Protection against methylglyoxal-derived AGEs by regulation of glyoxalase 1 prevents retinal neuroglial and vasodegenerative pathology.

AIMS/HYPOTHESIS: Methylglyoxal (MG) is an important precursor for AGEs. Normally, MG is detoxified by the glyoxalase (GLO) enzyme system (including component enzymes GLO1 and GLO2). Enhanced glycolytic metabolism in many cells during diabetes may overpower detoxification capacity and lead to AGE-related pathology. Using a transgenic rat model that overexpresses GLO1, we investigated if this enzyme can inhibit retinal AGE formation and prevent key lesions of diabetic retinopathy. METHODS: Transgenic rats were developed by overexpression of full length GLO1. Diabetes was induced in wild-type (WT) and GLO1 rats and the animals were killed after 12 or 24 weeks of hyperglycaemia. N ε)-(Carboxyethyl)lysine (CEL), N(ε)-(carboxymethyl)lysine (CML) and MG-derived-hydroimidazalone-1 (MG-H1) were determined by immunohistochemistry and by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MSMS). Müller glia dysfunction was determined by glial fibrillary acidic protein (GFAP) immunoreactivity and by spatial localisation of the potassium channel Kir4.1. Acellular capillaries were quantified in retinal flat mounts. RESULTS: GLO1 overexpression prevented CEL and MG-H1 accumulation in the diabetic retina when compared with WT diabetic counterparts (p < 0.01). Diabetes-related increases in Müller glial GFAP levels and loss of Kir4.1 at the vascular end-feet were significantly prevented by GLO1 overexpression (p < 0.05) at both 12- and 24-week time points. GLO1 diabetic animals showed fewer acellular capillaries than WT diabetic animals (p < 0.001) at 24 weeks' diabetes. CONCLUSIONS/INTERPRETATION: Detoxification of MG reduces AGE adduct accumulation, which, in turn, can prevent formation of key retinal neuroglial and vascular lesions as diabetes progresses. MG-derived AGEs play an important role in diabetic retinopathy.

[Transapical approach for aortic stented valve implantation: experimental results]. / Implantation transapicale d'une valve stentée aortique: résultats expérimentaux.

OBJECTIVE: Percutaneous aortic valve replacement has been performed in humans mainly for non-surgical candidates. We evaluated on animals a transapical approach to deliver an aortic stented valve without cardiopulmonary bypass. METHODS: A tubular pericardial valve fixed within a cobalt-nickel stent (Medtronic, Inc.) was implanted using a transapical approach in five adult sheep. A left thoracotomy was used to access the apex of the heart. The crimped valve was deployed in orthotopic position with a valvuloplasty balloon catheter on the beating heart after decreasing the left ventricular pressure by using either drugs or inferior vena cava occlusion. Deployments were performed under fluoroscopy and epicardial 2D Doppler echocardiography. Exact positioning of the valve into the target area was confirmed by autopsy at the end of the procedures. RESULTS: Valves were unsuccessfully deployed at the target site in all cases but one. Three valves were implanted in a supra-annular position with two of them in supracoronary position. One valve was implanted below the native annulus in the outflow tract. Valvular leak was noted in all but one implants. Coronary obstruction occurred twice and early valve retrograde migration once. Ventricular fibrillation or diastolic cardiac arrest occurred less than 20 minutes after stent deployment in all cases. CONCLUSION: In our experience the transapical approach does not facilitate delivery of a stented valve. Despite its technically feasibility, advanced stent design and improvements in delivery system are required before to continue experimental studies in transapical approach for aortic stented valve.