Protection of Salvianolate against Atherosclerosis via Regulating the Inflammation in Rats

Inflammation plays an essential role in the pathophysiology of atherosclerosis. Our study was aimed to investigate whether salvianolate, a novel water-soluble phenolic compound of Danshen, alleviates atherosclerosis via regulating the inflammation in rats. High fat diet feeding plus vitamin D3 injection was used to induce atherosclerosis in rats. Salvianolate （60, 120 or 240 mg/kg） or placebo was given to atherosclerotic rats. The plasma lipids, interleukin 6 （IL-6） and C reactive protein （CRP） were measured by ELISA. CD4＋CD25＋Foxp3＋ cells were determined by flow cytometry. Histological changes were examined by hematoxylin and eosin staining. The results showed that the levels of plasma IL-6 and CRP were elevated in the rats fed on high fat diet, and the histological analysis demonstrated the successful establishment of atherosclerosis models. Treatment with salvianolate alleviated the atherosclerotic process and decreased the levels of plasma IL-6 and CRP. Also the number of CD4＋CD25＋Foxp3＋ cells was increased in salvianolate-treated rats. It was concluded that salvianolate could treat atherosclerosis via modulating the inflammation at cytokine and cell levels.

Retinoic acid signaling acts as a rheostat to balance Treg function

Regulatory T cells(Tregs)promote immune homeostasis by maintaining self-tolerance and regulating inflammatory responses.Under certain inflammatory conditions,Tregs can lose their lineage stability and function.Previous studies have reported that ex vivo exposure to retinoic acid(RA)enhances Treg function and stability.However,it is unknown how RA receptor signaling in Tregs influences these processes in vivo.Herein,we employed mouse models in which RA signaling is silenced by the expression of the dominant negative receptor(DN)RARαin all T cells.Despite the fact that DNRARαconventional T cells are hypofunctional,Tregs had increased CD25 expression,STAT5 pathway activation,mTORC1 signaling and supersuppressor function.Furthermore,DNRARαTregs had increased inhibitory molecule expression,amino acid transporter expression,and metabolic fitness and decreased antiapoptotic proteins.Supersuppressor function was observed when wild-type mice were treated with a pharmacologic pan-RAR antagonist.Unexpectedly,Treg-specific expression of DNRARαresulted in distinct phenotypes,such that a single allele of DNRARαin Tregs heightened their suppressive function,and biallelic expression led to loss of suppression and autoimmunity.The loss of Treg function was not cell intrinsic,as Tregs that developed in a noninflammatory milieu in chimeric mice reconstituted with DNRARαand wild-type bone marrow maintained the enhanced suppressive capacity.Fate mapping suggested that maintaining Treg stability in an inflammatory milieu requires RA signaling.Our findings indicate that RA signaling acts as a rheostat to balance Treg function in inflammatory and noninflammatory conditions in a dose-dependent manner.