The HuoXue DiTan Recipe Attenuates Left Ventricular Hypertrophy in Spontaneously Hypertensive Rats by Increasing Autophagy Through the PTEN/PI3K/AKT/mTOR Pathway

Abstract Background Hypertension-induced left ventricular hypertrophy (LVH) is associated with a reduction in autophagy, which can be inhibited by disruption of the PTEN/PI3K/AKT/mTOR pathway. The HuoXue DiTan recipe (HDR) is a commonly used prescription that has shown therapeutic effects on hypertension and its complications. However, its mechanisms are still unclear. In the present study, we hypothesized that HDR can regulate the PTEN/PI3K/AKT/mTOR signaling pathway and thereby reverse LVH by increasing autophagy in spontaneously hypertensive rats. Methods Twelve-week-old male spontaneously hypertensive (SH) rats and age-matched normotensive-control Wistar-Kyoto (WKY) rats were divided into four groups. After 12 weeks of treatment, echocardiographic measurements were made on the left ventricle, blood samples were collected for oxidative stress analysis, left ventricle tissue was processed for hematoxylin and eosin, Masson's trichrome, and immunohistochemical/ immunofluorescence staining, and TUNEL, RT-qPCR and Western blot analyses were performed. Results Compared with age-matched WKY rats, SH rats at 16 weeks of age exhibited significantly greater myocardial hypertrophy and remodeling with abnormal heart function. There was a reduction in autophagy and increase in apoptosis, resulting in an imbalance of oxidative stress manifested as left ventricular hypertrophy and impaired cardiac function. These effects may be related to a decrease in PTEN expression, which leads to activation of the PI3K/AKT/mTOR signaling pathway, resulting in abnormal expression of autophagy- and apoptosis-related proteins. After 12 weeks of HDR administration, blood pressure and ventricular hypertrophy were reduced, MDA and SOD levels and NADPH oxidase activity were better regulated, and gene expression of myocardial hypertrophy markers (ANP and β-MHC) was inhibited. HDR can promote autophagy and inhibit apoptosis, which may be related to regulation of autophagy- and apoptosis-related genes and proteins. HDR can also induce autophagy by enhancing expression of PTEN and inhibiting activation of the PI3K/AKT/mTOR signal pathway. Importantly, we demonstrated that VO-Ohpic, an inhibitor of PTEN, could suppress the effect of HDR on LVH in spontaneously hypertensive rats. Conclusion In conclusion, these results provide evidence for an important role of HDR in inhibition of left ventricular hypertrophy in spontaneously hypertensive rats, and indicate that it may act by improving autophagy through the PTEN/PI3K/AKT /mTOR pathway.