Astragaloside IV inhibits the progression of hypertensive heart disease via the RXRA/PPARG/SIRT3 axis.

Astragaloside IV (AS-IV) is an active component of Astragalus membranaceus, which has a prominent role in cardiovascular diseases. AS-IV has been reported to alleviate vascular endothelial dysfunction and promote angiogenesis. However, its function in hypertensive heart disease (HHD), a key underlying mechanism for cardiovascular morbidity and mortality, remains to be defined. The objective here is to investigate the inhibiting effect of AS-IV on HHD. HHD mice were induced by N(omega)-nitro-L-arginine methyl ester (L-NAME, LN), followed by AS-IV treatment. LN caused arterial endothelial dysfunction and cardiomyocyte injury in mice, while AS-IV ameliorated the pathological changes. Moreover, LN reduced the viability of arterial endothelial cells and cardiomyocytes and diminished the migration and angiogenic capacity of arterial endothelial cells, which were alleviated by AS-IV. AS-IV ameliorated LN-induced loss of retinoic acid receptor RXR-alpha (RXRA) and promoted the transcription of sirtuin 3 (SIRT3) via the RXRA/peroxisome proliferator-activated receptor gamma (PPARG) heterodimer. Knockdown of RXRA resulted in a loss of the therapeutic effect of AS-IV, and the progression of HHD caused by knockdown of RXRA was reversed by PPARG or SIRT3 overexpression. Hence, we propose that AS-IV promotes the expression of RXRA in HHD and mediates the transcription of SIRT3 through RXRA/PPARG, thereby ameliorating endothelial dysfunction and cardiomyocyte injury. KEY MESSAGES: AS-IV inhibits LN-induced HHD in mice and cardiomyocyte injury. AS-IV promotes endothelial cell migration and angiogenesis. AS-IV inhibits the loss of RXRA expression induced by LN. RXRA/PPARG heterodimer regulates the transcriptional expression of SIRT3. The therapeutic effect of AS-IV on HHD is dependent on RXRA/PPARG/SIRT3 signaling.