BMI1 promotes cardiac fibrosis in ischemia-induced heart failure via the PTEN-PI3K/Akt-mTOR signaling pathway

Cardiac fibrosis has been known to play an important role in the etiology of heart failure following myocardial infarction (MI). B lymphoma Mo-MLV insertion region 1 homolog (BMI1), a transcriptional repressor, is important for fibrogenesis in the kidneys. However, the effect of BMI1 on ischemia-induced cardiac fibrosis remains unclear. BMI1 was strongly expressed in the infarct region one week post-MI in mice and was detected by Western blot and histological analysis. Lentivirus-mediated overexpression of BMI1 significantly promoted cardiac fibrosis, worsened cardiac function 4 weeks after the intervention in vivo, and enhanced the proliferation and migration capabilities of fibroblasts in vitro, while the downregulation of BMI1 decreased cardiac fibrosis and prevented cardiac dysfunction in mice 4 weeks post-MI in vivo. Furthermore, up-regulated BMI1 inhibited PTEN expression, enhanced PI3K expression, and increased the phosphorylation level of AKT and mTOR in mice 4 weeks after lentiviral infection, which was in accordance with the changes seen in their infarcted myocardial tissues. At the same time, the effects of BMI1 on cardiac fibroblasts were reversed in vitro when these cells were exposed to NVP-BEZ235, a dual kinase (PI3K/mTOR) inhibitor. In conclusion, BMI1 is associated with cardiac fibrosis and dysfunction following MI by regulating cardiac fibroblast proliferation and migration, and these effects could be partially explained by the regulation of the PTEN-PI3K/AKT-mTOR pathway.