PKC-PKD-NFκB signaling induces cardiomyocyte t-tubule loss via a conserved macropinocytic mechanism
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ID: 315819
2026
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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 signaling 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 remodeling 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 signaling. CONCLUSIONS: PKC-PKD-NFκB signaling triggers a macropinocytic form of membrane remodeling 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.
| Reference Key |
openalex_W7163415713
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| Authors | A Martinez-Vilchez, A -K M Pfeuffer, J Weßolowski, D J Fiegle, P Andrä, P Potue, L K Küpfer, T S Shankar, C H Selzman, S G Drakos, C Heim, T Volk, T Seidel |
| Journal | cardiovascular research |
| Year | 2026 |
| DOI |
10.1093/cvr/cvag121
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| URL | |
| Keywords | Keywords not found |
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