Hexarelin attenuates heart failure in rats by upregulating PTEN signaling and suppressing the Akt/mTOR pathway.

Hexarelin is a synthetic growth hormone-releasing peptide known for its cardioprotective properties, but the specific mechanisms behind its effectiveness against heart failure (HF) remained unclear. The progression of HF often involves maladaptive myocardial remodeling, oxidative stress, and apoptosis. Key signaling pathways like the Akt/mTOR pathway are frequently implicated in this process, where their over-activation can promote pathological cardiac hypertrophy. Understanding how Hexarelin interacts with these pathways is crucial for developing it as a targeted therapy. This study investigates if Hexarelin's benefits are mediated through modulation of PTEN, a known negative regulator of the Akt/mTOR cascade, providing a potential new therapeutic angle for HF.

Researchers induced myocardial infarction and heart failure in rats via permanent coronary artery ligation (CAL). After four weeks, the rats were randomized into four groups: control, sham, heart failure (HF), and Hexarelin-treated HF (HF + Hx). The treatment group received subcutaneous injections of Hexarelin (100 μg/kg) twice daily for 30 days, while the other groups received saline. Investigators then assessed left ventricular (LV) function, cardiac structure, oxidative stress, apoptosis, and performed molecular analyses to evaluate changes in key signaling pathways.

Hexarelin treatment significantly improved outcomes in rats with heart failure. The therapy led to enhanced left ventricular function, ameliorated myocardial remodeling, and reduced oxidative stress compared to the untreated HF group. The core mechanism identified was Hexarelin's ability to significantly upregulate the expression of phosphatase and tensin homologue (PTEN).

This upregulation of PTEN subsequently inhibited the phosphorylation of protein kinase B (Akt) and the mammalian target of rapamycin (mTOR). The study concluded that Hexarelin exerts its cardioprotective effects by modulating this critical signaling axis. By activating PTEN, Hexarelin effectively downregulates the pro-hypertrophic and pro-survival Akt/mTOR pathway, thereby mitigating the pathological changes associated with coronary artery ligation-induced heart failure.