USP38 deletion improved diastolic dysfunction and arrhythmogenesis in HFpEF mice

BACKGROUND Ventricular arrhythmias (VAs) are commonly observed in patients with heart failure with preserved ejection fraction (HFpEF) and are strongly associated with increased mortality. Ubiquitin-specific protease 38 (USP38) has been implicated in cardiac electrical disorders.OBJECTIVE This study aimed to determine the effects of USP38 in VAs in a mouse model of HFpEF.METHODS We utilized cardiac-specific USP38 knockout and transgenic USP38 mice, along with their respective control groups. HFpEF mice were established by subjected to uninephrectomy and continuous saline or D-aldosterone infusion and given 1% sodium chloride drinking water for 4 weeks. Comprehensive assessments, including echocardiography, electrophysiological studies, histological analyses, and molecular evaluations, were conducted.RESULTS USP38 expression is significantly elevated in the heart of HFpEF mice. Deletion of USP38 markedly ameliorated HFpEF-induced left ventricular (LV) hypertrophy and cardiac diastolic dysfunction. Additionally, USP38 deletion reduced susceptibility to VAs, as evidenced by reversed electrical conduction, inhibited LV fibrosis, and increased CX43 expression. Mechanistically, USP38 deletion suppresses the activation of HIPK2 and its downstream mediators. Overexpression of HIPK2 in the hearts of cardiac-specific USP38 knockout mice partially negated the beneficial effects of USP38 deletion on diastolic dysfunction and arrhythmogenesis. Conversely, cardiac-specific overexpression of USP38 exacerbated cardiac diastolic dysfunction and increased susceptibility to VAs in HFpEF mice.CONCLUSION Knockout of USP38 reduced the susceptibility of HFpEF hearts to VAs by inhibiting HIPK2 activation. USP38 thus represents a novel therapeutic target for the treatment of HFpEF-related diastolic dysfunction and VAs.