Loss of Timp3 Gene Leads to Abdominal Aortic Aneurysm Formation in Response to Angiotensin II

Basu, Ratnadeep; Fan, Daiming; Kandalam, Vijay; Lee, Jiwon; Das, Sajal Kumar; Wang, Xiuhua; Baldwin, Troy A.; Oudit, Gavin Y.; Kassiri, Zamaneh

doi:10.1074/jbc.m112.425652

Cited by 64 publications

(57 citation statements)

References 66 publications

(72 reference statements)

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“…This result is consistent with those of previous studies showing that MMP-2 expression is regulated by Hif-1α. The expression of tissue inhibitors of metalloproteinase-3, which suppresses activity of MMPs, 10 was unchanged in both groups ( Figure IX in the online-only Data Supplement). In addition, there was no difference in the expression of inflammation-related genes between the groups after 6 weeks.…”

Section: Discussionmentioning

confidence: 87%

Hypoxia-Inducible Factor-1α in Smooth Muscle Cells Protects Against Aortic Aneurysms—Brief Report

Imanishi

Chiba

Tomita

et al. 2016

ATVB

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A ortic aneurysmal lesions exhibit fragmentation and disruption of elastic laminas, inflammatory cell infiltration, and loss of vascular smooth muscle cells (VSMCs) with aortic wall expansion.1,2 Elastic lamina plays key roles in maintaining the elasticity of aortae; therefore, the disruption of elastin fiber is a major cause of aortic aneurysm formation. Degradation of elastin fiber, one of the extracellular matrix, is mainly caused by induction of matrix metalloproteinase (MMP)-2 or MMP-9 from VSMCs and inflammatory cells.3 However, dysfunction of elastin fiber maturation causes matrix failure, contributing significantly to aneurysm formation. See accompanying editorial on page 2138Tropoelastin, an uncross-linked soluble form of elastin, is a major component of elastin fiber. Elastin haploinsufficiency reduces the volume of the elastin cross-linking structure desmosine and enhances elastin fiber fragmentation. 4 Fibrillin-1 is a major component of the microfibrils that form a sheath surrounding elastin; mutations in the fibrillin-1 gene cause Marfan syndrome, which is characterized by matrix failure, and links to aneurysm formation. 5 Lysyl oxidase (LOX) is a crucial enzyme involved in elastin cross-linking and elastin coacervation; inactivation of the LOX gene leads to aortic aneurysms. 6 Additionally, studies involving the administration of the LOX inhibitor β-aminopropionitrile (BAPN) to adult rat or mouse models of aortic aneurysm 7,8 indicate that the mechanisms underlying elastin fiber formation, especially elastin crosslinking, protect against aortic wall expansion in mature aortae.Our previous report showed that smooth muscle cell-specific hypoxia-inducible factor-1α (Hif-1α) deficiency suppressed angiotensin II (Ang II)-induced medial thickening by suppressing VSMC hypertrophy and vascular fibrosis via decreased aortal mRNA expression of extracellular matrix-related genes, such as collagen I.9 However, it remains unclear whether suppression of vascular remodeling and extracellular matrix metabolism is a protective compensatory reaction against vascular vulnerability, which occurs in response to chronic exogenous stimuli. Here, we investigated the role of smooth muscle cell-derived Hif-1α in pharmacologically induced aortic aneurysms, using a mouse model of vascular vulnerability. Our results indicate that deficiency of smooth muscle cell-derived Hif-1α augments aortic aneurysms, accompanied by disruption of elastin fiber formation, but not changes of elastin fiber degradation. Materials and MethodsMaterials and Methods are available in the online-only Data Supplement.© 2016 American Heart Association, Inc. Objective-The purpose of this study was to determine the role of smooth muscle cell-derived hypoxia-inducible factor-1α (Hif-1α) in the pathogenesis of aortic aneurysms. Approach and Results-Control mice and smooth muscle cell-specific hypoxia-inducible factor-1α-deficient mice were infused with β-aminopropionitrile for 2 weeks and angiotensin II for 6 weeks to induce aortic aneurysm formation. Muta...

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Section: Discussionmentioning

confidence: 87%

Hypoxia-Inducible Factor-1α in Smooth Muscle Cells Protects Against Aortic Aneurysms—Brief Report

Imanishi

Chiba

Tomita

et al. 2016

ATVB

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“…Ang II-mediated AAA formation in ApoE -/-and LDLR -/-mice was independent of the blood pressure as suppression of hypertension (by hydralazin administration) did not prevent AAA or atheroscrlerosis in these mice [51]. Recently, we reported that despite the suppressed Ang II-induced hypertension in TIMP3 -/-mice, these mice develop AAA after 4 weeks of Ang II infusion while WT mice did not [48]. Overall, sufficient evidence indicate ECM degradation and as the central and initiating event in development of AAA, while comorbidities such as atherosclerosis and hypertension may or may not be present with AAA.…”

Section: Aortic Aneurysm Occurs Independently From Hypertension and Amentioning

confidence: 99%

“…-/-mice with a hypertensive dose of Ang II resulted in a suppressed hypertensive response [76], but development of AAA after 4 weeks of Ang II infusion, whereas wildtype mice, that had increased TIMP3 levels in the abdominal aorta, did not exhibit AAA [48], suggesting a protective function of TIMP3 in this process ( Figure 1). Although elevated MMP2 activation was detected in the abdominal aorta after 2 weeks of Ang II infusion, ablation of MMP2 in TIMP3 -/-mice exacerbated AAA dilation and increased the rate of aortic rupture, primarily due to heightened inflammation.…”

