Manipulation of Caveolin‐1 Protein in a Mouse Model of Marfan Syndrome: Impact on Cardiac & Aortic Function & Structure

Abstract

Marfan syndrome (MFS) is a systemic connective tissue disorder due to mutations in the fibrillin‐1 gene. Previous studies have shown that transforming growth factor β (TGF‐β) and angiotensin II type 1 receptor (ATII/AT1R) signalling play important roles during the progression of MFS aneurysm. Interestingly, both pathways are shown to be regulated by caveolin‐1 (Cav‐1), a structural protein within caveolae, a lipid rich membrane invagination with significant presence in vascular smooth muscle and endothelial cells. Previous studies have also shown that Cav‐1 can negatively regulate endothelial nitric oxide synthase (eNOS), the main enzyme responsible for vasodilation in blood vessels. In addition, it has been shown that eNOS overexpression and activation can play a protective role in MFS aneurysm. Considering the complexity of Cav‐1 regulatory functions and its impact on eNOS function, we aimed to investigate potential roles that Cav‐1 may plan during the progression of MFS‐associated aortic aneurysm in a well‐established mouse model.Four‐week old control C57BL/6 (Fbn1+/+) and MFS (Fbn1C1039G/+) received intra‐peritoneal injections (500mg/kg) of cholesterol depleting agent methyl‐β‐cyclodextrin (MβCD) with the aim of systemic disruption of caveolae formation. Cardiac and aortic structure/function was measured at 3 & 7 months of age using Vevo 2100 ultrasound imaging system. Measurements for aortic annulus, sinus of Valsalva and sinotubular junction showed an increase in MFS at 7 months as compared to controls. Measurements for pulse wave velocity (PWV), a reliable proxy for aortic wall stiffness, showed an increase in 3‐ and 7‐month old MFS mice as compared to controls. All these effects were exacerbated in MFS mice treated with MβCD. Cardiac function was evaluated measuring the cardiac output, stroke volume, ejection fraction, which showed no difference in MFS and control mice in the presence or absence of MβCD treatment. Early ventricular filling velocity and E/A ratio were decreased in MFS mice at 3 and 7 months, with no significant difference observed in the atrial filling velocity among experimental groups. Measurements for blood pressure showed higher systolic values in 7‐month old treated MFS mice as compared to 3‐month old groups. In a complementary set of experiments, we injected control and MFS mice intraperitoneally with vehicle control or a cell‐permeable Cav‐1 scaffolding domain (CSD) peptide, amplifying the inhibitory effects of Cav‐1 on eNOS in these mice. Interestingly, treatment with CSD improved aortic wall elastin fragmentation and wall elasticity in MFS mice as compared to vehicle treated groups. Our data indicate that systemic disruption of caveolae structure is detrimental, while specific targeting of Cav‐1 protein activity may be beneficial and protective in the context of MFS‐associated aortic aneurysm. This study provides insights into the role that caveolae may play during the progression of aortic aneurysm, and warrant further investigation into the potential value of Cav‐1 protein as a potential therapeutic target in MFS‐associated aortic aneurysm.Support or Funding InformationMarfan FoundationThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.