Aging Increases Aortic MMP-2 Activity and Angiotensin II in Nonhuman Primates

Wang, Mingyi; Takagi, Gen; Asai, Kuniya; Resuello, Ranilo G.; Natividad, Filipinas F.; Vatner, Dorothy E.; Vatner, Stephen F.; Lakatta, Edward G.

doi:10.1161/01.hyp.0000073843.56046.45

Cited by 215 publications

(250 citation statements)

References 50 publications

(58 reference statements)

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“…We evaluated the regulating effects of testosterone on MMP-2 activity, a critical downstream molecule of angiotensin II system (Wang et al 2003). Both the expression level and activity of MMP-2 were dramatically elevated in the central arterial wall with advancing age and played pivotal roles in facilitating age-associated ECM remodeling (Jiang et al 2012;).…”

Section: Discussionmentioning

confidence: 99%

Testosterone delays vascular smooth muscle cell senescence and inhibits collagen synthesis via the Gas6/Axl signaling pathway

Chen

Zhao

Jin

et al. 2016

AGE

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Testosterone deficiency is associated with a higher incidence of cardiovascular diseases in men. However, its effect on cell senescence, which plays a causal role in vascular aging, remains unclear. Here, we tested the hypothesis that testosterone alleviated vascular smooth muscle cell (VSMC) senescence and collagen synthesis via growth arrest-specific protein 6 (Gas6)/Axl-and Akt/FoxO1a-dependent pathways. Testosterone significantly ameliorated angiotensin IIinduced VSMC senescence and collagen overexpression. In addition, testosterone inhibited angiotensin IIinduced matrix metalloproteinase-2 (MMP-2) activity, which played a pivotal role in facilitating age-related collagen deposition. Testosterone increased the expression of tissue inhibitor of metalloproteinase-2 but decreased the expression of MMP-2 and membrane type-1 metalloproteinase which contributed to increase MMP-2 activity. The effects on VSMCs senescence and collagen synthesis were mediated by restoration of angiotensin II-induced downregulation of Gas6 and Axl expression and a subsequent reduction of Akt and FoxO1a phosphorylation. The effects of testosterone were reversed by a Gas6 blocker, AxlFc, and a specific inhibitor of Axl, R428. Treatment of VSMCs with PI3K inhibitor LY294002 abrogated the downregulating effect of testosterone on MMP-2 activity. Furthermore, when FoxO1a expression was silenced by using a specific siRNA, the inhibitory effect of testosterone on MMP-2 activity was revered as well, that indicated this process was Akt/FoxO1a dependence. Taken together, Gas6/Axl and Akt/ FoxO1a were involved in protective effects of testosterone on VSMCs senescence and collagen synthesis. Our results provide a novel mechanism underlying the protective effect of testosterone on vascular aging and may serve as a theoretical basis for testosterone replacement therapy.

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Section: Discussionmentioning

confidence: 99%

Testosterone delays vascular smooth muscle cell senescence and inhibits collagen synthesis via the Gas6/Axl signaling pathway

Chen

Zhao

Jin

et al. 2016

AGE

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“…Salient features of the age-associated changes in the media include the deposition of extracellular matrix proteins such as fibronectin and type-2 matrix metalloprotease (MMP- 2), 52,58,66 which promotes matrix protein degradation and facilitates VSMC migration. 67 Aortic medial VSMCs from older rats are larger in size and fewer in number than those in the aorta from young adult rats.…”

Section: Aging Of the Arterial Mediamentioning

confidence: 99%

Arterial Aging

2005

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Abstract-Age is the dominant risk factor for cardiovascular diseases. However, until recently, convincing mechanistic or molecular explanations for the increased cardiovascular risks conferred by aging have been elusive. Aging is associated with alterations in a number of structural and functional properties of large arteries, including diameter, wall thickness, wall stiffness, and endothelial function. Emerging evidence indicates that these age-associated changes are also accelerated in the presence of cardiovascular diseases, and that these changes are themselves risk factors for the appearance or progression of these diseases. In this review, the evidence demonstrating that arterial aging is accelerated in cardiovascular diseases and that accelerated arterial aging is a risk factor for adverse cardiovascular outcomes is briefly reviewed, and selected advances in vascular biology that provide insights into the mechanisms that may underlie the increased risks conferred by arterial aging are summarized. Remarkably, a host of biochemical, enzymatic, and cellular alterations that are operative in accelerated arterial aging have also been implicated in the pathogenesis and progression of arterial diseases. These vascular alterations are thus putative candidates that could be targeted by interventions aimed at attenuating arterial aging, similar to the lifestyle and pharmacological interventions that have already been proven effective. Therefore, the notion that aging is a chronological process and that its risky components cannot be modulated is no longer tenable. It is our hope that a greater appreciation of the links between arterial aging and cardiovascular diseases will stimulate further investigation into strategies aimed at preventing or retarding arterial aging.