Section: Infusion Of Timp3mentioning

confidence: 99%

“…-/-/MMP2 -/-mice [48]. Overall, these studies demonstrate that distinct molecular mechanisms are involved in different models of aortic aneurysm, and while it was once believed that generally a reduction in MMPs and increase in TIMPs would provide beneficial effects, it is important to acknowledge that the interaction between these molecules is quite complex and deserves detailed investigation in different AAA models .…”

Section: Infusion Of Timp3mentioning

confidence: 99%

“…AAA models in rats were reported over 2 decades ago [41] and since then AAA has been generated and studied in different rodent models [42][43][44], however mouse models have gained dominance over others primarily due to availability of genetically modified mice [18]. Three most common experimental models of AAA include transient intraluminal infusion of elastase (a pancreatic extract) [45], adventitial exposure of a high concentration CaCl 2 solution [46], or chronic subcutaneous infusion of a hypertensive dose of Angiotensin II (Ang II) in a hypercholestremic [47] or normocholestremic background [48]. Hypercholestremia in mice is achieved by deficiency of apolipoprotein-E (ApoE) or low density lipoprotein receptor (LDLR) combined with high fat or high cholesterol diet [49][50][51].…”

Section: Experimental Models Of Aaa Targeting Proteases and Their Inhmentioning

confidence: 99%

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Extracellular Matrix Remodelling and Abdominal Aortic Aneurysm

Basu¹,

Kassiri

2013

J Clin Exp Cardiolog

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Aorta is the largest artery in the body. Aortic wall is comprised of an intricate arrangement of extracellular matrix (ECM) structural proteins, primarily collagen and elastin, and layers of vascular smooth muscle cells. This gives the aortic wall the tensile strength to withstand the pressure of blood pumped from the heart during systole, and the elasticity to expand and accommodate the left ventricular stroke volume and to, subsequently, recoil to its original diameter and push the blood forward for systemic perfusion. Aortic aneurysm involves structural degradation of the aortic wall and focal dilatation of the aortic lumen. It is a devastating health problem with no effective treatment. Current management strategies for AAA patients include antihypertensive drugs and surgical repair for severe cases of AAA which are not without limitations and complications. A number of proteases (matrix metalloproteinases, serine and cystein proteases), and their inhibitors (tissue inhibitor of metalloproteases and cystatin) have been shown to contribute to AAA development and progression. In this review we will summarize the published literature on the role of ECM-regulatory proteins, mainly proteases and their inhibitors, in aortic function and aneurysm formation, with a focus on abdominal aortic aneurysm.

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Reducing Timp3 or vitronectin ameliorates disease manifestations in CADASIL mice

Capone

Cognat

Ghezali

et al. 2016

Annals of Neurology

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Objective CADASIL is a genetic paradigm of cerebral small vessel disease caused by NOTCH3 mutations that stereotypically lead to the extracellular deposition of NOTCH3 ectodomain (Notch3ECD) on the vessels. TIMP3 and vitronectin are 2 extracellular matrix proteins that abnormally accumulate in Notch3ECD-containing deposits on brain vessels of mice and patients with CADASIL. Herein, we investigated whether increased levels of TIMP3 and vitronectin are responsible for aspects of CADASIL disease phenotypes. Methods Timp3 and vitronectin expression were genetically reduced in TgNotch3R169C mice, a well-established preclinical model of CADASIL. A mouse overexpressing human TIMP3 (TgBAC-TIMP3) was developed. Disease-related phenotypes, including cerebral blood flow (CBF) deficits, white matter lesions, and Notch3ECD deposition, were evaluated between 6 and 20 months of age. Results CBF responses to neural activity (functional hyperemia), topical application of vasodilators, and decreases in blood pressure (CBF autoregulation) were similarly reduced in TgNotch3R169C and TgBAC-TIMP3 mice, and myogenic responses of brain arteries were likewise attenuated. These defects were rescued in TgNotch3R169C mice by haploinsufficiency of Timp3, although the number of white matter lesions was unaffected. In contrast, haploinsufficiency or loss of vitronectin in TgNotch3R169C mice ameliorated white matter lesions, although CBF responses were unchanged. Amelioration of cerebrovascular reactivity or white matter lesions in these mice was not associated with reduced Notch3ECD deposition in brain vessels. Interpretation Elevated levels of TIMP3 and vitronectin, acting downstream of Notch3ECD deposition, play a role in CADASIL, producing divergent influences on early CBF deficits and later white matter lesions.

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Loss of Timp3 Gene Leads to Abdominal Aortic Aneurysm Formation in Response to Angiotensin II

Cited by 64 publications

References 66 publications

Hypoxia-Inducible Factor-1α in Smooth Muscle Cells Protects Against Aortic Aneurysms—Brief Report

Hypoxia-Inducible Factor-1α in Smooth Muscle Cells Protects Against Aortic Aneurysms—Brief Report

Extracellular Matrix Remodelling and Abdominal Aortic Aneurysm

Reducing Timp3 or vitronectin ameliorates disease manifestations in CADASIL mice

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