cardiac fibroblast function through Transient Receptor Potential (TRP) channels. Methods Utilizing primary cardiac fibroblasts from human and rats, our investigation focused on intracellular calcium signaling. Through Ca2+ imaging techniques combined to synthetic fluorescent VD analogue, we explored Vitamin D's behavior within the cell. The study further employed biochemical assays to elucidate the interaction between VDR on the cell membrane and TRP channels signaling, providing a detailed map of the cellular choreography orchestrated by VD within cardiac fibroblasts. In addition, in vitro and ex vivo heart perfusion experiments were incorporated to assess cardiac cGMP production in response to VD. Results Our findings reveal a unique pathway wherein VD induces Ca2+ oscillations in human and rat cardiac fibroblasts specifically through the TRPC3 channel, sidelining other calcium sources. This process is regulated by the interaction between TRPC3 and the membrane-bound VDR, harmonizing with phospholipase C signaling to a crescendo of cGMP production in cardiac fibroblasts, and across the entire heart. This was associated with less pro-fibrotic potential of cardiac fibroblasts. Conclusion This study provides the first evidence of a TRP-mediated, VD non-genomic pathway within human and rat cardiac fibroblasts. Our findings herald a promising horizon for investigating vitamin D’s antifibrotic potential in heart disease.