Enhanced caspase activity contributes to aortic wall remodeling and early aneurysm development in a murine model of Marfan syndrome.

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. 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. 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.

Emrich FC ，Okamura H ，Dalal AR ，Penov K ，Merk DR ，Raaz U ，Hennigs JK ，Chin JT ，Miller MO ，Pedroza AJ ，Craig JK ，Koyano TK ，Blankenberg FG ，Connolly AJ ，Mohr FW ，Alvira CM ，Rabinovitch M ，Fischbein MP ... -  《-》

miR-29b participates in early aneurysm development in Marfan syndrome.

Merk DR ，Chin JT ，Dake BA ，Maegdefessel L ，Miller MO ，Kimura N ，Tsao PS ，Iosef C ，Berry GJ ，Mohr FW ，Spin JM ，Alvira CM ，Robbins RC ，Fischbein MP ... -  《-》

Resveratrol Inhibits Aortic Root Dilatation in the Fbn1C1039G/+ Marfan Mouse Model.

Hibender S ，Franken R ，van Roomen C ，Ter Braake A ，van der Made I ，Schermer EE ，Gunst Q ，van den Hoff MJ ，Lutgens E ，Pinto YM ，Groenink M ，Zwinderman AH ，Mulder BJ ，de Vries CJ ，de Waard V ... -  《-》

Long-term miR-29b suppression reduces aneurysm formation in a Marfan mouse model.

Aortic root aneurysm formation and subsequent dissection and/or rupture remain the leading cause of death in patients with Marfan syndrome. Our laboratory has reported that miR-29b participates in aortic root/ascending aorta extracellular matrix remodeling during early aneurysm formation in Fbn1C1039G/+ Marfan mice. Herein, we sought to determine whether miR-29b suppression can reduce aneurysm formation long-term. Fbn1C1039G/+ Marfan mice were treated with retro-orbital LNA-anti-miR-29b inhibitor or scrambled-control-miR before aneurysms develop either (1) a single dose prenatally (pregnant Fbn1C1039G/+ mice at 14.5 days post-coitum) (n = 8-10, each group) or (2) postnatally every other week, from 2 to 22 weeks of age, and sacrificed at 24 weeks (n = 8-10, each group). To determine if miR-29b blockade was beneficial even after aneurysms develop, a third group of animals were treated every other week, starting at 8 weeks of age, until sacrificed (n = 4-6, each group). miR-29b inhibition resulted in aneurysm reduction, increased elastogenesis, decreased matrix metalloproteinase activity and decreased elastin breakdown. Prenatal LNA-anti-miR-29b inhibitor treatment decreased aneurysm formation up to age 32 weeks, whereas postnatal treatment was effective up to 16 weeks. miR-29b blockade did not slow aortic growth once aneurysms already developed. Systemic miR-29b inhibition significantly reduces aneurysm development long-term in a Marfan mouse model. Drug administration during aortic wall embryologic development appears fundamental. miR-29b suppression could be a potential therapeutic target for reducing aneurysm formation in Marfan syndrome patients.

Okamura H ，Emrich F ，Trojan J ，Chiu P ，Dalal AR ，Arakawa M ，Sato T ，Penov K ，Koyano T ，Pedroza A ，Connolly AJ ，Rabinovitch M ，Alvira C ，Fischbein MP ... -  《Physiological Reports》

Lineage-Specific Induced Pluripotent Stem Cell-Derived Smooth Muscle Cell Modeling Predicts Integrin Alpha-V Antagonism Reduces Aortic Root Aneurysm Formation in Marfan Syndrome Mice.

Nakamura K ，Dalal AR ，Yokoyama N ，Pedroza AJ ，Kusadokoro S ，Mitchel O ，Gilles C ，Masoudian B ，Leipzig M ，Casey KM ，Hiesinger W ，Uchida T ，Fischbein MP ... -  《-》