Vasohibin 1 acts as a key regulator of arrhythmogenesis in pressure-overload-induced cardiac hypertrophy.

The morphology and dynamics of microtubules (MTs) are controlled by the posttranslational modification of tubulins and are critical for maintaining cardiac electrophysiological homeostasis. Recent studies have revealed that vasohibin (VASH) is a detyrosinating enzyme of tubulin, and the upregulation of VASH1 (the dominant VASH isoform in the heart) induces MT detyrosination and impaired cardiac function. It remains unknown whether VASH1 participates in the pathogenesis of ventricular arrhythmia, a lethal pathological change in cardiac hypertrophy. Here, we demonstrated that significantly increased expression of VASH1 and detyrosinated α-tubulin led to greater susceptibility of the heart to ventricular arrhythmia, as indicated by an increased number of caffeine and isoproterenol-stimulated premature ventricular complexes (PVCs) on electrocardiography in transverse aortic constriction (TAC)-induced cardiac hypertrophy in mice versus Sham mice. Cardiac-specific VASH1 overexpression induced MT detyrosination and polymerization, increasing the number of stimulated PVCs in normal mice. Optical mapping of the hearts demonstrated that VASH1 overexpression slowed electrical conductance. A mechanistic study revealed that VASH1 upregulation increased the Ca2+ spark frequency and post-pacing Ca2+-release events, disrupted the transverse tubule network, and altered the distribution of connexin-43 at gap junctions. In cultured cardiomyocytes, VASH1 overexpression similarly increased Ca2+ spark generation, which was abolished by the coexpression of tubulin tyrosine ligase (TTL) but not by TTL-E331Q, a mutant that lacks TTL catalytic activity but maintains its depolymerization effect. Furthermore, ablation of VASH1 decreased the susceptibility of TAC mice to ventricular arrhythmia by reducing the expression of arrhythmogenic substrates. In this study, we identified VASH1 as a master regulator of arrhythmogenesis in cardiac hypertrophy, reinforcing this protein as a promising therapeutic target for preventing ventricular arrhythmia.