Salvia miltiorrhiza-derived Sal-miR-58 induces autophagy and attenuates inflammation in vascular smooth muscle cells

Abstract Autophagy is associated with the cytoprotection of physiological processes against inflammation and oxidative stress. Salvia miltiorrhiza, possessed cardiovascular protective actions, has powerful anti-oxidative and anti-inflammatory effects, however, whether and how Salvia miltiorrhiz-derived miRNAs protect vascular smooth muscle cells (VSMCs) by inducing autophagy across species is unknown. We first screened and identified Sal-miR-58 from Salvia miltiorrhiza as a natural autophagy inducer. Synthetic Sal-miR-58 suppresses chronic angiotensin II (Ang II) infusion-induced abdominal aortic aneurysm (AAA) formation in mice, as well as induces autophagy in VSMCs and attenuates inflammatory response elicited by Ang II in vivo and in vitro. Mechanistically, Sal-miR-58 downregulates Kruppel-like factor 3 (KLF3) expression through direct binding to the 3’UTR of KLF3, which in turn relieves KLF3 repression of E3 ubiquitin ligase neural precursor cell expressed developmentally down-regulated 4-like (NEDD4L) expression, whereas NEDD4L upregulation increases the ubiquitination and degradation of the platelet isoform of phosphofructokinase (PFKP), subsequently leading to a decrease in the activation of Akt/mTOR signaling and facilitating VSMC autophagy induced by Sal-miR-58 in the context of chronic Ang II stimulation and aneurysm formation. Our results provide the first evidence that plant-derived Sal-miR-58 induces autophagy and attenuates inflammation in VSMCs through cross-species modulation of the KLF3/NEDD4L/PFKP regulatory pathway.