Dataset Information

Angiotensin-converting enzyme-induced activation of local angiotensin signaling is required for ascending aortic aneurysms in fibulin-4-deficient mice.

ABSTRACT: Aortic aneurysms are life-threatening and often associated with defects in connective tissues and mutations in smooth muscle cell (SMC) contractile proteins. Despite recent advances in understanding altered signaling in aneurysms of Marfan syndrome, the underlying mechanisms and options for pharmacological treatment for other forms of aneurysms are still under investigation. We previously showed in mice that deficiency in the fibulin-4 gene in vascular SMCs (Fbln4(SMKO)) leads to loss of the SMC contractile phenotype, hyperproliferation, and ascending aortic aneurysms. We report that abnormal up-regulation of angiotensin-converting enzyme (ACE) in SMCs and subsequent activation of angiotensin II (AngII) signaling are involved in the onset of aortic aneurysms in Fbln4(SMKO) mice. In this model, aneurysm formation was completely prevented by inhibition of the AngII pathway with losartan or captopril within a narrow therapeutic window during the first month of life, even though the altered mechanical properties of blood vessel walls were not reversed by the pharmacological treatment. The therapeutic effects of losartan in Fbln4(SMKO) mice do not require the AngII receptor type 2 (Agtr2) but likely require both type 1a (Agtr1a) and 1b (Agtr1b) receptors. The results indicate that fibulin-4 is a vascular matrix component required for regulation of local angiotensin signaling and development and maintenance of the SMC phenotype.

SUBMITTER: Huang J

PROVIDER: S-EPMC3867808 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Angiotensin-converting enzyme-induced activation of local angiotensin signaling is required for ascending aortic aneurysms in fibulin-4-deficient mice.

Huang Jianbin J Yamashiro Yoshito Y Papke Christina L CL Ikeda Yuichi Y Lin Yanling Y Patel Miteshkumar M Inagami Tadashi T Le Victoria P VP Wagenseil Jessica E JE Yanagisawa Hiromi H

Science translational medicine 20130501 183

Aortic aneurysms are life-threatening and often associated with defects in connective tissues and mutations in smooth muscle cell (SMC) contractile proteins. Despite recent advances in understanding altered signaling in aneurysms of Marfan syndrome, the underlying mechanisms and options for pharmacological treatment for other forms of aneurysms are still under investigation. We previously showed in mice that deficiency in the fibulin-4 gene in vascular SMCs (Fbln4(SMKO)) leads to loss of the SMC ...[more]

PMID: 23636094

Similar Datasets

Project description:Background and objectiveRecently, we demonstrated that angiotensin II (AngII)-infusion profoundly increased both aortic protein and activity of calpains, calcium-activated cysteine proteases, in mice. In addition, pharmacological inhibition of calpain attenuated AngII-induced abdominal aortic aneurysm (AA) in mice. Recent studies have shown that AngII infusion into mice leads to aneurysmal formation localized to the ascending aorta. However, the precise functional contribution of calpain isoforms (-1 or -2) in AngII-induced abdominal AA formation is not known. Similarly, a functional role of calpain in AngII-induced ascending AA remains to be defined. Using BDA-410, an inhibitor of calpains, and calpain-1 genetic deficient mice, we examined the relative contribution of calpain isoforms in AngII-induced ascending and abdominal AA development.Methodology/resultsTo investigate the relative contribution of calpain-1 and -2 in development of AngII-induced AAs, male LDLr -/- mice that were either calpain-1 +/+ or -/- were fed a saturated fat-enriched diet and infused with AngII (1,000 ng/kg/min) for 4 weeks. Calpain-1 deficiency had no significant effect on body weight or blood pressure during AngII infusion. Moreover, calpain-1 deficiency showed no discernible effects on AngII-induced ascending and abdominal AAs. Interestingly, AngII infusion induced increased expression of calpain-2 protein, thus compensating for total calpain activity in aortas of calpain-1 deficient mice. Oral administration of BDA-410, a calpain inhibitor, along with AngII-infusion significantly attenuated AngII-induced ascending and abdominal AA formation in both calpain-1 +/+ and -/- mice as compared to vehicle administered mice. Furthermore, BDA-410 administration attenuated AngII-induced aortic medial hypertrophy and macrophage accumulation. Western blot and immunostaining analyses revealed BDA-410 administration attenuated AngII-induced C-terminal fragmentation of filamin A, an actin binding cytoskeletal protein in aorta.ConclusionCalpain-2 compensates for loss of calpain-1, and both calpain isoforms are involved in AngII-induced aortic aneurysm formation in mice.

Dataset Information

Angiotensin-converting enzyme-induced activation of local angiotensin signaling is required for ascending aortic aneurysms in fibulin-4-deficient mice.

Publications

Angiotensin-converting enzyme-induced activation of local angiotensin signaling is required for ascending aortic aneurysms in fibulin-4-deficient mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets