| Autor: |
Cikach FS; Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA., Koch CD; Department of Biomedical Engineering, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, USA.; Department of Chemistry, Cleveland State University, Cleveland, Ohio, USA., Mead TJ; Department of Biomedical Engineering, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, USA., Galatioto J; Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Willard BB; Proteomics and Metabolomics Core, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, USA., Emerton KB; Cleveland Clinic Innovations., Eagleton MJ; Department of Vascular Surgery., Blackstone EH; Department of Thoracic and Cardiovascular Surgery, and., Ramirez F; Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Roselli EE; Department of Thoracic and Cardiovascular Surgery, and.; Aorta Center, Cleveland Clinic, Cleveland, Ohio, USA., Apte SS; Department of Biomedical Engineering, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, USA. |
| Abstrakt: |
Proteoglycan accumulation is a hallmark of medial degeneration in thoracic aortic aneurysm and dissection (TAAD). Here, we defined the aortic proteoglycanome using mass spectrometry, and based on the findings, investigated the large aggregating proteoglycans aggrecan and versican in human ascending TAAD and a mouse model of severe Marfan syndrome. The aortic proteoglycanome comprises 20 proteoglycans including aggrecan and versican. Antibodies against these proteoglycans intensely stained medial degeneration lesions in TAAD, contrasting with modest intralamellar staining in controls. Aggrecan, but not versican, was increased in longitudinal analysis of Fbn1mgR/mgR aortas. TAAD and Fbn1mgR/mgR aortas had increased aggrecan and versican mRNAs, and reduced expression of a key proteoglycanase gene, ADAMTS5, was seen in TAAD. Fbn1mgR/mgR mice with ascending aortic dissection and/or rupture had dramatically increased aggrecan staining compared with mice without these complications. Thus, aggrecan and versican accumulation in ascending TAAD occurs via increased synthesis and/or reduced proteolytic turnover, and correlates with aortic dissection/rupture in Fbn1mgR/mgR mice. Tissue swelling imposed by aggrecan and versican is proposed to be profoundly deleterious to aortic wall mechanics and smooth muscle cell homeostasis, predisposing to type-A dissections. These proteoglycans provide potential biomarkers for refined risk stratification and timing of elective aortic aneurysm repair. |
