Metformin represses the pathophysiology of AAA by suppressing the activation of PI3K/AKT/mTOR/autophagy pathway in ApoE−/− mice

Abstract

Background: The protective effect of metformin (MET) on abdominal aortic aneurysm (AAA) has been reported. However, the related mechanism is still poor understood. In this study, we deeply investigated the role of metformin in AAA pathophysiology. Methods: Angiotensin II (Ang-II) was used to construct the AAA model in ApoE −/− mice. The related mechanism was explored using Western blot and quantitative real time PCR (qRT-PCR). We also observed the morphological changes in the abdominal aorta and the influence of metformin on biological behaviors of rat abdominal aortic VSMCs. Results: The PI3K/AKT/mTOR pathway was activated in aneurysmal wall tissues of AAA patients and rat model. Treatment with metformin inhibited the breakage and preserved the elastin structure of the aorta, the loss of collagen, and the apoptosis of aortic cells. In addition, metformin significantly suppressed the activation of the PI3K/AKT/mToR pathway and decreased the mRNA and protein levels of LC3B and Beclin1, which were induced by Ang-II. Moreover, PI3K inhibitors enhanced the effect of metformin while PI3K agonists largely reversed this effect. Interestingly, the cell proliferation, apoptosis, migration and autophagy of vascular smooth muscle cells (VSMCs) induced by Ang-II were also decreased following metformin treatment. PI3K inhibitors and agonists strengthened and weakened the effects of metformin in VSMCs, respectively. Conclusions: Metformin represses the pathophysiology of AAA by inhibiting the activation of PI3K/AKT/mTOR/ autophagy pathway. This repression may be useful as a new therapeutic strategy for AAA.

Atg7 Mediates Metformin Protected Abdominal Aortic Aneurysm by Inducing Autophagy

“…Ang-II induced autophagy by increasing Beclin-1, Vps34, Atg-12-Atg5, Atg4 and Atg7 protein levels, Beclin-1 phosphorylation, and the number of autophagic vesicles [21]. Here, we found that Atg7 was up-regulated in Ang-II treated VSMCs, as our previous study showed that metformin represses the pathophysiology of AAA by inhibiting autophagy pathway [15], in this study, we showed that the induced expression of Atg7 in AAA was reversed by metformin. Until recently, there are no reports evaluating whether metformin regulate Atg7 in Ang-II induced VSMSs.…”

“…More importantly, metformin prescription status may be associated with a decreased risk of AAA [28]. Recently, we demonstrated that metformin protected Ang-II induced AAA by activating PI3K/Akt/mTOR/autophagy pathway [15], however, it remained unclear the molecular mechanism under this pathway. In this study, by using in vitro AAA model, we provide evidence that autophagy induced by Atg7 was reversed by metformin, suggesting that metformin reduced autophagy through suppressing Atg7.…”

“…Disruption of autophagic ux by VSMC-speci c deletion of Atg7 is linked to defective mitophagy and exacerbate VSMC apoptosis and in turn plaque vulnerability [12]. We and other studies have reported the critical roles of autophagy in the pathogenesis of AAA and found that metformin inhibited Ang-II induced AAA progression by decreasing the activation of NF-kB and STAT3 signaling pathway [13][14][15]. The levels of the autophagy factors, Beclin, and LC3 were elevated in human and mouse AAA tissue [16].…”

mTOR signaling pathway and mTOR inhibitors in cancer: progress and challenges

“…The mTOR signaling pathway is closely related to tumors, and it is closely related to its cell growth, metabolism, apoptosis and autophagy [47,81]. For example, the mTOR signaling pathway can affect gene transcription and protein synthesis to regulate cell growth and proliferation, affect the immune cell differentiation to participate in immune regulation, and play an important role in tumor metabolism.…”

<p>lncRNA DLX6-AS1 Promotes Proliferation of Laryngeal Cancer Cells by Targeting the miR-26a/TRPC3 Pathway</p>

“…The Quantitative reverse transcription-PCR was performed as previously described. 22 Total RNAs and miRNA were extracted using TRIzol and a miRNA isolation kit (Invitrogen, Waltham, MA, USA). The primers used were as follows: DLX6-AS1: F: 5′-AGTTTCTCTCTAGATTG CCTT-3′ and R: 5′-ATTGACATGTTAGTGCCCTT-3′; miR-26a: F: 5′-GGATCCGCAGAAACTCCAGAGAGA AGGA-3′ and R: 3′-AAGCTTGCCTTTAGCAGAAAGGA GGTT-5′; U6 primer: F: 5′-ATCCGCAAAGACCTGT-3′ and R: 5′-GGGTGTAACACTAAG-3′; and GAPDH: F: 5′-GGGAAATTCAACGGCACAGT-3′ and R: 5′-AGATGGT GATGGGCTTCCC-3′.…”