TRPC3 Channels in Cardiac Fibrosis

Abstract

Cardiac stiffness, caused by interstitial fibrosis due to deposition of extracellular matrix proteins, is thought as a major clinical outcome of heart failure with preserved ejection fraction (HFpEF). Canonical transient receptor potential (TRPC) subfamily proteins are components of Ca²⁺-permeable non-selective cation channels activated by receptor stimulation and mechanical stress, and have been attracted attention as a key mediator of maladaptive cardiac remodeling. How TRPC-mediated local Ca²⁺ influx encodes a specific signal to induce maladaptive cardiac remodeling has been long obscure, but our recent studies suggest a pathophysiological significance of channel activity-independent function of TRPC proteins for amplifying redox signaling in heart. This review introduces the current understanding of the physiological and pathophysiological roles of TRPCs, especially focuses on the role of TRPC3 as a positive regulator of reactive oxygen species (PRROS) in heart. We have revealed that TRPC3 stabilizes NADPH oxidase 2 (Nox2), a membrane-bound reactive oxygen species (ROS)-generating enzyme, by forming stable protein complex with Nox2, which leads to amplification of mechanical stress-induced ROS signaling in cardiomyocytes, resulting in induction of fibrotic responses in cardiomyocytes and cardiac fibroblasts. Thus, the TRPC3 function as PRROS will offer a new therapeutic strategy for the prevention or treatment of HFpEF.

Keywords: Ca2+; NADPH oxidase; canonical transient receptor potential; cardiac fibrosis; cardiac remodeling; reactive oxygen species.

Figure 1

Involvement of TRPC3 in the activation of NADPH oxidase 2 (Nox2). (A) TRPC3-mediated Ca²⁺ influx recruits and activates protein kinase C (PKC) which phosphorylates p47^phox and evokes Nox2 enzymatic activation. (B) Schematic illustration of the domain structure of TRPC3. TRPC3 interacts with Nox2 through the C-terminal region. Numbers represent the positions of amino acids from first methionine.

Figure 2

Physical interaction with TRPC3 prevents NADPH oxidase 2 (Nox2) from proteasome-dependent downregulation. In physiological condition, level of Nox2 expression is kept low by proteasomal degradation. Without interaction with p22^phox, actively gp91^phox is degraded. By physical interaction with TRPC3, both gp91^phox and p22^phox are protected from proteasomal degradation, which leads to excess expression of Nox2 enzyme on the plasma membrane.

Figure 3

Aberrant reactive oxygen species (ROS) production by TRPC3–NADPH oxidase 2 (Nox2) coupling evokes cardiac fibrosis. In pathological conditions, TRPC3 protein abundance is increased, which leads to Nox2 protein stabilization. This positive regulation of Nox2 induces accumulation of excessive Nox2 complex on the plasma membrane. The ROS production mediated by TRPC3–Nox2 axis activates RhoA in both cardiomyocytes and cardiac fibroblast activated by mechanical stress and TGFβ, respectively, leading to cardiac fibrosis.