PKC-PKD-NFκB signalling induces cardiomyocyte t-tubule loss via a conserved macropinocytic mechanism

Martinez-Vilchez A, Pfeuffer AK, Weßolowski J, Fiegle D, Andrä P, Potue P, Küpfer L, Shankar TS, Selzman CH, Drakos SG, Heim C, Volk T, Seidel T (2026)

Publication Type: Journal article

Publication year: 2026

Journal

Cardiovascular Research Oxford University Press

Book Volume: 122

Pages Range: 1470-1486

Journal Issue: 11

DOI: 10.1093/cvr/cvag121

Abstract

Aims: Deterioration of transverse-axial tubules (t-tubules) contributes to insufficient excitation-contraction coupling in heart failure, yet the key signals and mechanisms remain unclear. Here, we aimed to identify the signalling pathways that trigger cardiomyocyte t-tubule loss and its underlying cellular process. Methods and results: Adult rat, rabbit, and human ventricular cardiomyocytes and living myocardial slices were exposed to pharmacological activators of protein kinase C (PKC). PKC activation caused rapid t-tubule loss and impaired Ca2+ transients, which were prevented by inhibition of protein kinase D (PKD) or NFκB. RNA sequencing and phosphoprotein analysis showed activation and crosstalk between PKD-, ERK-, and NFκB-dependent pathways, with up-regulation of genes involved in membrane trafficking and endocytosis. Fluorescent dextran uptake assays revealed a clathrin-independent, PI3K- and myosin-I-dependent macropinocytic process whose rate matched the internalization of t-tubule membranes and which was blocked by NFκB inhibition. Constitutive activation of IKK2 in cardiomyocytes of transgenic mice reduced t-tubule density in vivo, confirming that prolonged NFκB activation is sufficient to induce t-tubule remodelling in intact hearts. NFκB inhibition suppressed PKC-induced macropinocytosis also in non-cardiac human cell lines, suggesting that this process represents a conserved cellular response to inflammatory signalling. Conclusion: PKC-PKD-NFκB signalling triggers a macropinocytic form of membrane remodelling that degrades the t-tubule network and impairs excitation-contraction coupling. This identifies a previously unrecognized mechanism linking inflammatory kinase activation to structural and functional decline of cardiomyocytes and suggests that targeting the PKD-NFκB axis could preserve t-tubule integrity and cardiac performance in heart failure.

Authors with CRIS profile

Aiora Martinez-Vilchez Professur für Herz-Kreislaufphysiologie Ann-Katrin Pfeuffer Institut für Zelluläre und Molekulare Physiologie Jonas Weßolowski Institut für Zelluläre und Molekulare Physiologie Dominik Fiegle Professur für Herz-Kreislaufphysiologie Prapassorn Potue Lehrstuhl für Physiologie (Vegetative Physiologie) Linda Küpfer Institut für Zelluläre und Molekulare Physiologie Christian Heim Department of Cardiac Surgery Tilmann Volk Professur für Herz-Kreislaufphysiologie Thomas Seidel Professur für Herz-Kreislaufphysiologie

Involved external institutions

University of Utah US United States (USA) (US)

How to cite

APA:

Martinez-Vilchez, A., Pfeuffer, A.-K., Weßolowski, J., Fiegle, D., Andrä, P., Potue, P.,... Seidel, T. (2026). PKC-PKD-NFκB signalling induces cardiomyocyte t-tubule loss via a conserved macropinocytic mechanism. Cardiovascular Research, 122(11), 1470-1486. https://doi.org/10.1093/cvr/cvag121

MLA:

Martinez-Vilchez, Aiora, et al. "PKC-PKD-NFκB signalling induces cardiomyocyte t-tubule loss via a conserved macropinocytic mechanism." Cardiovascular Research 122.11 (2026): 1470-1486.

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