Dysfunction of proteasome and autophagy will result in disturbance of endoplasmic reticulum (ER) proteostasis, and thus lead to long-term and chronic ER stress and subsequent unfolded protein response (UPR), which is implicated in the occurrence and development of insulin resistance. Curcumin exerts beneficial metabolic effects in in vitro cells and in vivo animal models of diabetes and diabetic complications including cardiovascular diseases, due to its powerful anti-oxidative and anti-inflammatory properties. However, its impacts on insulin resistance of endothelial cells and its underlying mechanism(s) remain ill-defined. Herein, we tested the hypothesis that curcumin action in ER protein quality control was related to improvement of insulin resistance in human umbilical vein endothelial cells (HUVECs) cultured with saturated fatty acid palmitate. We found that palmitate treatment induced insulin resistance of HUVECs and activated both the ubiquitin-proteasome system (UPS) and autophagy. Palmitate-stimulated activation of the UPS and autophagy was attenuated by pharmacological inhibition of ER stress. In addition, curcumin supplementation mitigated palmitate-induced insulin resistance, inhibited the UPS, and activated autophagy. Furthermore, curcumin administration suppressed palmitate-induced protein aggregation and ER stress. Genetic inhibition of autophagy by silencing autophagy protein 5 (Atg5) completely restored total protein ubiquitination and protein aggregation in HUVECs treated with combined curcumin and palmitate. Atg5-knockdown also abolished the beneficial effects of curcumin on palmitate-induced ER stress, JNK/IRS-1 pathway as well as insulin signaling. Our results reveal that curcumin-activated autophagy could maintain proteostasis in ER leading to attenuation of ER stress and subsequent inhibition of JNK/IRS-1 pathway and improvement of insulin resistance.

Tiron functions as an effective antioxidant alleviating the intracellular reactive oxygen species (ROS) or the acute toxic metal overload. Previous studies have shown that cardiac myocyte apoptosis can be effectively inhibited by tiron administration in streptozotocin (STZ)-induced diabetic rats, primary neonatal rat cardiomyocytes (NRVMs), and H9c2 embryonic rat cardiomyocytes. However, the underlying signalling mechanism is ill-defined. In the present study, we found that tiron supplementation significantly inhibited apoptosis of high glucose (HG)-treated NRVMs and the left ventricular cardiomyocytes from STZ-diabetic rat, accompanied with a reduction of osteopontin (OPN) levels as well as an inhibition of PKCδ phosphorylation. OPN knockdown protected NRVMs against HG-induced cell apoptosis. In addition, genetic inhibition of PKCδ mitigated HG-stimulated enhancement of intracellular OPN levels in NRVMs. These findings indicate that ROS-mediated activation of PKCδ upregulated OPN expression, leading to cardiac myocyte apoptosis. Interfering with ROS/PKCδ pathway by antioxidants such as tiron provides an optional therapeutic strategy for treatment and prevention of apoptosis-related cardiovascular diseases including diabetic cardiomyopathy.

Objective: To study the associations between manganese superoxide dismutase 9Ala/Val(MnSOD 9 Ala/Val) genetic polymorphisms and coronary heart disease(CHD).Methods: The ABI 3100 DNA sequencer was applied to identify the genotype of MnSOD 9 Ala/Val genetic polymorphisms,and colorimeter was used to detect plasma activities of total superoxide dismutase(T-SOD) and MnSOD in 147 CHD patients and 108 controls.Results: Compared with that of controls,the plasma activity of T-SOD and MnSOD reduced obviously,while C-reaction protein(CRP) concentration and intima-medium thickness(IMT) in carotid artery increased markedly in CHD patients.There were more VV genotype and V allele of MnSOD 9 Ala/Val genetic polymorphisms in CHD patients than in controls.The activity of plasma T-SOD and MnSOD decreased,while CRP and IMT increased in individuals with MnSOD 9 VV genotype compared in those with AA genotype,and MnSOD 9V allele correlated negatively with the activity of T-SOD,MnSOD and serum HDL level,positively with fasting plasma glucose,total cholesterol,triglyceride,LDL,systolic blood pressure,IMT and CRP.Conclusion: The antioxidative ability decreased,while inflammatory reaction and degree of atherosclerosis increased in CHD patients.Gene polymorphisms of MnSOD 9 Ala/Val involves in the pathogenesis of CHD by influencing the plasma activities of T-SOD,MnSOD and risk factors of CHD.