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.
Highlights
The physiological and pathophysiological significance of Ca2+ influx across the plasma membrane in cardiomyocytes has been discussed for a long time, but how the heart decodes a specific Ca2+ influx as pathological signal under the background of rhythmic Ca2+ entry is obscure
Kitajima et al demonstrated that overexpression of C-terminal fragment of TRPC3 that is a critical region for the interaction with NADPH oxidase 2 (Nox2) in cardiomyocytes abrogated TRPC3 channel activity-dependent reactive oxygen species (ROS) production (Figures 1 and 2) [5]
It will be no doubt that TRPC channels, especially TRPC3, play a key role in the development of maladaptive cardiac remodeling
Summary
The physiological and pathophysiological significance of Ca2+ influx across the plasma membrane in cardiomyocytes has been discussed for a long time, but how the heart decodes a specific Ca2+ influx as pathological signal under the background of rhythmic Ca2+ entry is obscure. We have reported that diacylglycerol-activated TRPC3 and TRPC6 heteromultimer channels (TRPC3/6) act as a key mediator of pathological hypertrophy in receptor-stimulated rat cardiomyocytes [2, 3] and pressure-overloaded mouse hearts [4], while our recent studies using TRPC3/6-deficient mice have revealed that TRPC3 mediates pressure overload-induced maladaptive cardiac fibrosis, independently of TRPC6 channels [5, 6]. This review focuses on the putative molecular mechanism underlying TRPC3-mediated maladaptive cardiac fibrosis in rodent hearts and discusses its therapeutic possibilities
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