Our Publications Database

reactive oxygen species, cardiac Ca²⁺ handling proteins, mechanotransduction, Bruton tyrosine kinase (BTK) inhibitor, protein phosphatase 2A (PP2A), mitochondria-associated proteins (MAM)

Calcium (Ca) is a universal intracellular second messenger. In muscle, Ca is best known for its role in contractile activation. However, in recent years the critical role of Ca in other myocyte processes has become increasingly clear. This review focuses on Ca signaling in cardiac myocytes as pertaining to electrophysiology (including action potentials and arrhythmias), excitation-contraction coupling, modulation of contractile function, energy supply-demand balance (including mitochondrial function), cell death, and transcription regulation. Importantly, although such diverse Ca-dependent regulations occur simultaneously in a cell, the cell can distinguish distinct signals by local Ca or protein complexes and differential Ca signal integration.

fibroblast; myofibroblast; Ca²⁺ signaling; cardiac fibrosis; pulmonary fibrosis; Ca²⁺ ion channels; Ca²⁺ transport mechanisms

Background

Fibrogenesis is a physiological process required for wound healing and tissue repair. It is induced by activation of quiescent fibroblasts, which first proliferate and then change their phenotype into migratory, contractile myofibroblasts. Myofibroblasts secrete extracellular matrix proteins, such as collagen, to form a scar. Once the healing process is terminated, most myofibroblasts undergo apoptosis. However, in some tissues, such as the heart, myofibroblasts remain active and sensitive to neurohumoral factors and inflammatory mediators, which lead eventually to excessive organ fibrosis. Many cellular processes involved in fibroblast activation, including cell proliferation, protein secretion and cell contraction, are highly regulated by intracellular Ca²⁺ signals. This review summarizes current research on Ca²⁺ signaling pathways underlying fibroblast activation. We present receptor- and ion channel-mediated Ca²⁺ signaling pathways, discuss how localized Ca²⁺ signals of the cell nucleus may be involved in fibroblast activation and present Ca²⁺-sensitive transcription pathways relevant for fibroblast biology. When investigated, we highlight how the function of Ca²⁺-handling proteins changes during cardiac and pulmonary fibrosis. Many aspects of Ca²⁺ signaling remain unexplored in different types of cardiovascular fibroblasts in relation to pathologies, and a better understanding of Ca²⁺ signaling in fibroblasts will help to design targeted therapies against fibrosis.