HDAC3 Inhibition In Diabetic Mice May Activate Nrf2 Preventing Diabetes-induced Liver Damage And FGF21 Synthesis And Secretion Leading To Aortic Protection

Diabetes(DM)and its related complications has become the domestic and international major public health problem.Due to the disorders of lipid metabolism and endothelial cell function,diabetic patients have earlier vascular diseases than non-diabetic patients.Among them,the onset of coronary heart disease is usually manifested as painless myocardial infarction,with large infarcts and mostly transural infarcts.The disease is more severe,with poor prognosis and high mortality.While arteriosclerosis caused by diabetes is not limited to a certain part of the body or organs,its vascular complications include all the arterial system,such as diabetic retinopathy,aortic sclerosis,cerebrovascular disease,lower limb vascular disease,coronary heart disease and so on.Traditional treatment with hypoglycemic drugs to control blood glucose can effectively reduce the incidence of microvascular complications,but in the treatment of large vascular diseases including atherosclerosis,the effect is poor.Therefore,how to effectively control the vascular complications of diabetes has become a research focus.In the past decade,a large number of studies have shown that fibroblast growth factor 21 FGF21 has a variety of beneficial effects on obesity,T2 D and its complications.Both acute and chronic administration of FGF21 can improve the metabolic status of T2 D patients.Further studies have found that FGF21 not only has important biological effects in T2 D patients,but also has hypoglycemic effects.It has been reported that FGF21 has antioxidant stress and anti-apoptotic functions in endothelial cells,thus inhibiting the development of atherosclerosis.Our previous study found that in mice with FGF21 gene knockout,diabetic aortic injury was aggravated,whereas in mice treated with exogenous FGF21,the opposite was true.Therefore,FGF21 can also be considered as a new method for the treatment of T1 D.In recent years,histone deacetylase(HDAC)inhibitors that effectively inhibit proliferation of vascular smooth muscle cells have been found to be successful in preventing atherosclerosis.Histone deacetylases catalyze epigenetic modifications that regulate chromatin structure and transcription.It has been found that inhibiting HDAC3 can prevent Diabetic cardiomyopathy DCM in T1 D mice.In addition,other research groups have found that HDAC inhibition protects the aorta from inflammatory damage through epigenetic mechanisms.Therefore,we speculate that HDAC inhibitors may also prevent diabetic aortic injury;It is not clear whether there is an association between FGF21,which was previously mentioned,which also reduces aortic injury.Therefore,in this study,a mouse model of OVE26 type 1 diabetes mellitus(T1D)was constructed and then treated with HDAC inhibitor in groups to observe the protection of HDAC inhibitor on the aorta of T1 D mice.To investigate the effect of HDAC3 inhibitor on diabetic aorta and its protective mechanism.Objective:(1)Clear HDAC3 inhibitor can reduce the injury of diabetic aorta;(2)To clarify the effect of HDAC3 inhibitor on the synthesis and secretion of FGF21 in diabetic liver;(3)To investigate the potential mechanism of HDAC3 inhibitor for the protection of diabetic liver and its association with the reduction of aortic injury.Methods: Male OVE26 type 1 diabetes(T1D)mice and wild-type FVB mice were treated with RGFP966(HDAC3 inhibitor),VAP(full HDAC inhibitor as control)or placebo for 3 months,respectively.Some of the mice were then sacrificed(3 months later)to extract liver,plasma and aortic tissues.Additional mice were kept alive for another 3 months without treatment with HDAC3 inhibitors(6 months point in time).The changes of the aorta were detected by pathology and immunohistochemical staining.Plasma FGF21 level and HDAC3 activity were determined by ELISA.The liver changes of each group were analyzed by RT-PCR and Western blot.Conclusion: our results support a model in which HDAC3 inhibition promotes Nrf2 activity by increasing mir-200 a expression and simultaneously decreasing keap1,thereby protecting the synthesis and secretion of FGF21 in the liver.Hepatic FGF21 synthesis and secretion eventually lead to the reduction of diabetic aortic lesions.Our novel finding is that in the same disease state,the existence of different organs(liver,vascular system)under certain treatment has the possibility of synergistic cure.