The Level of Hepatic ABCC6 Expression Determines the Severity of Calcification after Cardiac Injury
Year: 2013
Type: article
Abstract: Because vascular or cardiac mineralization is inversely correlated with morbidity and long-term survival, we investigated the role of ABCC6 in the calcification response to cardiac injury in mice. By using two models of infarction, nonischemic cryoinjury and the pathologically relevant coronary artery ligation, we confirmed a large propensity to acute cardiac mineralization in Abcc6−/− mice. Furthermore, when the expression of ABCC6 was reduced to approximately 38% of wild-type levels in Abcc6+/− mice, no calcium deposits in injured cardiac tissue were observed. In addition, we used a gene therapy approach to deliver a functional human ABCC6 via hydrodynamic tail vein injection to approximately 13% of mouse hepatocytes, significantly reducing the calcification response to cardiac cryoinjury. We observed that the level and distribution of known regulators of mineralization, such as osteopontin and matrix Gla protein, but not osteocalcin, were concomitant to the level of hepatic expression of human and mouse ABCC6. We notably found that undercarboxylated matrix Gla protein precisely colocalized within areas of mineralization, whereas osteopontin was more diffusely distributed in the area of injury, suggesting a prominent association for matrix Gla protein and osteopontin in ABCC6-related dystrophic cardiac calcification. This study showed that the expression of ABCC6 in liver is an important determinant of calcification in cardiac tissues in response to injuries and is associated with changes in the expression patterns of regulators of mineralization.
Source: American Journal Of Pathology
Institutions: University of Hawaiʻi at Mānoa, University of Hawaii System, Institute for Integrative and Experimental Genomics, German Centre for Cardiovascular Research, University of Lübeck, Centre National de la Recherche Scientifique, Inserm, Université Nantes Angers Le Mans, Netherlands Institute for Neuroscience, Amsterdam UMC Location University of Amsterdam, Deutsches Herzzentrum München, Institute of Molecular Life Sciences, Hungarian Academy of Sciences
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $2,800
Funders: American Heart Association, Hawaii Community Foundation, Hungarian Scientific Research Fund, Oogfonds, Algemene Nederlandse Vereniging ter voorkoming van Blindheid, Landelijke Stichting voor Blinden en Slechtzienden, Stichting Blinden-Penning, National Institutes of Health, National Heart, Lung, and Blood Institute, National Institute of General Medical Sciences, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Center for Research Resources, National Institute on Minority Health and Health Disparities
Awards: G1323720961, G2293949861, G2380416762, G2551434997, G3251619415, Bioscience Research Infrastructure Development for Grant Enhancement and Success, The Role of ABCC6 In Chronic & Acute Cardiovascular Mineralization, Bioscience Research Infrastructure Development for Grant Enhancement and Success, G3864985968, G5659760395, COBRE: Center for Cardiovascular Research, G657584568, G6675472093, G7128401112, COBRE III: Center for Cardiovascular Research, G8673104828
OpenAlex ID: W2020066766