TNIP3 overexpression protects against arrhythmogenic remodeling in the heart failure mice.

Aims: Ventricular arrhythmias (VAs), which can lead to sudden cardiac death, are the primary cause of mortality in patients with heart failure (HF). However, the precise mechanisms underlying these arrhythmias are not well understood. Recent studies have implicated tumor necrosis factor alpha-induced protein 3-interacting protein 3 (TNIP3) in pathological cardiac hypertrophy. Nevertheless, its role in isoproterenol (ISO)-associated VAs remains elusive.

Methods And Results: We overexpressed TNIP3 in the myocardium using an adeno-associated virus 9 (AAV9) system, administered via tail vein injection. C57BL/6 mice received daily subcutaneous injections of ISO for two consecutive weeks to establish a HF model. We performed histopathology and electrophysiological studies to assess ventricular structural remodeling, electrical remodeling, and susceptibility to VAs. Additionally, RNA sequencing (RNA-Seq) and Western blot analysis were conducted to elucidate the underlying mechanisms. The expression of TNIP3 was upregulated following ISO treatment. TNIP3 overexpression significantly reversed ISO-induced cardiac dysfunction, fibrosis, electrical remodeling and VAs susceptibility. Accordingly, RNA-sequencing identify that the inflammatory response takes important role in ISO-induced VAs and TNIP3 overexpression could alleviate ISO-induced cardiac proinflammatory response by promoting M1 to M2 macrophage polarization. Mechanistically, PI3K/Akt/NF-κB signaling is responsible for the protective effect of TNIP3 overexpression on ISO-induced HF. And PI3K/Akt signaling activation offset the protective effect of TNIP3 overexpression on ISO-induced cardiac inflammation and VAs.

Conclusions: The findings of this study highlight the critical role of TNIP3 in ISO-associated cardiac remodeling and VAs, which are induced by the inhibited activation of the PI3K/Akt/NF-κB signaling pathway.