Piperlongumine attenuates angiotensin-II-induced cardiac hypertrophy and fibrosis by inhibiting Akt-FoxO1 signalling

Cardiac hypertrophy and fibrosis are closely related to cardiac dysfunction, especially diastolic dysfunction. Limited medications can be used to simultaneously delay cardiac hypertrophy and fibrosis in clinical practice. Piperlongumine (PLG) is an amide alkaloid extracted from Piper longum and has been shown to have multiple biological effects, including anticancer and antioxidant effects. However, the role of PLG in cardiac hypertrophy and fibrosis is not clear.The aim of this study was to reveal the role of PLG in cardiac hypertrophy and fibrosis and the associated mechanism.Cardiac hypertrophy and fibrosis were induced by angiotensin II (Ang II) in vivo and in vitro. The effect of PLG in vivo, in vitro and its mechanism were investigated by proliferation and apoptosis assays, western blot, real-time PCR, immunofluorescence, histochemistry, echocardiography, flow cytometry and chromatin immunoprecipitation.Proliferation and apoptosis assays showed that 2.5 μM PLG slightly inhibited proliferation and did not promote apoptosis. Treatment with 5 mg/kg PLG obviously inhibited Ang II-induced cardiac hypertrophy and fibrosis in vivo. In vitro studies of neonatal rat cardiomyocytes (NRCMs) showed that the anti-hypertrophic effect of PLG was mediated by reducing the phosphorylation of Akt and thereby preserving the level of Forkhead box transcription factor O1 (FoxO1), since knockdown of FoxO1 by siRNA reversed the protective effect of PLG on NRCMs. In addition, PLG significantly decreased the Ang II-induced expression of profibrotic proteins in neonatal cardiac fibroblasts by reducing the expression of Krüppel-like factor 4 (KLF4) and the recruitment of KLF4 to the promoter regions of transforming growth factor-β and connective tissue growth factor.We demonstrate the cardioprotective effects of PLG in both cardiac hypertrophy and fibrosis and the potential value of PLG for developing novel medications for pathological cardiac hypertrophy and heart failure.