Key Provincial Laboratory of Basic Pharmacology, Nanchang University, Nanchang, Jiangxi 330006, PR China; Department of Pharmacology, School of Pharmacy, Nanchang University, Nanchang, Jiangxi 330006, PR China.
Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, PR China.
Vascul Pharmacol. 2019 Nov-Dec;122-123:106597. doi: 10.1016/j.vph.2019.106597. Epub 2019 Aug 31.
SUMOylation of peroxisome proliferator-activated receptor gamma (PPAR γ) plays important regulatory role in its transcriptional activity. Our recent studies in vitro found that over-SUMOylation of PPARγ, like high glucose and high fat (HG/HF), induced endothelial insulin resistance (IR). However, whether such an event occurs in rats remains unclear. Therefore, our study aimed at investigating whether PPARγ over-SUMOylation could mimic high sucrose/fat diet (HFD) to induce endothelial IR and dysfunction and explored its underlying mechanisms. Normal chow-fed rats were intravenously infected with adenoviruses carrying the wild type cDNAs encoding PPARγ, SUMO1 and PIAS1 (protein inhibitor of activated STAT1). HFD-fed rats were regarded as a positive control. Body physical and biochemical parameters, glucose tolerance and vessel function were detected. The expression and SUMOylation levels of PPARγ were measured by western blotting and co-immunoprecipitation. Our results showed that like HFD, PPARγ over-SUMOylation induced endothelial IR and dysfunction via a negative regulation of eNOS-NO pathway. More importantly, we found that PPARγ over-SUMOylation induced endogenous SUMOylation cascade and exacerbated endothelial IR and dysfunction.The findings will deepen the understanding on PPARγ SUMOylation-regulating insulin signaling network and offer a potential target for prevention and cure of diabetic vascular complications.
过泛素化修饰在过氧化物酶体增殖物激活受体γ（PPARγ）转录活性的调控中发挥着重要作用。我们最近的体外研究发现，过泛素化修饰的 PPARγ 与高糖和高脂（HG/HF）一样，可诱导内皮细胞胰岛素抵抗（IR）。然而，这种情况是否在大鼠中发生尚不清楚。因此，我们的研究旨在探讨 PPARγ 过泛素化是否可以模拟高蔗糖/脂肪饮食（HFD）诱导内皮细胞 IR 和功能障碍，并探讨其潜在机制。正常饮食喂养的大鼠经静脉感染携带野生型 cDNAs 编码 PPARγ、SUMO1 和 PIAS1（激活 STAT1 的蛋白抑制剂）的腺病毒。HFD 喂养的大鼠被视为阳性对照。检测大鼠的身体物理和生化参数、葡萄糖耐量和血管功能。通过 Western blot 和共免疫沉淀测定 PPARγ 的表达和泛素化水平。我们的结果表明，与 HFD 一样，PPARγ 过泛素化通过负向调控 eNOS-NO 通路诱导内皮细胞 IR 和功能障碍。更重要的是，我们发现 PPARγ 过泛素化诱导内源性 SUMO 化级联反应，加重内皮细胞 IR 和功能障碍。这些发现将加深对 PPARγ 泛素化调节胰岛素信号网络的理解，并为预防和治疗糖尿病血管并发症提供潜在靶点。
