USP38 regulates inflammatory cardiac remodeling after myocardial infarction

The inflammatory response and subsequent ventricular remodeling are key factors contributing to ventricular arrhythmias (VAs) after myocardial infarction (MI). Ubiquitin-specific protease 38 (USP38) is a member of the USP family, but the impact of USP38 in arrhythmia substrate generation after MI remains unclear. This study aimed to determine the role of USP38 in post-MI VAs and its underlying mechanisms.

Surgical left descending coronary artery ligation was used to construct MI models. Morphological, biochemical, histological, and electrophysiological studies and molecular analyses were performed after MI on days 3 and 28. We found that the USP38 expression was remarkably increased after MI. Cardiac-conditional USP38 knockout (USP38-CKO) reduces the expression of the inflammatory marker CD68 as well as the inflammatory factors TNF-α and IL-1β after MI, thereby alleviating advanced cardiac fibrosis, electrical remodeling, ion channel remodeling, and susceptibility to VAs. In contrast, cardiac-specific USP38 overexpression (USP38-TG) showed a significant opposite effect, exacerbating the early inflammatory response and cardiac remodeling after MI. Mechanistically, USP38 knockout inhibited activation of the TAK1/NF-κB signaling pathway after MI, whereas USP38 overexpression enhanced activation of the TAK1/NF-κB signaling pathway after MI.

Our study confirms that USP38-CKO attenuates the inflammatory response, improves ventricular remodeling after myocardial infarction, and reduces susceptibility to malignant VA by inhibiting the activation of the TAK1/NF-κB pathway, with USP38-TG playing an opposing role. These results suggest that USP38 may be an important target for the treatment of cardiac remodeling and arrhythmias after MI.