Membrane‐Tethered Metalloproteinase Expressed by Vascular Smooth Muscle Cells Limits the Progression of Proliferative Atherosclerotic Lesions

Autor: Daniel T. Eitzman, Takeshi Akama, Richard H. Barnes, Julian C. Bahr, Miina K. Öhman, Stephen J. Weiss, Tae Hwa Chun, Moon Sook Woo
Jazyk: angličtina
Rok vydání: 2017
Předmět:
0301 basic medicine
Apolipoprotein E
Male
Smooth Muscle Proliferation and Differentiation
Vascular smooth muscle
muscle
Mice
Knockout
ApoE
Cell Communication
Matrix metalloproteinase
Muscle
Smooth
Vascular
Extracellular matrix
Genetically Altered and Transgenic Models
Medicine
Aorta
Cells
Cultured
Original Research
Metalloproteinase
matrix metalloproteinases
Plaque
Atherosclerotic
Cell biology
Phenotype
MMP14
Female
medicine.symptom
Inflammation Mediators
Cardiology and Cardiovascular Medicine
Extracellular Matrix Degradation
smooth
Signal Transduction
Heterozygote
Myocytes
Smooth Muscle
Aortic Diseases
Inflammation
Vascular Remodeling
Iliac Artery
Cell-Matrix Junctions
03 medical and health sciences
Vascular Biology
Matrix Metalloproteinase 14
Animals
Genetic Predisposition to Disease
Cell Proliferation
business.industry
Atherosclerosis
Mice
Inbred C57BL
Disease Models
Animal
030104 developmental biology
inflammation
Immunology
aneurysm
business
Health Services and Outcomes Research
Zdroj: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
ISSN: 2047-9980
Popis: Background The MMP (matrix metalloproteinase) family plays diverse and critical roles in directing vascular wall remodeling in atherosclerosis. Unlike secreted‐type MMP s, a member of the membrane‐type MMP family, MT 1‐ MMP (membrane‐type 1 MMP; MMP 14), mediates pericellular extracellular matrix degradation that is indispensable for maintaining physiological extracellular matrix homeostasis. However, given the premature mortality exhibited by MT 1‐ MMP –null mice, the potential role of the proteinase in atherogenesis remains elusive. We sought to determine the effects of both MT 1‐ MMP heterozygosity and tissue‐specific gene targeting on atherogenesis in APOE (apolipoprotein E)–null mice. Methods and Results MT 1‐ MMP heterozygosity in the APOE ‐null background ( Mmp14 +/− Apoe −/− ) significantly promoted atherogenesis relative to Mmp14 +/+ Apoe −/− mice. Furthermore, the tissue‐specific deletion of MT 1‐ MMP from vascular smooth muscle cells ( VSMC s) in SM 22α‐Cre(+) Mmp14 F/F Apoe −/− ( VSMC ‐knockout) mice likewise increased the severity of atherosclerotic lesions. Although VSMC ‐knockout mice also developed progressive atherosclerotic aneurysms in their iliac arteries, macrophage‐ and adipose‐specific MT 1‐ MMP –knockout mice did not display this sensitized phenotype. In VSMC ‐knockout mice, atherosclerotic lesions were populated by hyperproliferating VSMC s (smooth muscle actin– and Ki67–double‐positive cells) that were characterized by a proinflammatory gene expression profile. Finally, MT 1‐ MMP –null VSMC s cultured in a 3‐dimensional spheroid model system designed to mimic in vivo–like cell–cell and cell–extracellular matrix interactions, likewise displayed markedly increased proliferative potential. Conclusions MT 1‐ MMP expressed by VSMC s plays a key role in limiting the progression of atherosclerosis in APOE ‐null mice by regulating proliferative responses and inhibiting the deterioration of VSMC function in atherogenic vascular walls.
Databáze: OpenAIRE
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