Abstract 13355: Loss of TIMP3 Leads to Adverse Remodeling of the Vascular Wall Structure and Development of Abdominal Aortic Aneurysm Following Angiotension II Treatment
BACKGROUND Abdominal Aortic Aneurysm (AAA) is a serious complication with no treatment to date and is lethal if ruptured. Integrity of the vascular wall structure and extracellular matrix (ECM) is maintained by a balance between matrix metalloproteinases (MMPs) and their inhibitors, TIMPs. TIMP3 is a potent inhibitor of a number of MMPs, and its levels are altered in patients with Marphan Syndrome and aortic aneurysm. We investigated the role of TIMP3 in Angiotensin II (AngII)-induced vascular remodeling and AAA development.
METHODS and RESULTS 9wk old male mice received AngII (1.5 mg/kg/d) or saline (Alzet micro-osmotic pumps, dorsal and subcutaneous). AngII-infusion in TIIMP3-/- mice led to increased compliance of carotid and mesenteric arteries (ex-vivo pressure myography), reduced collagen and elastin protein (Western blot) but not mRNA (Taqman RT-PCR) compared to WT-AngII mice, indicating excess protein degradation in the absence of TIMP3. This adverse arterial remodeling culminated to AAA in TIMP3-/-, but not WT mice, after 4wk of AngII infusion. TIMP3-/--AngII mice exhibited dilated abdominal aorta (supra renal) with suppressed aortic distensibility (echo), deteriorated aortic wall structure, reduced and disorganized elastin and collagen structures (VVG & Trichrome staining, Scanning EM) indicating excess proteolysis in the absence of the inhibitory function of TIMP3. Activation of MMP2, a key MMP in patients with AAA, was more pronounced in TIMP3-/--AngII arteries. Interestingly, additional deletion of MMP2 in TIMP3-/- mice (TIMP3-/-/MMP2-/-) prevented the early AngII-induced degradation of arterial wall structure (2wks), but led to more severe AAA after 4wks, with excess upregulation of MMP9 and exacerbated degradation of elastin fibers in the aortic wall. Treatment with a broad-spectrum MMP inhibitor (MMPi, PD166793, daily gavage) prevented the AngII-induced AAA in TIMP3-/- and TIMP3-/-/MMP2-/- mice.
CONCLUSION Lack of TIMP3 enhances susceptibility to AAA due to structural degradation of the aortic wall. Inhibition of one MMP can result in compensatory upregulation of other MMPs leading to exacerbated vascular degradation and worsening of AAA, whereas broad-spectrum inhibition of MMPs can be beneficial in treatment of AAA.
- © 2011 by American Heart Association, Inc.