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

Jianlin Feng,Albert S Yu,Bruce T Liang,Loren W Runnels,Maria K Armillei,Lixia Yue

doi:10.3390/jcdd6040034

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.

Highlights

Cardiac fibrosis is involved in pathological remodeling of the heart, causing abnormalities in cardiac conduction, stiffness of the ventricular walls, reduced contractility, and impaired overall heart performance [1]
TRPC3 channels have been shown to play a role in cardiac fibrosis and fibrosis-associated heart diseases, such as atrial fibrillation (AF) [70] and heart failure induced by pressure overload [166,167]
There are a multitude of signaling pathways, bioactive molecules, and various cell types that are involved in the cardiac fibrogenesis cascade

Summary

Introduction

Cardiac fibrosis is involved in pathological remodeling of the heart, causing abnormalities in cardiac conduction, stiffness of the ventricular walls, reduced contractility, and impaired overall heart performance [1]. Various fibrotic stimuli are known to activate Gq-coupled receptors in fibroblasts to induce Ca2+ influx through store-operated ion channels and TRP channels This short review summarizes recent advances in the understanding of the different components contributing to intracellular Ca2+ signals, including Ca2+ release and Ca2+ entry, and their roles in cardiac fibrosis and fibrosis-associated heart diseases (Figure 2). While store-operated Ca2+ release and entry were shown to increase, the expressions of Orai and STIM1 remained unchanged [67] These results suggest that Orai/STIM channels play a role in fibroblast Ca2+ signaling, and may contribute to cardiac remodeling under pathological conditions.

TRPC Channels

TRPV Channels in Fibroblasts and Cardiac Fibrosis

TRPM Channels and Cardiac Fibrosis

TRPA1 in Cardiac Fibroblasts

Findings

Conclusions and Future Perspectives