Ca2+ Signaling in Cardiac Fibroblasts and Fibrosis-Associated Heart Diseases

Abstract

Cardiac fibrosis is the excessive deposition of extracellular matrix proteins by cardiac fibroblasts and myofibroblasts, and is a hallmark feature of most heart diseases, including arrhythmia, hypertrophy, and heart failure. This maladaptive process occurs in response to a variety of stimuli, including myocardial injury, inflammation, and mechanical overload. There are multiple signaling pathways and various cell types that influence the fibrogenesis cascade. Fibroblasts and myofibroblasts are central effectors. Although it is clear that Ca²⁺ signaling plays a vital role in this pathological process, what contributes to Ca²⁺ signaling in fibroblasts and myofibroblasts is still not wholly understood, chiefly because of the large and diverse number of receptors, transporters, and ion channels that influence intracellular Ca²⁺ signaling. Intracellular Ca²⁺ signals are generated by Ca²⁺ release from intracellular Ca²⁺ stores and by Ca²⁺ entry through a multitude of Ca²⁺-permeable ion channels in the plasma membrane. Over the past decade, the transient receptor potential (TRP) channels have emerged as one of the most important families of ion channels mediating Ca²⁺ signaling in cardiac fibroblasts. TRP channels are a superfamily of non-voltage-gated, Ca²⁺-permeable non-selective cation channels. Their ability to respond to various stimulating cues makes TRP channels effective sensors of the many different pathophysiological events that stimulate cardiac fibrogenesis. This review focuses on the mechanisms of Ca²⁺ signaling in fibroblast differentiation and fibrosis-associated heart diseases and will highlight recent advances in the understanding of the roles that TRP and other Ca²⁺-permeable channels play in cardiac fibrosis.

Keywords: Ca2+ signaling pathways; TRP channels; cardiac fibroblasts; cardiac fibrosis; ion channels.

Figure 1

Schematic diagram illustrating cardiac fibrogenesis cascade and fibrosis-associated heart diseases. Pathological stresses stimulate fibroblasts to differentiate into myofibroblasts, during which an increase in intracellular Ca²⁺ plays a key role. Myofibroblasts synthesize and secrete extracellular matrix (ECM) proteins, matrix metalloproteinases (MMPs), and cytokines such as TGFβ1. Excessive deposition of ECM proteins results in cardiac fibrosis. This fibrogenesis cascade is perpetuated by TGFβ1 produced by myofibroblasts. Cardiac fibrosis is involved in a variety of pathological remodeling, which can lead to arrhythmia, hypertrophy and heart failure.

Figure 2

Ca²⁺ signaling mechanisms in cardiac fibroblasts and myofibroblasts. Intracellular Ca²⁺ levels are finely controlled by: (1) Ca²⁺ entry through Ca²⁺-permeable channels in the plasma membrane, including TRP channels, P2X receptors, and Orai/STIM channels; (2) Ca²⁺ release via IP₃Rs in the ER; and (3) Ca²⁺ extrusion pumps, including SERCA in the ER and PMCA4 in the plasma membrane. Pathophysiological stimuli can activate Gq-coupled receptors to induce Ca²⁺ release, which is secondarily followed by Ca²⁺ entry. Receptor stimulation can also directly activate Ca²⁺-permeable (TRP) channels in the plasma membrane. Other ion channels, including voltage-gated K⁺ (K_v) channels, Kir channels, Ca²⁺-activated potassium (K_Ca) channels, and Na_V channels, may influence the resting membrane potential or depolarization to indirectly influence Ca²⁺ entry in fibroblasts and myofibroblasts. An increase in intracellular Ca²⁺ activates the calcineurin/NFAT (CN/NFAT), ERK1/2, ROS/RhoA, and sFRP2 pathways to promote profibrotic gene expression.