Temporal Progression of Aortic Valve Pathogenesis in a Mouse Model of Osteogenesis Imperfecta
Organization of extracellular matrix (ECM) components, including collagens, proteoglycans, and elastin, is essential for maintaining the structure and function of heart valves throughout life. Mutations in ECM genes cause connective tissue disorders, including Osteogenesis Imperfecta (OI), and progr...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-08-01
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| Series: | Journal of Cardiovascular Development and Disease |
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| Online Access: | https://www.mdpi.com/2308-3425/10/8/355 |
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| author | Kaitlyn Thatcher Carol R. Mattern Daniel Chaparro Veronica Goveas Michael R. McDermott Jessica Fulton Joshua D. Hutcheson Brian R. Hoffmann Joy Lincoln |
| author_facet | Kaitlyn Thatcher Carol R. Mattern Daniel Chaparro Veronica Goveas Michael R. McDermott Jessica Fulton Joshua D. Hutcheson Brian R. Hoffmann Joy Lincoln |
| author_sort | Kaitlyn Thatcher |
| collection | DOAJ |
| description | Organization of extracellular matrix (ECM) components, including collagens, proteoglycans, and elastin, is essential for maintaining the structure and function of heart valves throughout life. Mutations in ECM genes cause connective tissue disorders, including Osteogenesis Imperfecta (OI), and progressive debilitating heart valve dysfunction is common in these patients. Despite this, effective treatment options are limited to end-stage interventions. Mice with a homozygous frameshift mutation in <i>col1a2</i> serve as a murine model of OI (<i>oim/oim</i>), and therefore, they were used in this study to examine the pathobiology of aortic valve (AoV) disease in this patient population at structural, functional, and molecular levels. Temporal echocardiography of <i>oim/oim</i> mice revealed AoV dysfunction by the late stages of disease in 12-month-old mice. However, structural and proteomic changes were apparent much earlier, at 3 months of age, and were associated with disturbances in ECM homeostasis primarily related to collagen and proteoglycan abnormalities and disorganization. Together, findings from this study provide insights into the underpinnings of late onset AoV dysfunction in connective tissue disease patients that can be used for the development of mechanistic-based therapies administered early to halt progression, thereby avoiding late-stage surgical intervention. |
| first_indexed | 2024-03-10T23:51:12Z |
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| institution | Directory Open Access Journal |
| issn | 2308-3425 |
| language | English |
| last_indexed | 2024-03-10T23:51:12Z |
| publishDate | 2023-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Journal of Cardiovascular Development and Disease |
| spelling | doaj.art-2d6f5df9379543fbbdfb52af7c2481e52023-11-19T01:38:38ZengMDPI AGJournal of Cardiovascular Development and Disease2308-34252023-08-0110835510.3390/jcdd10080355Temporal Progression of Aortic Valve Pathogenesis in a Mouse Model of Osteogenesis ImperfectaKaitlyn Thatcher0Carol R. Mattern1Daniel Chaparro2Veronica Goveas3Michael R. McDermott4Jessica Fulton5Joshua D. Hutcheson6Brian R. Hoffmann7Joy Lincoln8Department of Pediatrics, Division of Pediatric Cardiology, Medical College of Wisconsin, Milwaukee, WI 53226, USADepartment of Pediatrics, Division of Pediatric Cardiology, Medical College of Wisconsin, Milwaukee, WI 53226, USADepartment of Biomedical Engineering, Florida International University, Miami, FL 33174, USADepartment of Pediatrics, Division of Pediatric Cardiology, Medical College of Wisconsin, Milwaukee, WI 53226, USACenter for Cardiovascular Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USACenter for Cardiovascular Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USADepartment of Biomedical Engineering, Florida International University, Miami, FL 33174, USAMass Spectrometry and Protein Chemistry, Protein Sciences, The Jackson Laboratory, Bar Harbor, ME 04609, USADepartment of Pediatrics, Division of Pediatric Cardiology, Medical College of Wisconsin, Milwaukee, WI 53226, USAOrganization of extracellular matrix (ECM) components, including collagens, proteoglycans, and elastin, is essential for maintaining the structure and function of heart valves throughout life. Mutations in ECM genes cause connective tissue disorders, including Osteogenesis Imperfecta (OI), and progressive debilitating heart valve dysfunction is common in these patients. Despite this, effective treatment options are limited to end-stage interventions. Mice with a homozygous frameshift mutation in <i>col1a2</i> serve as a murine model of OI (<i>oim/oim</i>), and therefore, they were used in this study to examine the pathobiology of aortic valve (AoV) disease in this patient population at structural, functional, and molecular levels. Temporal echocardiography of <i>oim/oim</i> mice revealed AoV dysfunction by the late stages of disease in 12-month-old mice. However, structural and proteomic changes were apparent much earlier, at 3 months of age, and were associated with disturbances in ECM homeostasis primarily related to collagen and proteoglycan abnormalities and disorganization. Together, findings from this study provide insights into the underpinnings of late onset AoV dysfunction in connective tissue disease patients that can be used for the development of mechanistic-based therapies administered early to halt progression, thereby avoiding late-stage surgical intervention.https://www.mdpi.com/2308-3425/10/8/355aortic valve diseaseextracellular matrixconnective tissue disorder |
| spellingShingle | Kaitlyn Thatcher Carol R. Mattern Daniel Chaparro Veronica Goveas Michael R. McDermott Jessica Fulton Joshua D. Hutcheson Brian R. Hoffmann Joy Lincoln Temporal Progression of Aortic Valve Pathogenesis in a Mouse Model of Osteogenesis Imperfecta Journal of Cardiovascular Development and Disease aortic valve disease extracellular matrix connective tissue disorder |
| title | Temporal Progression of Aortic Valve Pathogenesis in a Mouse Model of Osteogenesis Imperfecta |
| title_full | Temporal Progression of Aortic Valve Pathogenesis in a Mouse Model of Osteogenesis Imperfecta |
| title_fullStr | Temporal Progression of Aortic Valve Pathogenesis in a Mouse Model of Osteogenesis Imperfecta |
| title_full_unstemmed | Temporal Progression of Aortic Valve Pathogenesis in a Mouse Model of Osteogenesis Imperfecta |
| title_short | Temporal Progression of Aortic Valve Pathogenesis in a Mouse Model of Osteogenesis Imperfecta |
| title_sort | temporal progression of aortic valve pathogenesis in a mouse model of osteogenesis imperfecta |
| topic | aortic valve disease extracellular matrix connective tissue disorder |
| url | https://www.mdpi.com/2308-3425/10/8/355 |
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