Circ Res. 2026 Feb 25. doi: 10.1161/CIRCRESAHA.125.327680. Online ahead of print.
ABSTRACT
BACKGROUND: Pathogenic cardiac hypertrophy, often driven by mechanical stress, is a leading cause of heart failure. However, effective therapeutic targets remain limited. TMC6 (transmembrane channel-like protein 6) is abundant in healthy myocardium but downregulated in hypertrophic hearts; its role in cardiac hypertrophy remains undefined.
METHODS: We combined cardiac-specific Tmc6 knockout mice subjected to transverse aortic constriction surgery, neonatal rat ventricular myocytes, and CRISPR/Cas9-edited human pluripotent stem cell-derived cardiomyocytes to assess hypertrophy and signaling readouts. Subcellular localization, protein-protein interaction, and competitive peptide assays were used to dissect the mechanism. Adeno-associated virus serotype 9 (AAV9)-cTnT (cardiac troponin T)-TMC6 was used for in vivo rescue.
RESULTS: TMC6 deficiency increased cardiomyocyte size, fetal gene expression, and adverse remodeling in vivo and in vitro, whereas TMC6 overexpression blunted hypertrophic responses. Full-length TMC6 localized to the endoplasmic reticulum and bound CIB1 (calcium and integrin-binding protein 1) to sequester it in the endoplasmic reticulum, limiting CIB1 access to sarcolemmal Ca2+ microdomains required to scaffold calcineurin and activate NFAT (nuclear factor of activated T cells). A cell-permeable TMC6161-180 peptide competitively displaced CIB1 from TMC6 and augmented hypertrophy in wild-type but not Tmc6 knockout cardiomyocytes, indicating a dominant-negative mechanism. Therapeutically, AAV9-cTnT-TMC6 restored TMC6-CIB1 engagement, suppressed calcineurin/NFAT readouts, and improved function after pressure overload.
CONCLUSIONS: TMC6 is an endogenous brake on pathological hypertrophy that restrains CIB1-calcineurin/NFAT signaling via endoplasmic reticulum sequestration of CIB1. Restoring full-length TMC6 mitigates pressure-overload remodeling, nominating the TMC6-CIB1 axis as a therapeutic target.
PMID:41738082 | DOI:10.1161/CIRCRESAHA.125.327680