Exercise improves heart failure by regulating cardiomyocyte autophagy via the ILF3/lncRNA NEAT1 axis.

Abstract

Heart failure (HF) is a common cardiovascular disease. It has been reported that the lncRNA NEAT1 is involved in the progression of HF and that exercise can regulate the expression of NEAT1 in muscle tissue. This study aimed to investigate whether exercise can influence HF progression by regulating NEAT1 expression and to elucidate its molecular mechanisms. Two independent rat HF models were established separately by intraperitoneal injection of isoproterenol hydrochloride (ISO) or by abdominal aortic constriction (AAC), whereas an in vitro HF model was induced by angiotensin II (Ang-II) in rat H9c2 cardiomyocytes. After 4 weeks of exercise training, serum NT-pro BNP levels were measured in the rats, and cardiac injury was assessed via HE staining and Masson staining. The expression of key genes and proteins was detected using RT‒qPCR, Western blotting, and immunofluorescence, and apoptosis was evaluated via TUNEL staining. RNA immunoprecipitation experiments were performed to validate the interaction between NEAT1 and ILF3. NEAT1 expression is upregulated in HF, and its knockdown can inhibit cellular damage in in vitro and in vivo HF models and improve cardiac function in rats. Additionally, exercise training reduces the expression of NEAT1 in the cardiac tissues of HF rats, and overexpression of NEAT1 weakens the inhibitory effect of exercise training on the progression of HF in rats, indicating that exercise training improves HF progression by suppressing NEAT1 expression. Mechanistic studies revealed that upregulated ILF3 in HF binds to NEAT1 to stabilize its expression, thereby activating the PI3K/AKT/mTOR signaling pathway, which subsequently inhibits autophagy, ultimately leading to HF. Exercise training can downregulate NEAT1 expression, thereby suppressing abnormal activation of the PI3K/AKT/mTOR signaling pathway and further relieving HF progression through the activation of autophagy. Additionally, NEAT1 expression is regulated by ILF3.