Cathepsin B, K, and S are expressed in cerebral aneurysms and promote the progression of cerebral aneurysms

Background and purpose: A cerebral aneurysm (CA) causes catastrophic subarachnoid hemorrhage. Degradation of extracellular matrix in arterial walls is a prominent feature of cerebral aneurysms. We investigated the expression and role of cysteine cathepsins, collagen- and elastin- degrading proteinases, in CA progression.

Methods: CAs were induced in Sprague-Dawley rats with or without cysteine Cathepsin Inhibitor, NC-2300. Expression of Cathepsin B, K, S, and Cystatin C, an endogenous inhibitor of cysteine cathepsins, in aneurysmal walls was examined in quantitative RT-PCR and immunohistochemistry. The activity of cysteine cathepsins and collagenase I and IV in aneurysmal walls was also assessed. Finally, expression of cysteine cathepsins and Cystatin C in human CAs was examined.

Results: Quantitative RT-PCR and immunohistochemistry revealed upregulated expression of Cathepsin B, K, and S in the late stage of aneurysm progression. In contrast, Cystatin C expression was reduced with aneurysm progression. Treatment with NC-2300 resulted in the decreased incidence of advanced CAs. The activity of cysteine cathepsins and collagenase I and IV in aneurysmal walls was reduced and elastin content was increased in the NC-2300-treated group. Finally, immunohistochemistry for cysteine cathepsins and Cystatin C expression in human CAs showed the same expression pattern as in the rat study.

Conclusions: Data obtained by using NC-2300 revealed an important role of cysteine cathepsins in the progression of CAs. Our findings strongly suggest that an imbalance between cysteine cathepsins and their inhibitor may cause the excessive breakdown of extracellular matrix in the arterial walls leading to the progression and rupture of CAs.