THE ROLE OF CAVEOLAE IN THE FORMATION OF ABDOMINAL AORTIC ANEURYSMS
|Crawford, Kevin John
|Abdominal aortic aneurysm (AAA) is a major cardiovascular disease and involves enhancement of renin-angiotensin system and recruitment/activation of inflammatory factors such as matrix metalloproteases (MMP's). Caveolae has been shown to play a role in a number of different cardiovascular diseases through different mechanisms including regulation of oxidative stress, inflammation and degradation of extracellular matrix components through MMP's. In addition, endothelial cell caveolae are known to localize the Ang-II (AT1) receptor and regulate renin-angiotensin signaling. Based on these findings, we evaluated the role of caveolae in AAA formation in the murine model. Here, eight week old mice were co-infused with Ang-II and BAPN, a lysyl oxidase inhibitor, to induce AAA. We found that mice lacking the main structural protein of caveolae, caveolin-1, did not develop AAA compared to WT animals in spite of hypertensive blood pressures measured by telemetry in both groups. This finding suggests that intact Ang-II signaling remains in place in caveolin-1 knockout mice. To begin to address the underlying mechanism by which caveolae contributes to AAA, we measured the level of oxidative stress and MMP's in aneurysms. We found an increased expression of MMP-2 and MMP-9 in vessels of WT mice displaying aneurysms. This increase in expression was not observed in Cav-1 knockout mice. Furthermore, KO mice showed less oxidative stress then their WT counterparts as assessed by anti-nitrotyrosine staining. Next we examined the characteristics of early AAA formation in wild-type mice. We found caveolae associated proteins, endothelial nitric oxide synthase (eNOS) and NADPH oxidase 2 (Nox2), were upregulated in early AAA formation, particularly in the endothelium. Also, Vascular Cell Adhesion Molecule (VCAM) was upregulated in the endothelium. However, macrophage infiltration and MMP-2 activation was not observed in early AAA development. In order to elucidate the role of endothelial caveolae in the formation of AAA, we induced AAA, as previously described, in endothelial specific cav-1 knockout mice. Preliminarily findings show endothelial specific knockout mice do not form AAA as compared to their WT littermates. In conclusion, caveolae appears to play a critical role in the formation of AAA in mice via oxidative stress, and recruitment and/or activation of MMPs, specifically MMP-2 and MMP-9. Early markers of AAA formation include VCAM, NOX2, eNOS, and protein nitration. Also, preliminary results indicate that endothelial specific knockout mice do not develop AAA.
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|Abdominal Aortic Aneurysm
|THE ROLE OF CAVEOLAE IN THE FORMATION OF ABDOMINAL AORTIC ANEURYSMS
|Popoff, Steven N.
|Autieri, Michael V.
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