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.
Highlights
We have previously shown that hyperuricemia plays an important role in the vascular complications of insulin resistance (IR)
The serum xanthine oxidase (XO) activity tended to increase in rats fed on high fructose high fat diet while allopurinol administration significantly inhibited serum XO activity compared to the high fructose high fat diet fed group (p < 0.05, Figure 1b)
The following findings support the conclusion that XO inhibition can counteract cardiac diastolic dysfunction and ischemia accompanying IR: (i) XO inhibition ameliorated the impaired left ventricular diastolic relaxation associated with IR; (ii) the prolongation of cardiac repolarization in IR was alleviated by XO inhibition; (iii) XO inhibition alleviated the exaggerated cardiac ischemia following isoproterenol injection in IR; (iv) XO inhibition alleviated the low grade inflammation and oxidative stress associated with IR; (v) XO inhibition blocked the IR-induced activation of the angiotensin system both in heart tissue and coronary artery
Summary
We have previously shown that hyperuricemia plays an important role in the vascular complications of insulin resistance (IR). Insulin resistance (IR) is a key component of metabolic syndrome (MetS). The prevalence of MetS in the US in 2002 is estimated at 24% while in the elderly (over 60 years) the prevalence is 44%, based upon the data from the National Health and Nutrition Examination Survey [2]. This is hyperuricemia is condition that frequently accompanies MetS, its role as a risk factor for cardiovascular complications in MetS is debated. We have previously shown that direct in vitro incubation of normal isolated aorta with uric acid at the same concentration
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
