Exogenous HS targeting PI3K/AKT/mTOR pathway alleviates chronic intermittent hypoxia-induced myocardial damage through inhibiting oxidative stress and enhancing autophagy.

AIMS

Hydrogen sulfide (HS) is a novel gas signaling molecule that has been researched in several physiological and pathological conditions, indicating that strategies targeting HS may provide clinical benefits in diseases such as chronic cardiomyopathy. Here, we reveal the effect of HS on chronic intermittent hypoxia (CIH)-related myocardial damage and its mechanistic relevance to phosphoinositol-3 kinase (PI3K).

MATERIALS

Mice were subjected to a 4-week CIH process to induce myocardial damage, which was accompanied by daily administration of NaHS (a HS donor) and LY294002 (an inhibitor of PI3K). Changes in heart function were evaluated via echocardiography. Histological examination was applied to assess heart tissue lesions. Myocardial apoptosis was detected by TUNEL staining and apoptosis-associated protein expression. Furthermore, the effects of NaHS on autophagy and the PI3K/AKT/mTOR pathway were investigated. Finally, the level of inflammation is also affected by related proteins.

KEY FINDINGS

The CIH group presented increased myocardial dysfunction and heart tissue lesions. Echocardiography and histological analysis revealed that, compared with control mice, CIH-treated mice presented significantly more severe left ventricular remodeling and decreased myocardial contractile function. In addition, the apoptosis index and oxidative markers were significantly elevated in the CIH group compared with those in the control group. The autophagy marker Beclin-1 was decreased, while p62 was elevated by CIH treatment. HS supplementation with NaHS significantly improved cardiac function and alleviated fibrosis, oxidative stress, and apoptosis but upregulated autophagy in CIH mice, and these effects were also observed in animals that underwent only PI3K blockade. Furthermore, PI3K/AKT pathway-mediated inhibition of the mammalian target of rapamycin (mTOR) pathway, the Nrf2/HO-1 pathway and proinflammatory NF-κB activity were shown to play a role in the therapeutic effect of NaHS after CIH stimulation.