MMP17/MT4-MMP and Thoracic Aortic Aneurysms

Abstract

In recent years, many advances have been made in understanding the pathophysiology of thoracic aortic aneurysms and dissections (TAAD). Mutations in several genes leading to aneurysm formation have been identified thus far, and include extracellular matrix (ECM) genes ( FBN1 , COL3A1 , EFEMP2, MFAP5 ), molecules involved in transforming growth factor-β signaling ( TGFBR1 , TGFBR2 , SMAD3 , TGFB2, TGFB3 ), and genes involved in regulation of the smooth muscle cell (SMC) contractile apparatus ( MYH11 , ACTA2 , MYLK , PRKG1 ).1–3 However, for the majority of TAAD patients, a causative genetic mutation has not yet been identified.4 A whole-exome sequencing approach to identifying new genes predisposing to TAAD has provided a means of rapidly identifying additional genetic alterations.5 Article, see p e13 Studies using mouse models have recapitulated some key molecular pathways disrupted by mutations in currently identified TAAD genes, including angiotensin II and transforming growth factor-β–mediated signaling pathways, vascular SMC phenotype, and pathways regulating SMC contractile function.6–9 In addition, multiple studies have highlighted the importance of the connections formed between the concentric layers of elastic fibers and SMCs in the aortic wall for transducing mechanical signals and maintaining vascular contractility and homeostasis.4 Despite advances in our understanding of the mechanisms underlying the development of aortic aneurysms, current pharmacological treatment of TAAD is limited. β-adrenergic receptor blockers are currently recommended for reducing aortic wall stress and potentially slowing the rate of aneurysm growth.10 Angiotensin II receptor blocker losartan showed great potential in preventing aortic aneurysms in a mouse model of Marfan syndrome: however, a larger scale clinical trial in Marfan patients showed losartan and the β-adrenergic receptor blocker atenolol to be equally effective.11 Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers were used in a cohort of patients with abdominal …