Luteolin Alleviates Diabetic Cardiomyopathy Related With Inhibiting SHP2/STAT3

Background: China has become the country with the largest number of diabetic patients(about 116.4 million)in the world.Diabetes cardiomyopathy(DCM),a chronic metabolic disturbance-induced heart disease independent of hypertension and coronary atherosclerosis,is one of the primary causes of high mortality in diabetic patients.Exploring effective intervention to prevent DCM has been a hot spot in clinical research.The pathogenesis of DCM is complex.Some studies showed that the src homology region 2-containing protein tyrosine phosphatase 2(SHP2)promotes diabetic retinopathy and nephropathy.Luteolin,a natural flavonoid compound widely distributed in varieties of Chinese herbals,fruits and vegetables,has multiple pharmacological activities such as anti-inflammation,anti-oxidative stress and to reduce cardiovascular injury.Luteolin and its derivatives can inhibit the activity of protein tyrosine phosphatase.Our previous studies revealed that luteolin potently protects the cardiovascular system against diabetes.Here,the protective effect of luteolin against DCM and the underlying mechanism related to SHP2 were explored.Methods: Male SD rats were randomly divided into five groups: non-diabetic control group(ND),diabetic group(D),low,medium and high dose luteolin-treated group(5,10 and 20 mg/kg,i.p.,luteolin-L,-M and-H).Diabetes was induced by feeding high fat and high sugar diet(HFD)and streptozotocin(STZ,30 mg/kg,i.p.).After 3 days of injection,the tail vein blood glucose of the rat was detected and the rat with blood glucose ≥16.7mmol/L was considered to be diabetic.Except ND group fed with standard common diet,other groups were continued to feed with HFD for 5 weeks.After 5 weeks,different doses of luteolin were treated every other day for 5 weeks.The body weight and random blood glucose level of rats were measured weekly from the beginning of modeling.After 5 weeks of treated with luteolin,the cardiac function of rats was measured by small animal ultrasound.The ratio of heart weight to tibia length(HW/TL)was measured.Enzyme-linked immunosorbent assay(ELISA)was adopted to determine pro-inflammatory factors IL-6,IL-1β and TNF-α,and the level of fibrosis indexes connective tissue growth factor(CTGF)and collagen in the rat cardiac tissue.The activity of SOD was measured by WST-8 method.HE staining,Masson staining,WGA staining and DHE staining were used to observe the pathological changes of cardiac tissue and the level of reactive oxygen species(ROS).The expression of SHP2,p-STAT3 and STAT3 proteins in cardiac tissue were detected by Western blot.Results: Compared with the non-diabetic control group,the blood glucose,HW/TL,the cardiomyocyte size,the expression of cardiac CTGF and collagen,cardiac pro-inflammatory factors IL-6,IL-1β and TNF-α,cardiac ROS,and the expression of cardiac SHP2 and p-STAT3 were significant increased(P<0.01),while the cardiac function was markedly decreased(P<0.01)in the diabetic rat.Compared with the diabetic group,treatment with luteolin didn’t significantly alter high blood glucose(P>0.05),but dose-dependently alleviated cardiac pathological changes(P<0.05)such as cardiac remodeling,inflammation and oxidative stress,improved cardiac function(P<0.01),and down-regulated the expression of cardiac SHP2 and p-STAT3(P<0.01)in diabetes.Conclusions: Luteolin reduces inflammation,oxidative stress,cardiac remodeling and dysfunction,thus alleviating DCM in the diabetic rat,which may be related to the down-regulation of myocardial SHP2 and STAT3.