No abstract

Abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) and the chronic inflammation regulated by various inflammatory factors are the major pathological processes in the development of neointimal hyperplasia and in-stent restenosis after angioplasty. Cantharidin is a potent and selective inhibitor of protein phosphatase 2A, which plays pivotal roles in cell cycle progression, cell fate, and inflammation. This study was to explore whether Cantharidin could inhibit VSMCs proliferation, migration and inflammation. Transwell migration assay, Cell Counting Kit 8 and flow cytometry were performed. Western blot, Quantitative real-time PCR, and enzyme-linked immunosorbent assay (ELISA) were used to detect the expression of the markers. Results showed that Cantharidin remarkably suppressed VSMCs proliferation and migration induced by platelet derived growth factor (PDGF)-BB. Meanwhile, Cantharidin could significantly inhibit the phosphorylation of Akt (P-AKT) and p38 mitogen-activated protein kinase (MAPK) (P-p38), the expression of p38 MAPK (p38), and also the phosphorylation level of nuclear factor-kappaB (NF-κB) p65 (p65). Cantharidin obviously inhibited the expression of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), and also the level of IL-6 and TNF-α in culture supernatants. Inhibitors for p38 MAPK, phosphatidylinositol 3-kinase (PI3K) /AKT and NF-κB signaling pathways did not affect the inhibition of Cantharidin on VSMCs proliferation, migration and inflammation. These findings indicated that Cantharidin could significantly inhibit the proliferation, migration and inflammatory response of VSMCs, which suggested that Cantharidin may be a potential inhibitor for neointimal hyperplasia and restenosis after angioplasty.

Cardiomyocyte autophagy plays an important role in myocardial ischemia-reperfusion injury (MIRI). P300/CBP-associated factor (PCAF) was involved in the regulation of autophagy. However, the role of PCAF in MIRI is currently unknown. This study was to investigate whether downregulation of PCAF attenuate MIRI. The results showed that the expression of PCAF was significantly increased in MIRI in vivo and in vitro. Downregulation of PCAF not only inhibited autophagy and damage of H9c2 cells induced by hypoxia-reoxygenation, but also reduced autophagy and myocardial infarct size during myocardial ischemia-reperfusion in rats. In addition, downregulation of PCAF promoted activation of PI3K/Akt/mTOR signaling pathway in cardiomyocytes during hypoxia-reoxygenation. Wortmannin, a PI3K/Akt inhibitor, could abrogate the effects of downregulation of PCAF on cardiomyocytes autophagy. These results demonstrated that downregulation of PCAF alleviated MIRI by inhibiting cardiomyocyte autophagy through PI3K/Akt/mTOR signaling pathway. Thus, PCAF may be a potential target for prevention and treatment of MIRI.