El-Bassossy Hany M, Watson Malcolm L
Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt.
J Transl Med. 2015 Mar 6;13:82. doi: 10.1186/s12967-015-0445-9.
We have previously shown that hyperuricemia plays an important role in the vascular complications of insulin resistance (IR). Here we investigated the effect of xanthine oxidase (XO) inhibition on the cardiac complications of IR.
IR was induced in rats by a high fructose high fat diet for 12 weeks. Allopurinol, a standard XO inhibitor, was administered in the last 4 weeks before cardiac hemodynamics and electrocardiography, serum glucose, insulin, tumor necrosis factor alpha (TNFα), 8-isoprostane, uric acid, lactate dehydrogenase (LDH) and XO activity were measured. Expression of cardiac angiotensin II (AngII) and angiotensin receptor 1 (AT1) were assessed by immunofluorescence.
IR animals had significant hyperuricemia which was inhibited by allopurinol administration. IR was associated with impaired ventricular relaxation (reflected by a decreased diastolic pressure increment and prolonged diastolic duration) and XO inhibition greatly attenuated impaired relaxation. IR was accompanied by cardiac ischemia (reflected by increased QTc and T peak trend intervals) while XO inhibition alleviated the ECG abnormalities. When subjected to isoproterenol-induced ischemia, IR hearts were less resistant (reflected by larger ST height depression and higher LDH level) while XO inhibition alleviated the accompanying ischemia. In addition, XO inhibition prevented the elevation of serum 8-isoprostane and TNFα, and blocked elevated AngII and AT1 receptor expression in the heart tissue of IR animals. However, XO inhibition did not affect the developed hyperinsulinemia or dyslipidemia.
XO inhibition alleviates cardiac ischemia and impaired relaxation in IR through the inhibition of low grade inflammation and the angiotensin system.
我们之前已经表明，高尿酸血症在胰岛素抵抗（IR）的血管并发症中起重要作用。在此，我们研究了黄嘌呤氧化酶（XO）抑制对IR心脏并发症的影响。
通过高果糖高脂肪饮食诱导大鼠发生IR，持续12周。在进行心脏血流动力学和心电图检查、测量血清葡萄糖、胰岛素、肿瘤坏死因子α（TNFα）、8-异前列腺素、尿酸、乳酸脱氢酶（LDH）和XO活性之前的最后4周，给予标准XO抑制剂别嘌醇。通过免疫荧光评估心脏血管紧张素II（AngII）和血管紧张素受体1（AT1）的表达。
IR动物存在明显的高尿酸血症，别嘌醇给药可抑制该症状。IR与心室舒张功能受损相关（表现为舒张压增量降低和舒张期延长），XO抑制可大大减轻舒张功能受损。IR伴有心脏缺血（表现为QTc和T峰趋势间期增加），而XO抑制可缓解心电图异常。当受到异丙肾上腺素诱导的缺血时，IR心脏的耐受性较差（表现为更大的ST段压低和更高的LDH水平），而XO抑制可减轻伴随的缺血。此外，XO抑制可防止血清8-异前列腺素和TNFα升高，并阻断IR动物心脏组织中AngII和AT1受体表达的升高。然而，XO抑制并未影响已出现的高胰岛素血症或血脂异常。
XO抑制通过抑制低度炎症和血管紧张素系统，减轻IR中的心脏缺血和舒张功能受损。
