Enhanced caspase activity contributes to aortic wall remodeling and early aneurysm development in a murine model of Marfan syndrome
Standard
Enhanced caspase activity contributes to aortic wall remodeling and early aneurysm development in a murine model of Marfan syndrome. / Emrich, Fabian C; Okamura, Homare; Dalal, Alex R; Penov, Kiril; Merk, Denis R; Raaz, Uwe; Hennigs, Jan K; Chin, Jocelyn T; Miller, Miquell O; Pedroza, Albert J; Craig, Juliana K; Koyano, Tiffany K; Blankenberg, Francis G; Connolly, Andrew J; Mohr, Friedrich W; Alvira, Cristina M; Rabinovitch, Marlene; Fischbein, Michael P.
In: ARTERIOSCL THROM VAS, Vol. 35, No. 1, 01.2015, p. 146-54.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
Harvard
APA
Vancouver
Bibtex
}
RIS
TY - JOUR
T1 - Enhanced caspase activity contributes to aortic wall remodeling and early aneurysm development in a murine model of Marfan syndrome
AU - Emrich, Fabian C
AU - Okamura, Homare
AU - Dalal, Alex R
AU - Penov, Kiril
AU - Merk, Denis R
AU - Raaz, Uwe
AU - Hennigs, Jan K
AU - Chin, Jocelyn T
AU - Miller, Miquell O
AU - Pedroza, Albert J
AU - Craig, Juliana K
AU - Koyano, Tiffany K
AU - Blankenberg, Francis G
AU - Connolly, Andrew J
AU - Mohr, Friedrich W
AU - Alvira, Cristina M
AU - Rabinovitch, Marlene
AU - Fischbein, Michael P
N1 - © 2014 American Heart Association, Inc.
PY - 2015/1
Y1 - 2015/1
N2 - OBJECTIVE: Rupture and dissection of aortic root aneurysms remain the leading causes of death in patients with the Marfan syndrome, a hereditary connective tissue disorder that affects 1 in 5000 individuals worldwide. In the present study, we use a Marfan mouse model (Fbn1(C1039G/+)) to investigate the biological importance of apoptosis during aneurysm development in Marfan syndrome.APPROACH AND RESULTS: Using in vivo single-photon emission computed tomographic-imaging and ex vivo autoradiography for Tc99m-annexin, we discovered increased apoptosis in the Fbn1(C1039G/+) ascending aorta during early aneurysm development peaking at 4 weeks. Immunofluorescence colocalization studies identified smooth muscle cells (SMCs) as the apoptotic cell population. As biological proof of concept that early aortic wall apoptosis plays a role in aneurysm development in Marfan syndrome, Fbn1(C1039G/+) mice were treated daily from 2 to 6 weeks with either (1) a pan-caspase inhibitor, Q-VD-OPh (20 mg/kg), or (2) vehicle control intraperitoneally. Q-VD-OPh treatment led to a significant reduction in aneurysm size and decreased extracellular matrix degradation in the aortic wall compared with control mice. In vitro studies using Fbn1(C1039G/+) ascending SMCs showed that apoptotic SMCs have increased elastolytic potential compared with viable cells, mostly because of 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.CONCLUSIONS: Caspase inhibition attenuates aneurysm development in an Fbn1(C1039G/+) Marfan mouse model. Mechanistically, during apoptosis, caspases are expressed on the cell surface of SMCs and likely contribute to elastin degradation and aneurysm development in Marfan syndrome.
AB - OBJECTIVE: Rupture and dissection of aortic root aneurysms remain the leading causes of death in patients with the Marfan syndrome, a hereditary connective tissue disorder that affects 1 in 5000 individuals worldwide. In the present study, we use a Marfan mouse model (Fbn1(C1039G/+)) to investigate the biological importance of apoptosis during aneurysm development in Marfan syndrome.APPROACH AND RESULTS: Using in vivo single-photon emission computed tomographic-imaging and ex vivo autoradiography for Tc99m-annexin, we discovered increased apoptosis in the Fbn1(C1039G/+) ascending aorta during early aneurysm development peaking at 4 weeks. Immunofluorescence colocalization studies identified smooth muscle cells (SMCs) as the apoptotic cell population. As biological proof of concept that early aortic wall apoptosis plays a role in aneurysm development in Marfan syndrome, Fbn1(C1039G/+) mice were treated daily from 2 to 6 weeks with either (1) a pan-caspase inhibitor, Q-VD-OPh (20 mg/kg), or (2) vehicle control intraperitoneally. Q-VD-OPh treatment led to a significant reduction in aneurysm size and decreased extracellular matrix degradation in the aortic wall compared with control mice. In vitro studies using Fbn1(C1039G/+) ascending SMCs showed that apoptotic SMCs have increased elastolytic potential compared with viable cells, mostly because of 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.CONCLUSIONS: Caspase inhibition attenuates aneurysm development in an Fbn1(C1039G/+) Marfan mouse model. Mechanistically, during apoptosis, caspases are expressed on the cell surface of SMCs and likely contribute to elastin degradation and aneurysm development in Marfan syndrome.
KW - Animals
KW - Aorta
KW - Aortic Aneurysm
KW - Apoptosis
KW - Autoradiography
KW - Caspase Inhibitors
KW - Caspases
KW - Cell Membrane
KW - Cells, Cultured
KW - Disease Models, Animal
KW - Disease Progression
KW - Elastin
KW - Female
KW - Fluorescent Antibody Technique
KW - Male
KW - Marfan Syndrome
KW - Mice, Inbred C57BL
KW - Mice, Mutant Strains
KW - Microfilament Proteins
KW - Microscopy, Electron, Scanning
KW - Muscle, Smooth, Vascular
KW - Mutation
KW - Myocytes, Smooth Muscle
KW - Time Factors
KW - Tomography, Emission-Computed, Single-Photon
KW - Vascular Remodeling
U2 - 10.1161/ATVBAHA.114.304364
DO - 10.1161/ATVBAHA.114.304364
M3 - SCORING: Journal article
C2 - 25359856
VL - 35
SP - 146
EP - 154
JO - ARTERIOSCL THROM VAS
JF - ARTERIOSCL THROM VAS
SN - 1079-5642
IS - 1
ER -
