Treatment with hydrogen molecule attenuates cardiac dysfunction in streptozotocin-induced diabetic mice.

INTRODUCTION: Diabetic cardiomyopathy, a disorder of the heart muscle in diabetic patients, is one of the major causes of heart failure. The aim of present study was to investigate the therapeutic effect of hydrogen molecule on streptozotocin-induced diabetic cardiomyopathy in mice. METHODS: Diabetes was induced in adult male mice by consecutive peritoneal injection of streptozotocin (50 mg/kg/day) for 5 days. Then, they were treated with hydrogen water (1.3±0.2 mg/l) for 8 weeks (four groups, n=83-88 in each group). RESULTS: Although treatment of diabetic mice with hydrogen water did not significantly affect blood glucose level, it significantly attenuated cardiac hypertrophy and reduced expression of atrial natriuretic factor and ß-myosin heavy chain; it alleviated cardiac fibrosis and reduced expression of collagen I and III, transforming growth factor beta, alpha-smooth muscle actin, and osteopontin; it reduced cardiac caspase-3 activity and ratio of bax/bcl-2. Importantly, hydrogen water treatment improved cardiac function in streptozotocin-diabetic mice. Furthermore, it was found that hydrogen water treatment abated oxidative stress, suppressed inflammation, and attenuated endoplasmic reticulum stress in the hearts of streptozotocin-diabetic mice. In addition, hydrogen water treatment suppressed activation of Jun NH2-terminal kinase and p38 mitogen activated protein kinase signaling and nuclear factor κB signaling in the hearts of streptozotocin-diabetic mice. CONCLUSION: Treatment with hydrogen molecule attenuated cardiac dysfunction in streptozotocin-induced diabetic mice, which was independent of glycemic control. SUMMARY: Treatment with hydrogen molecule attenuated cardiac dysfunction in streptozotocin-induced type 1 diabetic mice. Molecular hydrogen could thus be envisaged as a nutritional countermeasure for diabetic cardiomyopathy.

Activation of receptor for advanced glycation end products contributes to aortic remodeling and endothelial dysfunction in sinoaortic denervated rats.

OBJECTIVE: The aim of present study was to test the hypothesis that activation of receptor for advanced glycation end products (RAGE) pathway contributes to aortic remodeling and endothelial dysfunction in sinoaortic denervated (SAD) rats. METHODS AND RESULTS: Experiment 1: 8 weeks after sinoaortic denervation, aortas were removed for measurement of AGE/RAGE pathway. Sinoaortic denervation in rats resulted in enhanced activity of aldose reductase, reduced activity of glyoxalase 1, accumulation of methylglyoxal and AGE, and upregulated expression of RAGE in aortas. Experiment 2: 5 weeks after sinoaortic denervation, the rats received intraperitoneal injections of 500 µg soluble RAGE (sRAGE) daily for 3 weeks. Treatment of SAD rats with sRAGE attenuated aortic remodeling, marked by reduction in AW/length, wall thickness, proliferation of SMC, and collagen deposition, and improvement of endothelial function. Treatment of SAD rats with sRAGE abated aortic oxidative stress, marked by reduction in formation of malondialdehyde, reactive oxygen species, superoxide, peroxynitrite and 3-nitrotyrosine, and enhancement of ratio of GSH/GSSG. Treatment of SAD rats with sRAGE attenuated aortic mitochondrial dysfunction. Treatment of SAD rats with sRAGE suppressed aortic NFκB nuclear translocation and inflammation. Treatment of SAD rats with sRAGE restored aortic NO formation through upregulating eNOS and dimethylarginine dimethylaminohydrolase-2 and downregulating protein arginine methyltransferase-1. CONCLUSION: Activated RAGE contributed to aortic remodeling and endothelial dysfunction in SAD rats, possibly via induction of oxidative stress and inflammation, impairment of mitochondrial function, and reduction in NO bioavailability.

The potential role of local voltage potentials in right ventricular outflow tract arrhythmias: 47 cases with ventricular arrhythmias originating from right ventricular outflow tract.

OBJECTIVE: The object of this study was to investigate the possible role of local voltage potentials (LVPs) in mapping the ventricular arrhythmias originating from right ventricular outflow (RVOT). METHODS: Forty-seven patients with RVOT VAs (ventricular arrhythmias), referred for radiofrequency catheter ablation to our hospital, were analysed retrospectively for the prevalence, characteristics and electrophysiological evaluation of the LVPs recorded in successful and unsuccessful ablation sites. RESULTS: Radiofrequency ablation was successful immediately in all the 47 cases. Catheter ablation was performed at a mean of 8 +/- 6 sites per patient. There were 58 effective ablation sites, 5 cases with changing morphology of ventricular arrhythmias (VAs), and 318 invalid ablation sites. Activation times at effective ablation sites were slightly earlierthan those at invalid ablation sites (-28 +/- 8 ms vs-24 +/- 7 ms, P < 0.05). The LVPs appeared during VAs in 47 sites of the 58 effective ablation sites (81.0%), far more than the 22 sites of the 318 invalid ablation sites (6.9%) (P < 0.01). In two cases VAs recurred during follow-up. They received a second catheter ablation. CONCLUSIONS: Local ventricular potentials can be recorded in most patients with idiopathic VAs originating from the right outflow tract.The local potentials may facilitate successful radiofrequency ablation.

Down-regulation of DDAH2 and eNOS induces endothelial dysfunction in sinoaortic-denervated rats.

The aim of present study was to investigate whether downregulation of dimethylarginine dimethylaminohydrolase (DDAH2) and endothelial nitric oxide synthase (eNOS) induced endothelial dysfunction in sinoaortic-denervated (SAD) rats. SAD rats exhibited significantly higher blood pressure (BP) variability and markedly lower baroreflex sensitivity. However, there was no significant difference in BP between SAD rats and sham-operated rats. In SAD rats, ultrastructural analysis revealed that endothelial cells were degenerated and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) study showed that apoptotic aortic endothelial cells increased. Circulating angiotensinII (AngII), asymmetric dimethylarginine (ADMA) and malondialdehyde (MDA) levels in SAD rats were similar to sham-operated rats, but aortic AngII and MDA levels locally increased. Endothelium-mediated relaxation of thoracic aorta isolated from SAD rats was impaired compared to sham-operated rats, whereas the sodium nitroprusside-induced relaxation was quite similar. Western blotting results showed that DDAH2 and eNOS expressions decreased significantly in the aortae of SAD rats. Treatment of primary cultured rat aortic endothelial cells with AngII (1 µM) resulted in a marked reduction of DDAH2 and eNOS expressions, and coadministration of losartan (1 µM), an AT(1) receptor antagonist, abolished the effect. In conclusion, downregulation of DDAH2 and eNOS induced endothelial dysfunction in SAD rats. DDAH2 and eNOS may be the potential targets for treatment of endothelial dysfunction.