Abstract 15289: Apoptosis Participates in Early Aneurysm Development via ECM Remodeling in Marfan Syndrome
Rationale: Aortic root aneurysm rupture and dissection remain the leading causes of death in patients with the Marfan syndrome (MFS), a hereditary connective tissue disorder that affects 1/5000 individuals worldwide. Utilizing a MFS mouse model, we recently reported that increased TGF-β signaling enhances apoptosis in the aortic wall during early ascending aortic aneurysm development. Although investigators have suggested that increased apoptosis of vascular smooth muscle cells (SMC) contributes to aortic aneurysm formation in various model systems, it’s pathologic role in MFS remains controversial.
Objective: In the present study we utilize Fbn1C1039G/+ mice to investigate the biological importance of apoptosis during aneurysm formation in MFS.
Methods and Results: Using in vivo SPECT-imaging and ex vivo autoradiography for Tc99m-annexin, we discovered increased apoptosis in the Fbn1C1039G/+ ascending (AS) aorta during early aneurysm development peaking at 4 weeks of age. Immunofluorescence co-localization studies identified smooth muscle cells (SMC) as the apoptotic cell population. As biological proof of concept that early aortic wall apoptosis plays a role in aneurysm development in MFS, Fbn1C1039G/+ mice were treated daily from 2-6 weeks with either (a) pan-caspase inhibitor, Q-VD-OPh (20 mg/kg) or (b) dimethyl sulfoxide (vehicle control) intraperitoneally. Q-VD-OPh treatment led to a significant reduction in aneurysm size and decreased ECM degradation in the aortic wall compared to control mice. In vitro studies using Fbn1C1039G/+ AS SMCs showed that apoptotic SMCs have increased elastolytic potential compared to viable cells, mostly due to caspase activity. Moreover, in vitro (1) cell membrane isolation, (2) immunofluorescence staining, and (3) scanning electron microscopy studies illustrate that caspases are expressed on the exterior cell surface of apoptotic SMCs.
Conclusion: Caspase inhibition attenuates aneurysm formation in a Fbn1C1039G/+ Marfan mouse model. Mechanistically, during apoptosis, caspases are expressed on the cell surface of SMC and likely contribute to elastin degradation and aneurysm formation in MFS.
- © 2013 by American Heart Association, Inc.