The Action and Mechanism of Trehalose on GATA4 Autophagy Degradation and Ventricular Remodeling.

To probe the effect of trehalose on myocardial hypertrophy and its specific molecular mechanism. C57BL/6J male mice were divided into four subgroups: Sham operation subgroup (Sham), negative sham subgroup (Sham+Trehalose), transverse aortic constriction (TAC), and trehalose treatment subgroup (TAC+Trehalose). Immediately after the TAC operation, trehalose at a dose of 10 mg/kg was given daily via gavage. After four weeks, changes in cardiac function were evaluated using ultrasound to measure EF (ejection fraction), FS (fractional shortening), IVRT (isovolumic relaxation time), MPI (myocardial performance index), Tau (isovolumic relaxation time constant), LVESP (left ventricular end-systolic pressure), and EDPVR (end-diastolic pressure-volume relationship). The profiles of autophagy-associated proteins (p62, LC3II/I, and Beclin-1) and GATA4 protein in mice myocardial tissues were assessed by Western blotting (WB). Myocardial cells were classified from TAC mice into five groups: Control, Trehalose, Phenylephrine (PE), PE+Trehalose, and PE+Trehalose+autophagy inhibitor chloroquine groups. In the PE group, cardiomyocytes were treated with 50 μmol/L PE. Then, the cells were treated with trehalose (100 μmol/L), trehalose (100 μmol/L)+autophagy (20 μmol/L) for 24 hours respectively. The Control group was treated with the same amount of normal saline. Flow cytometry was utilized to detect myocardial cell apoptosis in each subgroup. The alterations in apoptosis and autophagy-correlated proteins (p62, LC3II/I, and Beclin-1) were assessed by WB. Additionally, the level of GATA4 protein upstream of autophagy was estimated. Furthermore, the expression levels of pro-apoptotic proteins Bad, BAX, Cleaved-caspase-3, and anti-apoptotic protein Bcl-2 were examined by WB. The TAC operation significantly augmented myocardial hypertrophy, heart weight-to-body weight ratio, and myocardial cell apoptosis in mice (p < 0.05). Trehalose significantly improved cardiac hypertrophy, cardiomyocyte apoptosis, and cardiac function decline in mice. Additionally, it also significantly enhanced autophagy in mouse cardiac tissues (p < 0.05). At the cellular level, trehalose significantly decreased PE-elicited apoptosis and promoted the protein expressions of Beclin-1 and LC3 II/I in cardiomyocytes while significantly dampening the profiles of p62 and GATA4 in cells. The effect of trehalose and chloroquine treatment was significantly greater than that of the trehalose group. Trehalose significantly abates myocardial hypertrophy and pressure overload-induced cardiomyocyte apoptosis in mice. The cardioprotective effect of trehalose on enhanced autophagy is attributed, at least in part, to the promotion of autophagic degradation of GATA4. © 2023 The Author(s). Published by Discovery Medicine.

Citation

Qiaoying Chai, Wei Zhang, Lijuan Gao, Yingtao Yang, Mengdan Miao, Da Liu, Lixia Chen, Mingqi Zheng, Shuanli Xin. The Action and Mechanism of Trehalose on GATA4 Autophagy Degradation and Ventricular Remodeling. Discovery medicine. 2023 Jun;35(176):394-404

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PMID: 37272106

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