Indian Journal of Biochemistry and Biophysics Vol. 51, December 2014, pp. 449-456 Review Vascular Aneurysms: A Perspective Sajal Chakraborti a *, Animesh Chowdhury a , Md Nur Alam a , Jaganmay Sarkar a , Amritlal Mandal b , Asmita Pramanik a and Tapati Chakraborti a a Department of Biochemistry & Biophysics, University of Kalyani, Kalyani 741235, West Bengal, India b Department of Physiology, University of Arizona, Tucson, Arizona, USA Received 20 May 2014; revised 10 September 2014 Aneurysms develop as a result of chronic inflammation of vascular bed, where progressive destruction of structural proteins, especially elastin and collagen of smooth muscle cells has been shown to manifest. The underlying mechanisms are an increase in local production of proinflammatory cytokines and subsequent increase in proteases, especially matrix metalloproteinases (MMPs) that degrade the structural proteins. The plasminogen system: urokinase-type PA (u-PA), tissue- type PA (t-PA) and plasminogen activator inhibitor-1 (PAI-1) and the MMPs system-MMPs and TIMPs contribute to the progression and development of aneurysms. Recent studies suggest that aneurysms may be genetically determined. To date, most observable candidate genes for aneurysm (elastin, collagen, fibrillin, MMPs and TIMPs) have been explored with little substantiation of the underlying cause and effect. Recently, overexpression of the MMP-2 gene has been suggested as an important phenomenon for aneurysm formation. Along with MMPs, matrix formation also depends on JNK (c-Jun N-terminal kinase) as its activation plays important role in downregulating several genes of matrix production. Under stress, activation of JNK by various stimuli, such as angiotensin II, tumor necrosis factor- and interleukin-1 has been noted significantly in vascular smooth muscle cells. Several therapeutic indications corroborate that inhibition of MMP-2 and JNK is useful in preventing progression of vascular aneurysms. This review deals with the role of proteases in the progression of vascular aneurysm. Keywords: Aneurysm, Proteinase, Antiproteinase, Plasminogen system. Introduction Vascular aneurysm, often asymptomatic, is a major disease generally of the adult aorta caused by progressive medial degeneration of the aortic wall. Aneurysm is a complex multi-factorial disease with life threatening implications. About 50,000 patients undergo surgical repair of only abdominal aortic aneurysm and another 15,000 patients die from the ruptured aneurysms each year in USA 1,2 . There is accumulating evidence that the incidence of aneurysms is increasing worldwide despite a general decline in other forms of atherosclerotic cardiovascular diseases 3 . Recent estimates suggest that aneurysms affect about 15% of the US population over 65 yrs of age 4 . The biochemical and histopathological changes established in aneurysms have been extensively characterized. Aneurysms demonstrate arterial dilatation, wall thickening and a reduction in the elastin and collagen ratio of the extracellular matrix (ECM) 5 . These structural changes are accompanied by a wide spread inflammatory infiltrate, a rich cytokine milieu and excessive local concentrations of a number of matrix metalloproteinases (MMPs), such as MMP-2 and -9. These MMPs have been considered responsible for the widespread degradation and remodeling of the ECM matrix that is demonstrated in established and expanding aneurysms 5 . Proinflammatory stimuli increase expression of MMPs through activation of transcription factor activating protein-1, which is frequently a downstream target of c-jun N-terminal kinase (JNK) 6,7 . The levels of activated JNK are high in —————— *Author for correspondence: E.mail: saj_chakra@rediffmail.com Cell: 91-9831228224 Abbreviations: AP-1, activating protein-1; ECM, extracellular matrix; ERK1/2, extracellular signal regulated kinase (p 42 /p 44 mitogen activated protein kinase); IB, inhibitory B; JNK, IKK, kappa B kinase; Janus kinase; 5-LO, 5-lipoxygenase; MIP, macrophage inflammatory protein; MMP-2, matrix metalloproteinase-2; MMP-9, matrix metalloproteinase-9; MT1-MMP, membrane type-1 matrix metalloproteinase; NFB, nuclear factor B; p 38 MAPK, p 38 mitogen activated protein kianse; PKC-, protein kinase C-; SMC, smooth muscle cell; SNP, single nucleotide polymorphism; TIMP, tissue inhibitor of matrix metalloproteinase; TNF-, tumor necrosis factor-; u-PA, urokinase plasminogen activator; VSMCs, vascular smooth muscle cells.