Assessing Efficacy of Afatinib toward Elastic Matrix Repair in Aortic Aneurysms

Abstract

Abdominal aortic aneurysm (AAA) is a critical, multifactorial cardiovascular disorder marked by localized dilatation of the abdominal aorta. A major challenge to countering the pathophysiology of AAAs lies in the naturally irreversible breakdown of elastic fibers in the aorta wall, which is linked to the poor elastogenicity of adult and diseased vascular smooth muscle cells (SMCs) and their impaired ability to assemble mature elastic fibers in a chronic proteolytic tissue milieu. We have previously shown that these are downstream effects of neutrophil elastase-induced activation of the epidermal growth factor receptor (EGFR) activity in aneurysmal SMCs. The novelty of this study lies in investigating the benefits of an EGFR inhibitor drug, afatinib (used to treat nonsmall cell lung cancer), for proelastogenic and antiproteolytic stimulation of aneurysmal SMCs. In in vitro cell cultures, we have shown that safe doses of 0.5 and 1 nM afatinib inhibit EGFR and p-extracellular signal-regulated kinases 1/2 protein expression by 50–70% and downstream elastolytic matrix metalloprotease 2 (MMP2) versus untreated control cultures. In addition, elastin production on a per cell basis was significantly upregulated by afatinib doses within the 0.1–1 nM dose range, which was further validated through transmission electron microscopy showing significantly increased presence of tropoelastin coacervates and maturing elastic fibers upon afatinib treatment at the above doses. Therefore, our studies for the first time demonstrate the therapeutic benefits of afatinib toward use for elastic matrix repair in small AAAs.

Impact statement

There are currently no treatments to reverse pathophysiology of abdominal aortic aneurysms (AAAs; localized aortal expansions that grow to rupture). Restoring elastic matrix structure and wall elasticity in the proteolytic milieu of the AAA wall is an unsurmounted challenge to nonsurgical AAA repair. In this work, we show the efficacy of afatinib drug in providing an antiproteolytic and elastogenic stimulus to aneurysmal smooth muscle cells via the inhibition of epidermal growth factor receptor (EGFR) pathway. This can lead to future development of EGFR-targeted therapies for elastic matrix regeneration and repair in AAAs as well as other proteolytic disorders.