allopurinol and Diabetic-Cardiomyopathies

Allopurinol (ALP) attenuates oxidative stress and diabetic cardiomyopathy (DCM), but the mechanism is unclear. Activation of nuclear factor erythroid 2-related factor 2 (Nrf2) following the disassociation with its repressor Keap1 under oxidative stress can maintain inner redox homeostasis and attenuate DCM with concomitant attenuation of autophagy. We postulated that ALP treatment may activate Nrf2 to mitigate autophagy over-activation and consequently attenuate DCM. Streptozotocin-induced type 1 diabetic rats were untreated or treated with ALP (100 mg/kg/d) for 4 weeks and terminated after heart function measurements by echocardiography and pressure-volume conductance system. Cardiomyocyte H9C2 cells infected with Nrf2 siRNA or not were incubated with high glucose (HG, 25 mmol/L) concomitantly with ALP treatment. Cell viability, lactate dehydrogenase, 15-F2t-Isoprostane and superoxide dismutase (SOD) were measured with colorimetric enzyme-linked immunosorbent assays. ROS, apoptosis, was assessed by dihydroethidium staining and TUNEL, respectively. The Western blot and qRT-PCR were used to assess protein and mRNA variations. Diabetic rats showed significant reductions in heart rate (HR), left ventricular eject fraction (LVEF), stroke work (SW) and cardiac output (CO), left ventricular end-systolic volume (LVVs) as compared to non-diabetic control and ALP improved or normalized HR, LVEF, SW, CO and LVVs in diabetic rats (all P < .05). Hearts of diabetic rats displayed excessive oxidative stress manifested as increased levels of 15-F2t-Isoprostane and superoxide anion production, increased apoptotic cell death and cardiomyocytes autophagy that were concomitant with reduced expressions of Nrf2, heme oxygenase-1 (HO-1) and Keap1. ALP reverted all the above-mentioned diabetes-induced biochemical changes except that it did not affect the levels of Keap1. In vitro, ALP increased Nrf2 and reduced the hyperglycaemia-induced increases of H9C2 cardiomyocyte hypertrophy, oxidative stress, apoptosis and autophagy, and enhanced cellular viability. Nrf2 gene silence cancelled these protective effects of ALP in H9C2 cells. Activation of Nrf2 subsequent to the suppression of Keap1 and the mitigation of autophagy over-activation may represent major mechanisms whereby ALP attenuates DCM.

Topics: Allopurinol; Animals; Apoptosis; Cell Line; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Diastole; Glucose; Heart Ventricles; Hemodynamics; Hyperglycemia; Kelch-Like ECH-Associated Protein 1; Male; Models, Biological; Myocytes, Cardiac; NF-E2-Related Factor 2; Oxidative Stress; Rats, Sprague-Dawley; Sequestosome-1 Protein; Signal Transduction; Systole

Atrial fibrillation (AF) is a common arrhythmia which is associated with higher risk of stroke, heart failure and all-cause mortality. Abnormal Ca. Adult male SD rats were used to establish a diabetic rat model, divided into three groups: the control group, DM group and allopurinol group. Hemodynamic and ECG indicators were recorded, after which electrophysiological studies were conducted. The protein expression of CaMKII, p-CaMKII, XO, MnSOD and NCX was measured by Western blot and immunohistochemistry. H&E and Masson staining were applied for observing myocardial fibrosis. HL-1 cells were cultured for the measurement of ROS generation.. The arrangement of atrial myocytes was disordered and the collagen volume fraction of the atrium tissue was elevated in the DM group compared with the control group, and improved by allopurinol. Higher incidence of inducible AF, reduced conduction velocity and higher conduction inhomogeneity were observed in diabetic rats. These electrophysiological abnormalities were accompanied by higher oxidative stress and protein expression of p-CaMKII and NCX. Allopurinol prevented the development of these abnormal changes.. Allopurinol can improve atrial electrical remodeling by inhibiting CaMKII activity and protein expression of NCX. These data indicate xanthine oxidase inhibition can reduce oxidative stress and ameliorate atrial electrical remodeling.

