Xanthine oxidase inhibition alleviates the cardiac complications of insulin resistance: effect on low grade inflammation and the angiotensin system

Abstract

BackgroundWe 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.MethodsIR 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.ResultsIR 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.ConclusionsXO inhibition alleviates cardiac ischemia and impaired relaxation in IR through the inhibition of low grade inflammation and the angiotensin system.

Cinnamaldehyde and allopurinol reduce fructose-induced cardiac inflammation and fibrosis by attenuating CD36-mediated TLR4/6-IRAK4/1 signaling to suppress NLRP3 inflammasome activation

“…In our previous studies, allopurinol ameliorated fructose-induced metabolic syndrome and protects tissue injury by inhibiting NLRP3 inflammasome activation and IL-1β production 39 40 . Recently, allopurinol is found to restore a high-fat and high-fructose diet-induced cardiomyocyte oxidative stress, inflammation and hypertrophy in mice 41 , and alleviates cardiac ischemia in insulin resistance through inhibiting low grade inflammation and angiotensin system in rats fed with a high fructose and fat diet 42 . Thus, the cardioprotective effects of cinnamaldehyde and allopurinol against cardiac inflammation may be involved in heart injury under fructose-induced oxidative stress, but the molecular mechanism has not been understood yet.…”

Xanthine Oxidase Activity in Type 2 Diabetes Mellitus Patients with and without Diabetic Peripheral Neuropathy

“…Their study demonstrated that inhibition of XOD improved blood flow in sciatic and cervical nerve ganglion, thereby suggesting that upregulated XOD present in nerve microvasculature, including endothelium and perivascular space, can cause neurovascular dysfunction leading to diabetic neuropathy. Allopurinol also prevented cardiac ischemia and impaired relaxation in an experimental model of insulin resistance [34], normalized endothelial function in T2DM patients with mild hypertension [35], alleviated oxidative injury and improved cardiovascular functions in diabetics in several intervention studies [36], and acted antinociceptive against various noxious stimuli in mice [37]. On the other side, peripheral neuropathy can be a side effect of allopurinol treatment, and this drug failed to prevent the progression of DPN in type 1 diabetes mellitus patients with mild-to-moderate cardiovascular autonomic neuropathy [38].…”

Moderate (20%) fructose-enriched diet stimulates salt-sensitive hypertension with increased salt retention and decreased renal nitric oxide

“…Ingestion of 60% fructose for over 8 weeks (Behr‐Roussel et al. ), or 10% over 12 weeks (El‐Bassossy and Watson ), has been reported to increase 8‐isoprostane excretion, a marker for renal reactive oxygen species production. High salt diets have been shown to increase urinary nitric oxide excretion (Shultz and Tolins ).…”

“…There is substantial literature regarding nitric oxide deficiency and/or oxidative stress that may contribute to hypertension (Wilcox 2005). Ingestion of 60% fructose for over 8 weeks (Behr-Roussel et al 2008), or 10% over 12 weeks (El-Bassossy and Watson 2015), has been reported to increase 8-isoprostane excretion, a marker for renal reactive oxygen species production. High salt diets have been shown to increase urinary nitric oxide excretion (Shultz and Tolins 1993).…”