ArticleThe Journal of biological chemistry2012
Loss of Timp3 gene leads to abdominal aortic aneurysm formation in response to angiotensin II.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 69 citations in OpenAlex.
- Proteome Differences in Smooth Muscle Cells from Diabetic and Non-Diabetic Abdominal Aortic Aneurysm Patients Reveal Metformin-Induced Mechanisms.Medical sciences (Basel, Switzerland) · 2025Article
- Nox1/PAK1 is required for angiotensin II-induced vascular inflammation and abdominal aortic aneurysm formation.Redox biology · 2025Article
- Pharmacological Inhibition of MMP-12 Exerts Protective Effects on Angiotensin II-Induced Abdominal Aortic Aneurysms in Apolipoprotein E-Deficient Mice.International journal of molecular sciences · 2024Article
- The contribution of matrix metalloproteinases and their inhibitors to the development, progression, and rupture of abdominal aortic aneurysms.Frontiers in cardiovascular medicine · 2023Review
- Attenuation of Smooth Muscle Cell Phenotypic Switching by Angiotensin 1-7 Protects against Thoracic Aortic Aneurysm.International journal of molecular sciences · 2022Article
- Protective Effects of Circulating TIMP3 on Coronary Artery Disease and Myocardial Infarction: A Mendelian Randomization Study.Journal of cardiovascular development and disease · 2022Article
- Disintegrin and Metalloproteinases (ADAMs [A Disintegrin and Metalloproteinase] and ADAMTSs [ADAMs With a Thrombospondin Motif]) in Aortic Aneurysm.Hypertension (Dallas, Tex. : 1979) · 2022Review
- Altered TIMP-3 Levels in the Cerebrospinal Fluid and Plasma of Patients with Alzheimer's Disease.Journal of personalized medicine · 2022Article
- Transcriptional analysis of gasoline engine exhaust particulate matter 2.5-exposed human umbilical vein endothelial cells reveals the different gene expression patterns related to the cardiovascular diseases.Biochemistry and biophysics reports · 2022Article
- Tissue Inhibitor of Metalloproteases 3 (TIMP-3): In Vivo Analysis Underpins Its Role as a Master Regulator of Ectodomain Shedding.Membranes · 2022Review
- Neutrophils as Regulators and Biomarkers of Cardiovascular Inflammation in the Context of Abdominal Aortic Aneurysms.Biomedicines · 2021Review
- Genetic and Epigenetic Mechanisms Underlying Vascular Smooth Muscle Cell Phenotypic Modulation in Abdominal Aortic Aneurysm.International journal of molecular sciences · 2020Review
- Cyclodextrin Prevents Abdominal Aortic Aneurysm via Activation of Vascular Smooth Muscle Cell Transcription Factor EB.Circulation · 2020Article
- ADAM (a Disintegrin and Metalloproteinase) 15 Deficiency Exacerbates Ang II (Angiotensin II)-Induced Aortic Remodeling Leading to Abdominal Aortic Aneurysm.Arteriosclerosis, thrombosis, and vascular biology · 2020Article
- Pathogenic mechanisms and the potential of drug therapies for aortic aneurysm.American journal of physiology. Heart and circulatory physiology · 2020Review
- Biology of Tissue Inhibitor of Metalloproteinase 3 (TIMP3), and Its Therapeutic Implications in Cardiovascular Pathology.Frontiers in physiology · 2020Review
- GSK2593074A blocks progression of existing abdominal aortic dilation.JVS-vascular science · 2020Article
- Extracellular matrix, regional heterogeneity of the aorta, and aortic aneurysm.Experimental & molecular medicine · 2019Review
- Matrix Metalloproteinase in Abdominal Aortic Aneurysm and Aortic Dissection.Pharmaceuticals (Basel, Switzerland) · 2019Review
- Apelin protects against abdominal aortic aneurysm and the therapeutic role of neutral endopeptidase resistant apelin analogs.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
Abstract
Aortic aneurysm is dilation of the aorta primarily due to degradation of the aortic wall extracellular matrix (ECM). Tissue inhibitors of metalloproteinases (TIMPs) inhibit matrix metalloproteinases (MMPs), the proteases that degrade the ECM. Timp3 is the only ECM-bound Timp, and its levels are altered in the aorta from patients with abdominal aortic aneurysm (AAA). We investigated the causal role of Timp3 in AAA formation. Infusion of angiotensin II (Ang II) using micro-osmotic (Alzet) pumps in Timp3(-/-) male mice, but not in wild type control mice, led to adverse remodeling of the abdominal aorta, reduced collagen and elastin proteins but not mRNA, and elevated proteolytic activities, suggesting excess protein degradation within 2 weeks that led to formation of AAA by 4 weeks. Intriguingly, despite early up-regulation of MMP2 in Timp3(-/-)Ang II aortas, additional deletion of Mmp2 in these mice (Timp3(-/-)/Mmp2(-/-)) resulted in exacerbated AAA, compromised survival due to aortic rupture, and inflammation in the abdominal aorta. Reconstitution of WT bone marrow in Timp3(-/-)/Mmp2(-/-) mice reduced inflammation and prevented AAA in these animals following Ang II infusion. Treatment with a broad spectrum MMP inhibitor (PD166793) prevented the Ang II-induced AAA in Timp3(-/-) and Timp3(-/-)/Mmp2(-/-) mice. Our study demonstrates that the regulatory function of TIMP3 is critical in preventing adverse vascular remodeling and AAA. Hence, replenishing TIMP3, a physiological inhibitor of a number of metalloproteinases, could serve as a therapeutic approach in limiting AAA development or expansion.
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Registered trials
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