Topics: Allopurinol; Animals; Atrial Remodeling; Blotting, Western; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Echocardiography; Hemodynamics; Male; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Signal Transduction; Xanthine Oxidase

There are several mechanisms, including inflammation, oxidative stress and abnormal calcium homeostasis, involved in the pathogenesis of atrial fibrillation. In diabetes mellitus (DM), increased oxidative stress may be attributable to higher xanthine oxidase activity. In this study, we examined the relationship between oxidative stress and atrial electrical and structural remodeling, and calcium handling abnormalities, and the potential beneficial effects of the xanthine oxidase inhibitor allopurinol upon these pathological changes.. Ninety rabbits were randomly and equally divided into 3 groups: control, DM, and allopurinol-treated DM group. Echocardiographic and hemodynamic assessments were performed in vivo. Serum and tissue markers of oxidative stress and atrial fibrosis, including the protein expression were examined. Atrial interstitial fibrosis was evaluated by Masson trichrome staining. I. Allopurinol, via its antioxidant effects, reduces atrial mechanical, structural, ion channel remodeling and mitochondrial synthesis abnormalities induced by DM-related increases in oxidative stress.

Topics: Allopurinol; Alloxan; Animals; Atrial Remodeling; Calcium Signaling; Cells, Cultured; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Enzyme Inhibitors; Female; Fibrosis; Heart Atria; Male; Myocytes, Cardiac; Oxidative Stress; Rabbits; Xanthine Oxidase

Hyperuricemia/gout and atrial fibrillation (AF) are two pathological conditions that are highly prevalent in type 2 diabetes and share multiple cardiovascular risk factors. However, the relationship between elevated levels of serum uric acid and risk of AF in type 2 diabetes is currently poorly known.. We studied a hospital-based sample of 842 (male/female = 463/379) patients with type 2 diabetes discharged from our Division of Endocrinology during 2007-2011. Hyperuricemia was defined as a serum uric acid level >7 mg/dl for men and >6 mg/dl for women or allopurinol use. The diagnosis of AF was confirmed in affected participants on the basis of ECGs and medical history by experienced cardiologists.. Overall, 243 (28.9 %) patients had hyperuricemia and 91 (10.8 %) patients had persistent or permanent AF. Compared with those with normal serum uric acid levels, patients with hyperuricemia had a remarkably greater prevalence of AF (20.6 vs. 7.1 %; p < 0.001). Hyperuricemia was significantly associated with an increased risk of prevalent AF (odds ratio 3.41, 95 % CI 2.19-5.32; p < 0.001). Adjustments for age, sex, smoking, hemoglobin A1c, hypertension status, chronic kidney disease, chronic obstructive pulmonary disease and previous histories of hyperthyroidism, ischemic heart disease and valvular heart diseases did not weaken this association (adjusted-odds ratio 6.27, 95 % CI 1.82-21.5; p < 0.01).. These results indicate that hyperuricemia is associated with an increased prevalence of AF in hospitalized patients with type 2 diabetes, independently of multiple risk factors and potential confounders.

Topics: Aged; Aged, 80 and over; Allopurinol; Atrial Fibrillation; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Electronic Health Records; Female; Gout; Gout Suppressants; Hospitalization; Hospitals, University; Humans; Hyperuricemia; Italy; Male; Middle Aged; Prevalence; Retrospective Studies; Risk; Uric Acid

