Cathepsin K gene disruption does not affect murine aneurysm formation.
Cathepsin K (catK), a lysosomal cysteine protease, exerts strong elastinolytic and collagenolytic activity and is implicated in a range of pathological disorders including cardiovascular disease. CatK expression was found to be elevated in human aortic aneurysm pointing to a role in this vasculopathy. In the angiotensin II (Ang II)-induced mouse model for aneurysm formation, catK, S and C expression was strongly upregulated. Therefore, we investigated the effect of catK deficiency on Ang II-induced aneurysm formation in the abdominal aorta of apoE-/- mice. Contrary to our expectations, catK deficiency did not protect against aneurysm formation, nor did it affect medial elastin breaks. Proteolytic activity in abdominal aortic lysates were comparable between apoE-/- and catK-//-apoE-/- mice. Adventitial presence of catS- and catC-expressing cells was significantly increased in catK-/-//apoE-/- versus apoE-/- mice, which might have compensated for the deficiency of catK-derived proteolysis in the aneurysm tissue of catK deficient apoE-/- mice. Circulating granulocytes and activated T cell numbers were significantly increased in Ang II-infused catK-/-//apoE-/- mice, which is consistent with the borderline significant increase in adventitial leukocyte content in catK-/-//apoE-/- compared to apoE-/- mice. Strikingly, despite unchanged proteolytic activity in AAA lesions, collagen content in the aneurysm was significantly increased in catK-//-apoE-/- mice. In conclusion, while catK deficiency has major impact on various vasculopathies, it did not affect murine aneurysm formation.
Experimental Vascular Pathology Group, Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, P. Debyelaan 25, Maastricht, The Netherlands.
Lili
L
Bai
Linda
L
Beckers
Erwin
E
Wijnands
Suzanne P M
SP
Lutgens
M Verónica
MV
Herías
Paul
P
Saftig
Mat J A P
MJ
Daemen
Kitty
K
Cleutjens
Esther
E
Lutgens
Erik A L
EA
Biessen
Sylvia
S
Heeneman
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics; D020789:Cathepsin C / Q000235:genetics; D056657:Cathepsin K / Q000235:genetics*; D002403:Cathepsins / Q000235:genetics; D003094:Collagen / Q000378:metabolism; D006098:Granulocytes / Q000187:drug effects / Q000276:immunology; D018655:Lymphocyte Count; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
D001057:Apolipoproteins E; D000804:Angiotensin II; D003094:Collagen; D002403:Cathepsins; D020789:Cathepsin C; C533919:Ctsc protein, mouse; C028217:cathepsin S; D056657:Cathepsin K; C534132:Ctsk protein, mouse