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Resumen La alcaptonuria es una enfermedad rara autosomica recesiva del metabolismo de la tirosina que provoca el acumulo de acido homogentisico en determinados tejidos del cuerpo humano, como el tejido cartilaginoso, causando calcificacion, degeneracion y fibrosis. Las manifestaciones cardiovasculares son poco frecuentes, habiendo pocos casos descritos en la literatura en los que se produce afectacion valvular cardiaca. Presentamos el caso de una mujer de 76 anos con historia de alcaptonuria que fue diagnosticada de doble lesion aortica severa e insuficiencia mitral moderada, requiriendo intervencion quirurgica para recambio valvular aortico y mitral. Revisamos la etiologia, la patogenesis, las manifestaciones clinicas, el diagnostico y el tratamiento de esta patologia.

Fil: Dube, Prabhatchandra R. University of Toledo. College of Medicine and Life Sciences. Center for Hypertension and Personalized Medicine. Department of Physiology and Pharmacology; Estados Unidos Fil: Chikkamenahalli, Lakshmikanth L. University of Toledo. College of Medicine and Life Sciences. Center for Hypertension and Personalized Medicine. Department of Physiology and Pharmacology; Estados Unidos Fil: Birnbaumer, Lutz. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina Fil: Birnbaumer, Lutz. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Birnbaumer, Lutz. National Institute of Environmental Health Sciences. Research Triangle Park. Neurobiology Laboratory; Estados Unidos Fil: Vazquez, Guillermo. University of Toledo. College of Medicine and Life Sciences. Center for Hypertension and Personalized Medicine. Department of Physiology and Pharmacology; Estados Unidos Abstract: Background and aims—Recent in vitro studies have showed that in macrophages deletion of the non-selective Ca2+-permeable channel TRPC3 impairs expression of the osteogenic protein BMP-2. The pathophysiological relevance of this effect in atherosclerotic plaque calcification remains to be determined. Methods—We used Ldlr −/− mice with macrophage-specific loss of TRPC3 (MacTrpc3 −/−/Ldlr −/−) to examine the effect of macrophage Trpc3 on plaque calcification and osteogenic features in advanced atherosclerosis. Results—After 25 weeks on high fat diet, aortic root plaques in MacTrpc3 −/−/Ldlr −/− mice showed reduced size, lipid and macrophage content compared to controls. Plaque calcification was decreased in MacTrpc3 −/−/Ldlr −/− mice, and this was accompanied by marked reduction in BMP-2, Runx-2 and phospho-SMAD1/5 contents within macrophage-rich areas. Expression of Bmp-2 and Runx-2 was also reduced in bone marrow-derived macrophages from MacTrpc3 −/−/ Ldlr −/− mice. Conclusions—These findings show that, in advanced atherosclerosis, selective deletion of TRPC3 in macrophages favors plaque regression and impairs the activity of a novel macrophageassociated, BMP-2-dependent mechanism of calcification.

Fil: Dube, Prabhatchandra R. University of Toledo. College of Medicine and Life Sciences. Center for Hypertension and Personalized Medicine. Department of Physiology and Pharmacology; Estados Unidos Fil: Birnbaumer, Lutz. National Institute of Environmental Health Sciences. Neurobiology Laboratory; Estados Unidos Fil: Birnbaumer, Lutz. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina Fil: Birnbaumer, Lutz. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Vazquez, Guillermo. University of Toledo. College of Medicine and Life Sciences. Center for Hypertension and Personalized Medicine. Department of Physiology and Pharmacology; Estados Unidos Abstract: Mechanisms mediating vascular calcification recapitulate osteogenic processes encompassing bone formation and imply participation of bone related proteins such as bone morphogenetic protein-2 (BMP-2). Macrophages are amongst the cells that contribute to vascular ossification by releasing cytokines that induce an osteogenic program in vascular smooth muscle cells, and also by becoming themselves osteoclast-like cells. In inflammatory vascular disease, the macrophage population in the vascular wall is diverse, with the M1 or inflammatory, and the M2 or anti-inflammatory macrophage types being dominant. Yet, the osteogenic potential of M1 and M2 macrophages remains unknown. Prompted by recent studies from our laboratory showing that in macrophages the Transient Receptor Potential Canonical 3 (TRPC3) channel contributes to endoplasmic reticulum (ER) stress-induced apoptosis in M1, but not in M2 macrophages, and given the strong relationship between ER stress and vascular calcification, we wished to examine whether TRPC3 would play a role in the osteogenic signaling of polarized macrophages. The findings reported here indicate that a constitutive BMP-2-dependent signaling operates in M1 macrophages, which is not affected by deletion of Trpc3 and is not subject to regulation by ER stress. Our studies suggest operation of an auto/paracrine mechanism by which BMP-2 secreted by M1 macrophages maintains constitutive activation of a BMP-2 receptor/SMAD1/5 signaling axis.