Ubiquitin-positive foam cells are identified in the aortic and mitral valves with atherosclerotic involvement.

AIM Our aim was to determine the roles of the ubiquitin (Ub)-proteasome system (UPS) in valvular diseases by immunohistochemically identifying Ub-positive cells in aortic and mitral valves and determining if Ub+cells were associated with the severity of valvular diseases. METHODS We evaluated surgically removed aortic and mitral valves from 60 patients (mean age, 64.5 years) for thickening, fibrosis, foam cell infiltration, thrombus, and atheromatous plaques by using grading scores. U+cells were detected immunohistochemically. RESULTS We found Ub+cells in 16 (26.7%) of the 60 patients. Eleven (28.2%) of the 39 aortic valves and 5 (23.8%) of the 21 mitral valves were Ub-positive. Ub was found with granular depositions in the cytoplasm of monocyte-derived foam cells that were CD68+. The aortic valvular thickness of the Ub+group was significantly greater than that of the Ub- group (3.9+/-1.6mm vs. 3.2+/-1.6mm, p<0.05). Foam cells and fibrosis were greater in the Ub+group (p<0.05), and calcifications were prominent in aortic valves. There was no difference in the number of apoptotic cells in Ub+ and Ub- groups. Ub+cells were present in the affected valves and ubiquitinated proteins were accumulated in macrophage-derived foam cells. CONCLUSIONS Ub+ foam cells are present in valves that are vulnerable to valvular disease, and UPS may contribute to the development of atherosclerosis through the inflammatory process.

[1]  Y. Kawabata,et al.  Ubiquitin‐positive pneumocytes are present in non‐specific interstitial pneumonia with immunohistochemical analyses , 2008, Histopathology.

[2]  J. Wrana,et al.  Transforming Growth Factor-β-stimulated Endocardial Cell Transformation Is Dependent on Par6c Regulation of RhoA* , 2008, Journal of Biological Chemistry.

[3]  G. Paolisso,et al.  Effects of ubiquitin-proteasome system deregulation on the vascular senescence and atherosclerosis process in elderly patients. , 2008, The journals of gerontology. Series A, Biological sciences and medical sciences.

[4]  L. Lerman,et al.  Chronic Proteasome Inhibition Contributes to Coronary Atherosclerosis , 2007, Circulation research.

[5]  R. Kaufman,et al.  Inhibition of the ubiquitin-proteasome system induces stress granule formation. , 2007, Molecular biology of the cell.

[6]  H. Akiyama,et al.  TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. , 2006, Biochemical and biophysical research communications.

[7]  Xin Wu,et al.  Differential response between the p53 ubiquitin-protein ligases Pirh2 and MdM2 following DNA damage in human cancer cells. , 2006, Experimental cell research.

[8]  Bruce L. Miller,et al.  Ubiquitinated TDP-43 in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis , 2006, Science.

[9]  F. Meyer,et al.  Dysregulation of the Ubiquitin-Proteasome System in Human Carotid Atherosclerosis , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[10]  智彦 水谷,et al.  UIP病変（Usual Interstitial Pneumonia Pattern/Lesion）を有する個体での術後急性増悪 , 2006 .

[11]  S. French,et al.  Mallory body (cytokeratin aggresomes) formation is prevented in vitro by p38 inhibitor. , 2006, Experimental and molecular pathology.

[12]  Y. Kawabata,et al.  Immunohistochemical detection of ubiquitin‐positive intracytoplasmic eosinophilic inclusion bodies in diffuse alveolar damage , 2006, Histopathology.

[13]  H. Sievers,et al.  Ubiquitin fusion degradation 1-like gene dysregulation in bicuspid aortic valve. , 2005, The Journal of thoracic and cardiovascular surgery.

[14]  D. Schrijvers,et al.  7-Ketocholesterol Induces Protein Ubiquitination, Myelin Figure Formation, and Light Chain 3 Processing in Vascular Smooth Muscle Cells , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[15]  Aaron Ciechanover,et al.  The ubiquitin system: pathogenesis of human diseases and drug targeting. , 2004, Biochimica et biophysica acta.

[16]  C. Wójcik,et al.  Ubiquitin-Proteasome System and Proteasome Inhibition: New Strategies in Stroke Therapy , 2004, Stroke.

[17]  A. Goldberg,et al.  Protein degradation and protection against misfolded or damaged proteins , 2003, Nature.

[18]  A. Ciechanover,et al.  Oxidative stress‐related increase in ubiquitination in early coronary atherogenesis , 2003, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[19]  T. Andersson,et al.  Oxidized low-density lipoprotein induces calpain-dependent cell death and ubiquitination of caspase 3 in HMEC-1 endothelial cells. , 2003, The Biochemical journal.

[20]  J. Schaper,et al.  Progression From Compensated Hypertrophy to Failure in the Pressure-Overloaded Human Heart: Structural Deterioration and Compensatory Mechanisms , 2003, Circulation.

[21]  A. Ciechanover,et al.  Increased ubiquitin immunoreactivity in unstable atherosclerotic plaques associated with acute coronary syndromes. , 2002, Journal of the American College of Cardiology.

[22]  K. Nakayama,et al.  Formation of Mallory body-like inclusions and cell death induced by deregulated expression of keratin 18. , 2002, Molecular biology of the cell.

[23]  Masashi Kobayashi,et al.  Inhibition of proteasome activity is involved in cobalt-induced apoptosis of human alveolar macrophages. , 2002, American journal of physiology. Lung cellular and molecular physiology.

[24]  Avram Hershko,et al.  The Cyclin-Ubiquitin Ligase Activity of Cyclosome/APC Is Jointly Activated by Protein Kinases Cdk1-Cyclin B and Plk* , 2002, The Journal of Biological Chemistry.

[25]  P. Kloetzel,et al.  Ubiquitin-Proteasome Pathway as a New Target for the Prevention of Restenosis , 2002, Circulation.

[26]  G. Kovacs,et al.  Apoptosis caused by oxidized LDL is manganese superoxide dismutase and p53 dependent , 1998, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[27]  J. Bilbao,et al.  Ubiquitin expression in inclusion body myositis. An immunohistochemical study. , 1993, Archives of Pathology & Laboratory Medicine.

[28]  R. Mayer,et al.  Anti-ubiquitin immunocytochemistry is more sensitive than conventional techniques in the detection of diffuse Lewy body disease. , 1989, Journal of neurology, neurosurgery, and psychiatry.

[29]  I. Grundke‐Iqbal,et al.  Lewy Bodies Contain Epitopes Both Shared and Distinct from Alzheimer Neurofibrillary Tangles , 1988, Journal of neuropathology and experimental neurology.

[30]  A. Hershko,et al.  Ubiquitin-activating enzyme. Mechanism and role in protein-ubiquitin conjugation. , 1982, The Journal of biological chemistry.

[31]  M. Knaapen,et al.  Histological evaluation of autophagic cell death in calcified aortic valve stenosis. , 2006, The Journal of heart valve disease.

[32]  A. Ciechanover,et al.  The ubiquitin-proteasome system in cardiovascular diseases-a hypothesis extended. , 2004, Cardiovascular research.

[33]  Y. Furukawa,et al.  Induction of ubiquitin-conjugating enzyme by aggregated low density lipoprotein in human macrophages and its implications for atherosclerosis. , 2000, Arteriosclerosis, thrombosis, and vascular biology.

[34]  T. Oinuma,et al.  Effects of copper-zinc type superoxide dismutase on the proliferation and migration of cultured vascular smooth muscle cells induced by oxidized low density lipoprotein. , 1997, Journal of atherosclerosis and thrombosis.