RESUMO
Vitamin K plays a crucial role in the regulation of vascular calcifications by allowing activation of matrix Gla protein. The dietary requirement for vitamin K is low because of an efficient recycling of vitamin K by vitamin K epoxide reductase (VKORC1). However, decreased VKORC1 activity may result in vascular calcification. More than 30 coding mutations of VKORC1 have been described. While these mutations have been suspected of causing anticoagulant resistance, their association with an increase in the risk of vascular calcification has never been considered. We thus investigated functional cardiovascular characteristics in a rat model mutated in VKORC1. This study revealed that limited intake in vitamin K in mutated rat induced massive calcified areas in the media of arteries of lung, aortic arch, kidneys and testis. Development of calcifications could be inhibited by vitamin K supplementation. In calcified areas, inactive Matrix Gla protein expression increased, while corresponding mRNA expression was not modified. Mutation in VKORC1 associated with a limited vitamin K intake is thus a major risk for cardiovascular disease. Our model is the first non-invasive rat model that shows spontaneous medial calcifications and would be useful for studying physiological function of vitamin K.
Assuntos
Arteriosclerose/genética , Esclerose Calcificante da Média de Monckeberg/genética , Calcificação Vascular/genética , Vitamina K Epóxido Redutases/genética , Vitamina K/metabolismo , Animais , Anticoagulantes/administração & dosagem , Aorta Torácica/patologia , Artérias/patologia , Arteriosclerose/patologia , Modelos Animais de Doenças , Humanos , Rim/irrigação sanguínea , Rim/patologia , Pulmão/irrigação sanguínea , Pulmão/patologia , Masculino , Esclerose Calcificante da Média de Monckeberg/patologia , Mutação , Mutação de Sentido Incorreto/genética , Polimorfismo de Nucleotídeo Único/genética , Ratos , Testículo/irrigação sanguínea , Testículo/patologia , Calcificação Vascular/patologia , Vitamina K/genética , Vitamina K Epóxido Redutases/metabolismoRESUMO
Calcific disease of the cardiovascular system, including atherosclerotic calcification, medial calcification in diabetes and calcific aortic valve disease, is an important risk factor for many adverse cardiovascular events such as ischemic cardiac events and subsequent mortality. Although cardiovascular calcification has long been considered to be a passive degenerative occurrence, it is now recognized as an active and highly regulated process that involves osteochondrogenic differentiation, apoptosis and extracellular vesicle release. Nonetheless, despite numerous studies on the pathogenesis of cardiovascular calcification, the underlying mechanisms remain poorly understood. High mobility group box 1 (HMGB1), a nuclear protein bound to chromatin in almost all eukaryotic cells, acts as a damage-associated molecular pattern (DAMP) when released into the extracellular space upon cell activation, injury or death. Moreover, HMGB1 also functions as a bone-active cytokine participating in bone remodeling and ectopic calcification pathogenesis. However, studies on the roles of HMGB1 in promoting cardiovascular calcification are limited to date, and the mechanisms involved are still unclear. In this review, we summarize recent studies investigating the mechanism of cardiovascular calcification and discuss multiple roles of HMGB1 in its development.
Assuntos
Estenose da Valva Aórtica/genética , Valva Aórtica/patologia , Calcinose/genética , Complicações do Diabetes/genética , Proteína HMGB1/genética , Esclerose Calcificante da Média de Monckeberg/genética , Animais , Valva Aórtica/metabolismo , Valva Aórtica/fisiopatologia , Estenose da Valva Aórtica/metabolismo , Estenose da Valva Aórtica/fisiopatologia , Remodelação Óssea/genética , Calcinose/metabolismo , Calcinose/fisiopatologia , Diferenciação Celular/genética , Cromatina/genética , Complicações do Diabetes/metabolismo , Complicações do Diabetes/fisiopatologia , Proteína HMGB1/metabolismo , Humanos , Esclerose Calcificante da Média de Monckeberg/metabolismo , Esclerose Calcificante da Média de Monckeberg/fisiopatologia , Ligação Proteica , Transdução de SinaisRESUMO
Peripheral arterial disease (PAD) is a global health issue that is becoming more prevalent in an aging world population. Diabetes mellitus and chronic kidney disease are also on the increase, and both are associated with accelerated vascular calcification and an unfavorable prognosis in PAD. These data challenge the traditional athero-centric view of PAD, instead pointing toward a disease process complicated by medial arterial calcification. Like atherosclerosis, aging is a potent risk factor for medial arterial calcification, and accelerated vascular aging may underpin the devastating manifestations of PAD, particularly in patients prone to calcification. Consequently, this review will attempt to dissect the relationship between medial arterial calcification and atherosclerosis in PAD and identify common as well as novel risk factors that may contribute to and accelerate progression of PAD. In this context, we focus on the complex interplay between oxidative stress, DNA damage, and vascular aging, as well as the unexplored role of neuropathy.
