Induction of Macrophage Chemotaxis by Aortic Extracts from Patients with Marfan Syndrome Is Related to Elastin Binding Protein

Abstract

Marfan syndrome is an autosomal dominantly inherited disorder of connective tissue with prominent skeletal, ocular, and cardiovascular manifestations. Aortic aneurysm and dissection are the major determinants of premature death in untreated patients. In previous work, we showed that extracts of aortic tissues from the mgR mouse model of Marfan syndrome showed increased chemotactic stimulatory activity related to the elastin-binding protein. Aortic samples were collected from 6 patients with Marfan syndrome and 8 with isolated aneurysms of the ascending aorta. Control samples were obtained from 11 organ donors without known vascular or connective tissue diseases. Soluble proteins extracted from the aortic samples of the two patient groups were compared against buffer controls and against the aortic samples from controls with respect to the ability to induce macrophage chemotaxis as measured using a modified Boyden chamber, as well as the reactivity to a monoclonal antibody BA4 against bioactive elastin peptides using ELISA. Samples from Marfan patients displayed a statistically significant increase in chemotactic inductive activity compared to control samples. Additionally, reactivity to BA4 was significantly increased. Similar statistically significant increases were identified for the samples from patients with idiopathic thoracic aortic aneurysm. There was a significant correlation between the chemotactic index and BA4 reactivity, and the increases in chemotactic activity of extracts from Marfan patients could be inhibited by pretreatment with lactose, VGVAPG peptides, or BA4, which indicates the involvement of EBP in mediating the effects. Our results demonstrate that aortic extracts of patients with Marfan syndrome can elicit macrophage chemotaxis, similar to our previous study on aortic extracts of the mgR mouse model of Marfan syndrome (Guo et al., Circulation 2006; 114:1855-62).

Inflammation Aggravates Disease Severity in Marfan Syndrome Patients

“…Aortic wall extracts of Marfan mice induced increased chemotaxis of macrophages in vitro, mainly induced by elastin binding protein, showing a chemotactic stimulatory activity of fibrillin-1fragments [11]. These results were recently confirmed in MFS patients' aortas [12]. Furthermore, macrophages found in the aortic wall of these mice are positive for certain matrix metalloproteinases, which are enzymes that contribute to the degradation of the extracellular matrix.…”

Structure and function of the mammalian fibrillin gene family: Implications for human connective tissue diseases

“…Although there was no inflammation or invasion by macrophages observed in one study of aneurysmal aorta of MFS [82], another report showed infiltration by macrophages and lymphocytes [88]. Consistent with this, fibrillin-1 fragments and extracts of the aortic wall of Fbn1 deficient mice and MFS patients can increase chemotaxis of macrophages [89,90]. An analysis of gene expression in MFS patients [91] found that inflammation was correlated with many clinical features of the condition.…”

Enhanced Caspase Activity Contributes to Aortic Wall Remodeling and Early Aneurysm Development in a Murine Model of Marfan Syndrome

“…Several groups propose that SMC apoptosis promotes aortic wall macrophage recruitment, 25 major sources of ECM-degrading enzymes, including the matrix metalloproteinases. 13,24,26 Although our laboratory has reported that MMPs participate in aneurysm development in Marfan Fbn1 C1039G/+ mice, 4 the absence of inflammatory cell infiltration suggests that apoptotic SMCs must contribute to early aneurysm development through an alternative mechanism.…”