Diabetic cardiomyopathy, a disorder of the heart muscle in diabetic patients, is one of the major causes of heart failure. Since diabetic cardiomyopathy is now known to have a high prevalence in the asymptomatic diabetic patient, prevention at the earliest stage of development by existing molecules would be appropriate in order to prevent the progression of heart failure. In this study, we investigated the protective role of multiple antioxidants (MA), on cardiac dysfunction and cardiac cell apoptosis in streptozotocin (STZ)-induced diabetic rat. Diabetic cardiomyopathy in STZ-treated animals was characterized by declined systolic, diastolic myocardial performance, oxidative stress and apoptosis in cardiac cells. Diabetic rats on supplementation with MA showed decreased oxidative stress evaluated by the content of reduced levels of lipid per-oxidation and decreased activity of catalase with down-regulation of heme-oxygenase-1 mRNA. Supplementation with MA also resulted in a normalized lipid profile and decreased levels of pro-inflammatory transcription factor NF-kappaB as well as cytokines such as TNF-α, IFN-γ, TGF-β, and IL-10. MA was found to decrease the expression of ROS-generating enzymes like xanthine oxidase, monoamine oxidase-A along with 5-Lipoxygenase mRNA and/or protein expression. Further, left ventricular function, measured by a microtip pressure transducer, was re-established as evidenced by increase in ±dp/dtmax, heart rate, decreased blood pressure, systolic and diastolic pressure as well as decrease in the TUNEL positive cardiac cells with increased Bcl-2/Bax ratio. In addition, MA supplementation decreased cell death and activation of NF-kappaB in cardiac H9c2 cells. Based on our results, we conclude that MA supplementation significantly attenuated cardiac dysfunction in diabetic rats; hence MA supplementation may have important clinical implications in terms of prevention and management of diabetic cardiomyopathy.

Topics: Animals; Antioxidants; Arachidonate 5-Lipoxygenase; Blood Pressure; Catalase; Cytokines; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Gene Expression; Heart; Heart Failure; Heart Rate; Heme Oxygenase (Decyclizing); Humans; Lipid Peroxidation; Male; Monoamine Oxidase; Myocytes, Cardiac; NF-kappa B; Oxidative Stress; Rats; Rats, Wistar; Streptozocin; Xanthine Oxidase

Xanthine oxidase-derived superoxide production and oxidative stress contribute to the development of diabetic complications including diabetic cardiomyopathy. We hypothesized that xanthine oxidase-inhibitor allopurinol (ALP) may decrease hyperglycemia-induced oxidative stress, ameliorate cardiomyocyte hypertrophy and fibrosis, and attenuate the development of left ventricle (LV) diastolic dysfunction in rats with streptozotocin (STZ)-induced diabetes.. Control Sprague Dawley (C) or streptozotocin-induced diabetic (D) rats were either untreated or treated with allopurinol (100 mg/kg/day) for 4 weeks starting at 1 week after streptozotocin injection. Free 15-F2t-isoprostane, a specific indicator of oxidative stress was measured by enzymatic immunoassay. The cardiomyocyte cross-sectional area was assessed by hematoxylin and eosin-stained paraffin-embedded sections of LVs. Myocardial collagens I and III were assessed by immunol histochemistry and Western blotting. Echocardiography was performed to characterize cardiac structure and function.. In diabetic rats, both plasma and cardiac tissue levels of free 15-F2t-isoprostane were increased (p < 0.05 vs. control), accompanied with significant increase (p < 0.05 vs. control) in cross-section area and myocardial collagen deposition of LV cardiomyocyte. Echocardiography in diabetic rats showed that LV weight/body weight ratio was significantly higher than in control rats, whereas the levels of LV end-diastolic volume and stroke volume were decreased (all p < 0.05 diabetic vs. control). All these changes were either attenuated or prevented by allopurinol. In addition, LV ejection fraction in diabetic rats treated with allopurinol was higher than that in untreated diabetic rats (p < 0.05).. Allopurinol can attenuate hyperglycemia-induced oxidative stress, ameliorate cardiomyocyte hypertrophy and fibrosis and subsequently prevent left ventricular dysfunction in early diabetes.

Topics: Allopurinol; Animals; Antimetabolites; Blotting, Western; Collagen Type I; Diabetes Complications; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Dinoprost; Echocardiography; Immunoenzyme Techniques; Isoprostanes; Male; Myocytes, Cardiac; Rats; Rats, Sprague-Dawley; Ventricular Dysfunction, Left