Osteoprotegerin Is Associated With Aneurysm Diameter and Proteolysis in Abdominal Aortic Aneurysm Disease

Abstract

A bdominal aortic aneurysm (AAA) is an abnormal focal dilation of the aortic wall that affects 5% of men aged 60 years. The risk of aortic rupture increases with AAA size, and AAA rupture is associated with a 80% to 90% mortality rate.1 Currently, the only treatment option for AAA is open or endovascular surgery; however, there is significant interest in developing medical therapies to limit AAA growth and rupture. [2][3][4] Osteoprotegerin (OPG) is a secreted glycoprotein member of the tumor necrosis factor receptor superfamily.5 It acts as a decoy receptor for receptor activator of nuclear factor kB ligand (RANKL) and tumor necrosis factorrelated apoptosis-inducing ligand.6 Cells described to secrete OPG include osteoblasts, endothelial cells, human aortic vascular smooth muscle cells (VSMCs), dendritic cells, lymphocytes, and plasma cells. [7][8][9] OPG is a key regulator of bone remodeling 5,10 but has also been implicated in tumorigenesis, immunologic pathways, and vascular diseases. 6,7,[11][12][13][14][15] The precise role of OPG in vascular disease is currently controversial.Evidence from animal studies suggests that OPG prevents arterial calcification and stabilizes plaque formation. 16,17 However, clinical studies have associated serum OPG concentrations with the presence and progression of cardiovascular disease. [18][19][20][21] Circulating OPG concentrations have also been reported to be higher in patients with AAA and positively associated with AAA progression. 4,22 In vitro experiments have suggested that OPG stimulates matrix metalloprotease (MMP) secretion from human monocytes and VSMCs, and that OPG secretion is downregulated by irbesartan. 4 These data suggest a potential role of OPG in AAA; however, currently we are aware of no studies that have reported the concentration of OPG in human AAA biopsies.The aim of this study was to assess the concentration of OPG in a large number of AAA biopsies and assess whether OPG expression was related to markers of AAA severity. We hypothesized that OPG is locally produced in vessel walls of patients with AAA disease and is associated with markers of aortic proteolysis. Osteoprotegerin is Associated With Aneurysm diameter and Proteolysis in Abdominal Aortic Aneurysm disease Patient inclusionIn this study, consecutive patients undergoing open repair of intact or ruptured AAA were included. The indications for intervention were based on current guidelines and included the following: AAA diameter exceeding 55 mm for males, AAA diameters between 50 and 55 mm for females, rapidly expanding aortic diameters (5 mm in 6 months with a minimum diameter of 40 mm), saccular aneurysms, symptoms attributable to AAA and AAA rupture. 1,24 Patients with AAA diameters between 50 and 55 mm were selected for surgery based on the clinical judgment of the surgeon and in consultation with the patient. Open repair was performed in patients in whom AAAs were not anatomically suited for endovascular repair. Patients with terminal malignancies or severe dementia were excluded ...

Osteoprotegerin Deficiency Limits Angiotensin II–Induced Aortic Dilatation and Rupture in the Apolipoprotein E–Knockout Mouse

“…In line with this, we have previously reported that AAA patients have elevated aortic and serum OPG concentrations that are positively associated with aneurysm diameter and growth [9,10], and independently associated with AAA after adjusting for other risk factors such as coronary heart disease [11]. In vitro , OPG stimulates production of elastolytic enzymes in human monocyte/macrophages and AoSMC [9,10], and promotes an aneurysm phenotype in healthy AoSMC through limiting cell proliferation and inducing apoptosis [10]. The in vivo role of OPG in AAA pathogenesis remains unclear.…”

“…High concentrations of serum OPG have been identified as a marker and risk factor for cardiovascular disease, as well as a predictor for future incident cardiovascular events and mortality [5–8]. In line with this, we have previously reported that AAA patients have elevated aortic and serum OPG concentrations that are positively associated with aneurysm diameter and growth [9,10], and independently associated with AAA after adjusting for other risk factors such as coronary heart disease [11]. In vitro , OPG stimulates production of elastolytic enzymes in human monocyte/macrophages and AoSMC [9,10], and promotes an aneurysm phenotype in healthy AoSMC through limiting cell proliferation and inducing apoptosis [10].…”

“…Aortic and serum OPG concentrations are elevated in patients with AAA and positively associated with AAA expansion in humans [9,10]. The in vivo importance of OPG in the development of aortic aneurysm was investigated in Opg -deficient mice infused with AngII.…”

“…We positively correlated human AAA concentrations of OPG with aneurysm diameter in a recent study [9]. Historically, matrix metalloproteinases (MMP) have been the main proteolytic enzymes implicated in ECM degradation in AAA [12].…”

Thoracic Aortic Rupture and Aortopulmonary Fistulation in the Friesian Horse

“…This mechanism is seen in abdominal aortic aneurysms in humans, where vascular smooth muscle cells promote matrix metalloproteinase release resulting in medial damage. 24 In such cases, inflammation is a prominent and consistent secondary finding characterized by extensive infiltrates of B and T lymphocytes, plasma cells, and dispersed macrophages in the adventitia. 17 Since smooth muscle hypertrophy, fibrosis, and the infiltration of lymphocytes and macrophages were observed in the affected Friesian horses, involvement of proteinases cannot be excluded.…”