TMC6 Is a Novel Therapeutic Target for Pathogenic Cardiac Hypertrophy.

Area of Science:

• Cardiology
• Molecular Biology
• Cell Biology

Background:

• Pathogenic cardiac hypertrophy, a major cause of heart failure, lacks effective therapeutic targets.
• Transmembrane channel-like protein 6 (TMC6) is downregulated in hypertrophic hearts, but its function is unknown.

Purpose of the Study:

• To investigate the role of TMC6 in cardiac hypertrophy.
• To elucidate the molecular mechanism by which TMC6 regulates cardiac hypertrophy.
• To assess the therapeutic potential of TMC6 in pressure-overload induced cardiac remodeling.

Main Methods:

• Utilized cardiac-specific Tmc6 knockout mice subjected to transverse aortic constriction.
• Employed neonatal rat ventricular myocytes and CRISPR/Cas9-edited human iPSC-derived cardiomyocytes.
• Performed subcellular localization, protein-protein interaction, and competitive peptide assays.
• Used adeno-associated virus serotype 9 (AAV9)-cTnT-TMC6 for in vivo rescue experiments.

Main Results:

• TMC6 deficiency exacerbated cardiomyocyte hypertrophy and fetal gene expression.
• TMC6 localized to the endoplasmic reticulum, binding and sequestering CIB1.
• TMC6 sequestration of CIB1 prevented calcineurin/NFAT activation, a key hypertrophic pathway.
• Overexpression of TMC6 or in vivo AAV9-cTnT-TMC6 delivery blunted hypertrophic responses and improved cardiac function.

Conclusions:

• TMC6 acts as an endogenous suppressor of pathological cardiac hypertrophy.
• The TMC6-CIB1 interaction at the endoplasmic reticulum inhibits the calcineurin/NFAT signaling pathway.
• Restoring TMC6 function represents a promising therapeutic strategy for heart failure due to pressure overload.