Defective Extracellular Pyrophosphate Metabolism Promotes Vascular Calcification in a Mouse Model of Hutchinson-Gilford Progeria Syndrome That Is Ameliorated on Pyrophosphate Treatment
| العنوان: | Defective Extracellular Pyrophosphate Metabolism Promotes Vascular Calcification in a Mouse Model of Hutchinson-Gilford Progeria Syndrome That Is Ameliorated on Pyrophosphate Treatment |
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| المؤلفون: | Rebeca Acín-Pérez, José Rivera-Torres, José Antonio Enríquez, Fernando G. Osorio, Ricardo Villa-Bellosta, Vicente Andrés, Carlos López-Otín |
| المساهمون: | Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III, Progeria Research Foundation, Botín Foundation, Fundación Cajastur, Fundación ProCNIC |
| المصدر: | Repisalud Instituto de Salud Carlos III (ISCIII) |
| بيانات النشر: | Ovid Technologies (Wolters Kluwer Health), 2013. |
| سنة النشر: | 2013 |
| مصطلحات موضوعية: | Male, Premature aging, congenital, hereditary, and neonatal diseases and abnormalities, Pyrophosphate, medicine.medical_specialty, Vascular smooth muscle, muscle, Muscle, Smooth, Vascular, Progerin, Mice, chemistry.chemical_compound, Adenosine Triphosphate, Progeria, Physiology (medical), Internal medicine, medicine, Extracellular, Animals, Tissue-non specific alkaline phosphatase, Vascular Calcification, Aorta, Cells, Cultured, integumentary system, business.industry, Alkaline Phosphatase, Lamin Type A, medicine.disease, Mice, Mutant Strains, Hutchinson-Gilford progeria syndrome, Mitochondria, Muscle, ATP, Diphosphates, Mice, Inbred C57BL, Disease Models, Animal, Treatment Outcome, Endocrinology, chemistry, Alkaline phosphatase, Smooth, Cardiology and Cardiovascular Medicine, business, Lamin |
| الوصف: | Background— Progerin is a mutant form of lamin A responsible for Hutchinson-Gilford progeria syndrome (HGPS), a premature aging disorder characterized by excessive atherosclerosis and vascular calcification that leads to premature death, predominantly of myocardial infarction or stroke. The goal of this study was to investigate mechanisms that cause excessive vascular calcification in HGPS. Methods and Results— We performed expression and functional studies in wild-type mice and knock-in Lmna G609G/+ mice expressing progerin, which mimic the main clinical manifestations of HGPS. Lmna G609G/+ mice showed excessive aortic calcification, and primary aortic vascular smooth muscle cells from these progeroid animals had an impaired capacity to inhibit vascular calcification. This defect in progerin-expressing vascular smooth muscle cells is associated with increased expression and activity of tissue-nonspecific alkaline phosphatase and mitochondrial dysfunction, which leads to reduced ATP synthesis. Accordingly, Lmna G609G/+ vascular smooth muscle cells are defective for the production and extracellular accumulation of pyrophosphate, a major inhibitor of vascular calcification. We also found increased alkaline phosphatase activity and reduced ATP and pyrophosphate levels in plasma of Lmna G609G/+ mice without changes in phosphorus and calcium. Treatment with pyrophosphate inhibited vascular calcification in progeroid mice. Conclusions— Excessive vascular calcification in Lmna G609G mice is caused by reduced extracellular accumulation of pyrophosphate that results from increased tissue-nonspecific alkaline phosphatase activity and diminished ATP availability caused by mitochondrial dysfunction in vascular smooth muscle cells. Excessive calcification is ameliorated on pyrophosphate treatment. These findings reveal a previously undefined pathogenic process in HGPS that may also contribute to vascular calcification in normal aging, because progerin progressively accumulates in the vascular tissue of individuals without HGPS. |
| تدمد: | 1524-4539 0009-7322 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::5eeca915fc92287e9fb93044252acc65Test https://doi.org/10.1161/circulationaha.112.000571Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....5eeca915fc92287e9fb93044252acc65 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15244539 00097322 |
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