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Upregulation of transient receptor potential melastatin 4 (TRPM4) in ventricular fibroblasts from heart failure patients

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Abstract

The transient receptor potential melastatin 4 (TRPM4) is a Ca2+-activated nonselective monovalent cation channel belonging to the TRP channel superfamily. TRPM4 is widely expressed in various tissues and most abundantly expressed in the heart. TRPM4 plays a critical role in cardiac conduction. Patients carrying a gain-of-function or loss-of-function mutation of TRPM4 display impaired cardiac conduction. Knockout or over-expression of TRPM4 in mice recapitulates conduction defects in patients. Moreover, recent studies have indicated that TRPM4 plays a role in hypertrophy and heart failure. Whereas the role of TRPM4 mediated by cardiac myocytes has been well investigated, little is known about TRPM4 and its role in cardiac fibroblasts. Here we show that in human left ventricular fibroblasts, TRPM4 exhibits typical Ca2+-activation characteristics, linear current–voltage (I–V) relation, and monovalent permeability. TRPM4 currents recorded in fibroblasts from heart failure patients (HF) are more than 2-fold bigger than those from control individuals (CTL). The enhanced functional TRPM4 in HF is not resulted from changed channel properties, as TRPM4 currents from both HF and CTL fibroblasts demonstrate similar sensitivity to intracellular calcium activation and extracellular 9-phenanthrol (9-phen) blockade. Consistent with enhanced TRPM4 activity, the protein level of TRPM4 is about 2-fold higher in HF than that of CTL hearts. Moreover, TRPM4 current in CTL fibroblasts is increased after 24 hours of TGFβ1 treatment, implying that TRPM4 in vivo may be upregulated by fibrogenesis promotor TGFβ1. The upregulated TRPM4 in HF fibroblasts suggests that TRPM4 may play a role in cardiac fibrogenesis under various pathological conditions.

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Abbreviations

BMI:

body mass index

CAD:

coronary artery disease

DM:

diabetes mellitus

EF:

ejection fraction

Eth:

ethnicity

Gen:

gender

HF:

heart failure

HLD:

hyperlipidemia

HTN:

hypertension

Med:

outpatient medication

MI:

myocardial infarction

VD:

valve diseases

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Funding

This work was partially supported by the National Institute of Health (P01-HL06426, R01-AA024769, and R01-HL146744 to XA; and R01-HL143750 to LY) and American Heart Association (19TPA34890022 to LY).

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Author notes

  1. Jianlin Feng and Pengyu Zong contributed equally to this work.

Authors and Affiliations

  1. Calhoun Cardiology Center, Department of Cell Biology, University of Connecticut School of Medicine (UConn Health), Farmington, CT, 06030, USA

    Jianlin Feng, Pengyu Zong, Zhichao Yue, Xin Li, Chevaughn Smith & Lixia Yue

  2. Department of Physiology and Biophysics, Rush University Medical Center, Chicago, IL, 60612, USA

    Jiajie Yan & Xun Ai

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  1. Jianlin Feng
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  7. Xun Ai
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  8. Lixia Yue
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Correspondence to Lixia Yue.

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This article is part of the special issue on Calcium Signal Dynamics in Cardiac Myocytes and Fibroblasts: Mechanisms in Pflügers Archiv—European Journal of Physiology

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Feng, J., Zong, P., Yan, J. et al. Upregulation of transient receptor potential melastatin 4 (TRPM4) in ventricular fibroblasts from heart failure patients. Pflugers Arch - Eur J Physiol 473, 521–531 (2021). https://doi.org/10.1007/s00424-021-02525-2

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  • DOI: https://doi.org/10.1007/s00424-021-02525-2

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