Trans-cinnamaldehyde targets VASH1 to reverse microtubule detyrosination and cardiac hypertrophy.

Trans-cinnamaldehyde (TCA) is a bioactive compound derived from cinnamon. Our previous study demonstrated that TCA exerts anti-cardiac hypertrophy effects associated with reduced tubulin detyrosination, but its precise mechanism remains unknown. This study investigated the therapeutic potential of TCA against PE-induced myocardial hypertrophy and its mechanism via the VASH1-dependent α-tubulin detyrosination pathway. PE-induced cardiac hypertrophy models were established in C57BL/6 mice (in vivo) and neonatal/adult cardiomyocytes (in vitro), with TCA administered at 5 μM (in vitro) and 50 mg/kg/d (in vivo), consistent with our previous work. Cardiac structure and function, hypertrophy, tubulin detyrosination, T-tubule integrity, and related protein expression were assessed. Molecular docking and CETSA confirmed the binding of TCA to VASH1, CHX chase assays verified that TCA accelerates VASH1 protein degradation. Further mechanistic validation was performed using VASH1 overexpression rescue experiments. TCA ameliorated PE-induced cardiac remodeling, fibrosis, and diastolic dysfunction in vivo, and reversed cardiomyocyte hypertrophy and excitation-contraction coupling impairment in vitro. Mechanistically, TCA directly binds to VASH1, restrains its overexpression and excessive α-tubulin detyrosination, and further maintains T-tubule structural integrity. It thereby preserves normal JPH2-RyR2 colocalization, rectifies abnormal STIM1-Orai1 distribution, improves defective excitation-contraction coupling and inhibits excessive SOCE, ultimately restoring intracellular calcium homeostasis and sarcomere contractile function. VASH1 overexpression completely abrogates the cardioprotective actions of TCA. Collectively, these results demonstrate that TCA ameliorates PE-triggered myocardial hypertrophy and cardiac dysfunction via targeting VASH1 to normalize microtubule detyrosination, suggesting VASH1 as a promising therapeutic target for adverse cardiac remodeling.