Regression of Abdominal Aortic Aneurysms through Pharmacologic Therapy

Abstract

Abdominal aortic aneurysm (AAA) is a common disease that eventually results in aortic rupture with high mortality. Although a pharmacologic therapy for AAA is eagerly awaited, the destruction of the aortic walls in AAA has been considered an irreversible process. Recently, we identified c-Jun N-terminal kinase (JNK) as a key molecule in the pathogenesis of AAA. JNK was highly activated in the aortic walls of AAA patients. In in vitro studies, JNK not only enhanced expression of matrix metalloproteinases (MMPs), but also reduced expression of biosynthetic enzymes for extracellular matrix (ECM). An AAA model induced by CaCl2 in mice was accompanied by activation of JNK and MMP-9. Treatment with a specific JNK inhibitor, SP600125, completely prevented AAA formation. SP600125 also caused a significant reduction in aneurysmal diameter in established AAA. Surprisingly, SP600125 was effective in normalizing tissue architecture. Furthermore, treatment with SP600125 caused significant regression of angiotensin II-induced AAA in ApoE-null mice after its establishment. These data indicated that pharmacologic inhibition of JNK caused healing of aneurysmal tissue and regression of established AAA, providing a novel therapeutic option for treatment of AAA.