Caveolin 1 is critical for abdominal aortic aneurysm formation induced by angiotensin II and inhibition of lysyl oxidase

Document Type

Article

Abstract

Although AngII (angiotensin II) and its receptor AT1R (AngII type 1 receptor) have been implicated in AAA (abdominal aortic aneurysm) formation, the proximal signalling events primarily responsible for AAA formation remain uncertain. Caveolae are cholesterol-rich membrane microdomains that serve as a signalling platform to facilitate the temporal and spatial localization of signal transduction events, including those stimulated by AngII. Cav1 (caveolin 1)-enriched caveolae in vascular smooth muscle cells mediate ADAM17 (a disintegrin and metalloproteinase 17)-dependent EGFR (epidermal growth factor receptor) transactivation, which is linked to vascular remodelling induced by AngII. In the present study, we have tested our hypothesis that Cav1 plays a critical role for the development of AAA at least in part via its specific alteration of AngII signalling within caveolae. Cav1-/- mice and the control wild-type mice were co-infused with AngII and β-aminopropionitrile to induce AAA. We found that Cav1-/- mice with the co-infusion did not develop AAA compared with control mice in spite of hypertension. We found an increased expression of ADAM17 and enhanced phosphorylation of EGFR in AAA. These events were markedly attenuated in Cav1-/- aortas with the co-infusion. Furthermore, aortas from Cav1-/- mice with the co-infusion showed less endoplasmic reticulum stress, oxidative stress and inflammatory responses compared with aortas from control mice. Cav1 silencing in cultured vascular smooth muscle cells prevented AngII-induced ADAM17 induction and activation. In conclusion, Cav1 appears to play a critical role in the formation of AAA and associated endoplasmic reticulum/oxidative stress, presumably through the regulation of caveolae compartmentalized signals induced by AngII.

Medical Subject Headings

ADAM Proteins (metabolism); ADAM17 Protein; Adenoviridae (metabolism); Angiotensin II (metabolism); Animals; Aortic Aneurysm, Abdominal (metabolism); Caveolin 1 (metabolism); Cells, Cultured; Gene Expression Regulation; Gene Silencing; Heparin-binding EGF-like Growth Factor; Immunohistochemistry; Inflammation; Intercellular Signaling Peptides and Proteins (metabolism); Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myocytes, Smooth Muscle (cytology); Oxidative Stress; Promoter Regions, Genetic; Protein-Lysine 6-Oxidase (antagonists & inhibitors); RNA Interference; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System; Signal Transduction

Publication Date

6-1-2014

Publication Title

Clinical science (London, England : 1979)

E-ISSN

1470-8736

Volume

126

Issue

11

First Page

785

Last Page

94

PubMed ID

24329494

Digital Object Identifier (DOI)

10.1042/CS20130660

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