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“…The age‐associated increase in activation of MMP2 is mediated via an imbalance of its activator, membrane type 1 MMPs (MT1‐MMP), and its inhibitor, TIMP2 8, 18. Immunostaining analysis demonstrated that the expression of aortic membrane type 1 MMP (brown) and TIMP2 (brown) was substantially increased in old versus young AL, but this effect was markedly reduced in CR rats (Figure 8A through 8C).…”

Section: Resultsmentioning

confidence: 99%

“…PDGF‐BB is not only a potent mitogen, but also a strong chemoattractant of VSMCs, creating a permissive tissue microenvironment for VSMC migration and invasion, promoting formation of a thickened intima in vivo 1, 2, 3, 8, 41, 42. Prior findings indicate that PDGF‐BB treatment induces invasion and migration of old VSMCs in vitro 8, 9. The capacity of VSMC to repopulate a damaged area in vitro, a model for the cellular process of thickening intimal or neointimal formation, is markedly increased after PDGF‐BB treatment 43, 44.…”

Section: Discussionmentioning

confidence: 99%

“…Increases in the local arterial wall proinflammatory molecules, platelet‐derived growth factor (PDGF), matrix metalloproteinase type II (MMP2) and transforming growth factor beta 1 (TGF‐β1), promote cellular and matrix phenotypic shifts that contribute to aortic wall thickening and stiffening that accompany advancing age in mammals, a prominent arterial phenotype of biological aging 4, 5, 6, 7, 8, 9. Interestingly, arterial proinflammatory conditions reduces the threshold or increases the susceptibility for pernicious inflammatory arterial events under hostile conditions such as hyperlipidemia 1, 10…”

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Calorie Restriction Curbs Proinflammation That Accompanies Arterial Aging, Preserving a Youthful Phenotype

Wang

Zhang

Zhu

et al. 2018

JAHA

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BackgroundAging exponentially increases the incidence of morbidity and mortality of quintessential cardiovascular disease mainly due to arterial proinflammatory shifts at the molecular, cellular, and tissue levels within the arterial wall. Calorie restriction (CR) in rats improves arterial function and extends both health span and life span. How CR affects the proinflammatory landscape of molecular, cellular, and tissue phenotypic shifts within the arterial wall in rats, however, remains to be elucidated.Methods and ResultsAortae were harvested from young (6‐month‐old) and old (24‐month‐old) Fischer 344 rats, fed ad libitum and a second group maintained on a 40% CR beginning at 1 month of age. Histopathologic and morphometric analysis of the arterial wall demonstrated that CR markedly reduced age‐associated intimal medial thickening, collagen deposition, and elastin fractionation/degradation within the arterial walls. Immunostaining/blotting showed that CR effectively prevented an age‐associated increase in the density of platelet‐derived growth factor, matrix metalloproteinase type II activity, and transforming growth factor beta 1 and its downstream signaling molecules, phospho‐mothers against decapentaplegic homolog‐2/3 (p‐SMAD‐2/3) in the arterial wall. In early passage cultured vascular smooth muscle cells isolated from AL and CR rat aortae, CR alleviated the age‐associated vascular smooth muscle cell phenotypic shifts, profibrogenic signaling, and migration/proliferation in response to platelet‐derived growth factor.Conclusions CR reduces matrix and cellular proinflammation associated with aging that occurs within the aortic wall and that are attributable to platelet‐derived growth factor signaling. Thus, CR reduces the platelet‐derived growth factor–associated signaling cascade, contributing to the postponement of biological aging and preservation of a more youthful aortic wall phenotype.

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Aging Increases Aortic MMP-2 Activity and Angiotensin II in Nonhuman Primates

Cited by 215 publications

References 50 publications

Testosterone delays vascular smooth muscle cell senescence and inhibits collagen synthesis via the Gas6/Axl signaling pathway

Testosterone delays vascular smooth muscle cell senescence and inhibits collagen synthesis via the Gas6/Axl signaling pathway

Arterial Aging

Calorie Restriction Curbs Proinflammation That Accompanies Arterial Aging, Preserving a Youthful Phenotype

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