TRP Channels: Current Perspectives in the Adverse Cardiac Remodeling

Abstract

Calcium is an important second messenger required not only for the excitation-contraction coupling of the heart but also critical for the activation of cell signaling pathways involved in the adverse cardiac remodeling and consequently for the heart failure. Sustained neurohumoral activation, pressure-overload, or myocardial injury can cause pathologic hypertrophic growth of the heart followed by interstitial fibrosis. The consequent heart's structural and molecular adaptation might elevate the risk of developing heart failure and malignant arrhythmia. Compelling evidences have demonstrated that Ca²⁺ entry through TRP channels might play pivotal roles in cardiac function and pathology. TRP proteins are classified into six subfamilies: TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPA (ankyrin), TRPML (mucolipin), and TRPP (polycystin), which are activated by numerous physical and/or chemical stimuli. TRP channels participate to the handling of the intracellular Ca²⁺ concentration in cardiac myocytes and are mediators of different cardiovascular alterations. This review provides an overview of the current knowledge of TRP proteins implication in the pathologic process of some frequent cardiac diseases associated with the adverse cardiac remodeling such as cardiac hypertrophy, fibrosis, and conduction alteration.

Keywords: TRP channels; calcium; cardiac remodeling; conduction disorders; fibrosis; hypertrophy.

Figure 1

Scheme summarizing the role of TRP channels in cardiac hypertrophy. Activation of TRP channels can be preceded by stimulation of G-coupled receptors with hypertrophic agonists, by mechanical stress, or pressure overload. The consequent increase of the intracellular Ca²⁺ concentration stimulates different signaling protein, such as PKC, AKT, calcineurin, and NFAT, whose activation promotes TRP channels overexpression and the activation of fetal genes reprograming leading to cardiac hypertrophy.

Figure 2

Scheme summarizing the role of TRP channels in cardiac fibrosis. In pathological conditions, different kind of stress stimulates Ca²⁺ entry in cardiac myocyte through TRP channels and other signaling pathway as RhoA dependent on reactive oxygen species (ROS) production, which lead to profibrotic gene’s expression. Profibrotic agonists and other stimuli activate cardiac fibroblast (green) leading to their proliferation and differentiation. The intracellular Ca²⁺ concentration increase through TRP channels promotes the expression of pro-fibrotic agonist (TGF-β1), α-SMA, collagen, and different isoforms of TRP channels, leading to exacerbated extracellular matrix synthesis and fibrosis.