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SMAD3 deficiency promotes inflammatory aortic aneurysms in angiotensin II-infused mice via activation of iNOS.

ABSTRACT: BACKGROUND: Ninety percent of the patients carrying distinct SMAD3 mutations develop aortic aneurysms and dissections, called aneurysms-osteoarthritis syndrome (AOS). However, the etiology and molecular events downstream of SMAD3 leading to the pathogenesis of aortic aneurysms in these patients still remain elusive. Therefore, we aimed to investigate the vascular phenotypes of SMAD3-knockout mice. METHODS AND RESULTS: We have shown that angiotensin II-induced vascular inflammation, but not hypertension, leads to aortic aneurysms and dissections, ultimately causing aortic rupture and death in mice. Lipopolysaccharide-triggered inflammation confirmed that enhanced aortic macrophage recruitment was essential for aneurysm formation in angiotensin II-infused SMAD3-knockout mice. In contrast, phenylephrine-triggered hypertension alone was insufficient to induce aortic aneurysms in mice. Using uniaxial tensile and contractility tests, we showed that SMAD3 deficiency resulted in defective aortic biomechanics and physiological functions, which caused weakening of the aortic wall and predisposed the mice to aortic aneurysms. Chromatin immunoprecipitation (ChIP) and re-ChIP assays revealed that the underlying mechanism involved aberrant upregulation of inducible nitric oxide synthase (iNOS)-derived nitric oxide production and activation of elastolytic matrix metalloproteinases 2 and 9. Administration of clodronate-liposomes and iNOS inhibitor completely abrogated these aortic conditions, thereby identifying iNOS-mediated nitric oxide secretion from macrophages as the downstream event of SMAD3 that drives this severe pathology. CONCLUSIONS: Macrophage depletion and iNOS antagonism represent 2 promising approaches for preventing aortic aneurysms related to SMAD3 mutations and merit further investigation as adjunctive strategies for the life-threatening manifestations of AOS.

SUBMITTER: Tan CK

PROVIDER: S-EPMC3698794 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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SMAD3 deficiency promotes inflammatory aortic aneurysms in angiotensin II-infused mice via activation of iNOS.

Tan Chek K CK Tan Eddie H EH Luo Baiwen B Huang Charlotte L CL Loo Joachim S JS Choong Cleo C Tan Nguan S NS

Journal of the American Heart Association 20130619 3

<h4>Background</h4>Ninety percent of the patients carrying distinct SMAD3 mutations develop aortic aneurysms and dissections, called aneurysms-osteoarthritis syndrome (AOS). However, the etiology and molecular events downstream of SMAD3 leading to the pathogenesis of aortic aneurysms in these patients still remain elusive. Therefore, we aimed to investigate the vascular phenotypes of SMAD3-knockout mice.<h4>Methods and results</h4>We have shown that angiotensin II-induced vascular inflammation, ...[more]

PMID: 23782924

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Project description:Angiotensin II (AngII) infusion profoundly increases activity of calpains, calcium-dependent neutral cysteine proteases, in mice. Pharmacological inhibition of calpains attenuates AngII-induced aortic medial macrophage accumulation, atherosclerosis, and abdominal aortic aneurysm in mice. However, the precise functional contribution of leukocyte-derived calpains in AngII-induced vascular pathologies has not been determined. The purpose of this study was to determine whether calpains expressed in bone marrow (BM)-derived cells contribute to AngII-induced atherosclerosis and aortic aneurysms in hypercholesterolemic mice.To study whether leukocyte calpains contributed to AngII-induced aortic pathologies, irradiated male low-density lipoprotein receptor(-/-) mice were repopulated with BM-derived cells that were either wild-type or overexpressed calpastatin, the endogenous inhibitor of calpains. Mice were fed a fat-enriched diet and infused with AngII (1000 ng/kg per minute) for 4 weeks. Overexpression of calpastatin in BM-derived cells significantly attenuated AngII-induced atherosclerotic lesion formation in aortic arches, but had no effect on aneurysm formation. Using either BM-derived cells from calpain-1-deficient mice or mice with leukocyte-specific calpain-2 deficiency generated using cre-loxP recombination technology, further studies demonstrated that independent deficiency of either calpain-1 or -2 in leukocytes modestly attenuated AngII-induced atherosclerosis. Calpastatin overexpression significantly attenuated AngII-induced inflammatory responses in macrophages and spleen. Furthermore, calpain inhibition suppressed migration and adhesion of macrophages to endothelial cells in vitro. Calpain inhibition also significantly decreased hypercholesterolemia-induced atherosclerosis in the absence of AngII.The present study demonstrates a pivotal role for BM-derived calpains in mediating AngII-induced atherosclerosis by influencing macrophage function.

Project description:Rationale: The progressive disruption of extracellular matrix (ECM) proteins, particularly early elastin fragmentation followed by abnormalities in collagen fibril organization, are key pathological processes that contribute to dissecting abdominal aortic aneurysm (AAA) pathogenesis. Lysyl hydroxylase 1 (LH1) is essential for type I/III collagen intermolecular crosslinking and stabilization. However, its function in dissecting AAA has not been explored. Here, we investigated whether LH1 is significantly implicated in dissecting AAA progression and therapeutic intervention. Methods and Results: Sixteen-week-old male LH1-deficient and wild-type (WT) mice on the C57Bl/6NCrl background were infused with angiotensin II (Ang II, 1000 ng/kg per minute) via subcutaneously implanted osmotic pumps for 4 weeks. Ang II increased LH1 levels in the abdominal aortas of WT mice, whereas mice lacking LH1 developed dissecting AAA. To evaluate the related mechanism, we performed whole-transcriptomic analysis, which demonstrated that LH1 deficiency aggravated gene transcription alterations; in particular, the expression of thrombospondin-1 was markedly upregulated in the aortas of LH1-deficient mice. Furthermore, targeting thrombospondin-1 with TAX2 strongly inhibited the proinflammatory process, matrix metalloproteinase (MMP) activity and vascular smooth muscle cells (VSMCs) apoptosis, ultimately decreasing the incidence of dissecting AAA. Restoration of LH1 protein expression in LH1-deficient mice by intraperitoneal injection of an adeno-associated virus normalized thrombospondin-1 levels, subsequently alleviating dissecting AAA formation and preserving aortic structure and function. Consistently, in human AAA specimens, decreased LH1 expression was associated with increased thrombospondin-1 levels. Conclusions: LH1 deficiency contributes to dissecting AAA pathogenesis, at least in part, by upregulating thrombospondin-1 expression, which subsequently enables proinflammatory processes, MMP activation and VSMCs apoptosis. Our study provides evidence that LH1 is a potential critical therapeutic target for AAA.

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.

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SMAD3 deficiency promotes inflammatory aortic aneurysms in angiotensin II-infused mice via activation of iNOS.

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SMAD3 deficiency promotes inflammatory aortic aneurysms in angiotensin II-infused mice via activation of iNOS.

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