Acacetin inhibits myocardial mitochondrial dysfunction by activating PI3K/AKT in SHR rats fed with fructose

• DOI: 10.1007/s11418-022-01666-7
• Publication Date: 2022-12-15T14:09:24Z
• Authors: Peipei Yuan; Qi Zhang; Yang Fu; Ying Hou; Liyuan Gao; Yaxin Wei; Weisheng Feng; Xiaoke Zheng
• Keywords: 0301 basic medicine; 0303 health sciences; Kelch-Like ECH-Associated Protein 1; NF-E2-Related Factor 2; Insulins; Apoptosis; Hydrogen Peroxide; Fructose; Rats; Mitochondria; Phosphatidylinositol 3-Kinases; 03 medical and health sciences; Rats, Inbred SHR; Hypertension; Animals; Myocytes, Cardiac; Proto-Oncogene Proteins c-akt

To explore the effect of acacetin on myocardial mitochondrial dysfunction in spontaneously hypertensive rats (SHR) with insulin resistance (IR), and the possible mechanism. Rapid IR was first induced in fructose-fed SHR, and they were then treated with acacetin (25, 50 mg/kg). After 7 weeks, the rats were tested for hypertension, IR, cardiac function, and mitochondrial damage status. Potential mechanisms of action were explored in terms of oxidative stress, mitochondrial fission and division, apoptosis, and the insulin signaling pathway. Subsequently, the PI3K gene was silenced, after intervention with acacetin (5 μM) for 24 h, and H2O2 was used to stimulate H9c2 for 4 h, it was evaluated whether silencing PI3K would affect the therapeutic effect of acacetin. In SHR fed with fructose, acacetin can improve hypertension, IR, cardiac function (LVEF, LVFS), and mitochondrial damage (mitochondria number, ATP); inhibit oxidative stress (ROS, SOD, Nrf2, Keap1), mitochondrial fission (MFF, Drp1), and myocardial cell apoptosis (apoptosis rate, Bax, Bcl-2, cytochrome c); promote mitochondrial fusion (Mfn2) and activate insulin signaling pathways (PI3K/AKT). However, silencing PI3K inhibited the abovementioned effects of acacetin. In conclusion, acacetin improved myocardial mitochondrial dysfunction through regulating oxidative stress, mitochondrial fission and fusion, and mitochondrial pathway apoptosis mediated by PI3K/AKT signaling pathway in hypertensive rats with IR.