Ca²⁺ Signaling in Cardiac Fibroblasts: An Emerging Signaling Pathway Driving Fibrotic Remodeling in Cardiac Disorders

Area of Science:

• Cardiovascular Research
• Cellular Biology
• Molecular Medicine

Background:

• Cardiac fibrosis is myocardial scarring from various heart disorders.
• Fibroblast to myofibroblast differentiation drives extracellular matrix deposition.
• Elevated intracellular calcium ([Ca2+]i) in cardiac fibroblasts is a critical fibrogenic mediator.

Purpose of the Study:

• To review mechanisms of intracellular calcium signaling in cardiac fibroblast to myofibroblast differentiation.
• To highlight the role of inositol-1,4,5-trisphosphate receptors (InsP3Rs) and store-operated calcium entry (SOCE).
• To discuss other calcium entry pathways and pharmacological interventions.

Main Methods:

• Review of existing literature on calcium signaling in cardiac fibrosis.
• Focus on the interplay between InsP3Rs and SOCE in Gq-protein coupled receptor (GqPCR) signaling.
• Discussion of receptor-operated calcium entry (ROCE), TRP channels, P2X receptors, and Piezo1 channels.

Main Results:

• InsP3Rs and SOCE are key drivers of the calcium response in GqPCR-mediated fibrotic remodeling.
• Multiple pathways, including ROCE, P2X, TRP, and Piezo1 channels, contribute to sustained extracellular calcium entry.
• Calcium handling machinery modulation is a potential therapeutic strategy.

Conclusions:

• Intracellular calcium signaling is central to cardiac fibroblast activation and fibrosis.
• Targeting specific calcium channels and pathways offers a promising therapeutic avenue for cardiac fibrosis.
• Pharmacological manipulation of calcium handling may mitigate or reverse fibrotic remodeling.