Age-related vascular gene expression profiling in mice

Rammos, Christos; Hendgen‐Cotta, Ulrike B.; Deenen, René; Pohl, Julia; Stock, Pia; Hinzmann, Christian; Kelm, Malte; Rassaf, Tienush

doi:10.1016/j.mad.2014.01.001

Cited by 33 publications

(31 citation statements)

References 63 publications

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“…This study showed that the activity of SOD1 did not change between young and aged mice, although the blood pressure was noted to be markedly higher in the aged group (25). Another recent study (26) has shown that antioxidative therapy with TEMPOL improved arterial stiffness and decreased endothelial dysfunction in mice, but it had no effect on blood pressure, and this study did not find any increase in blood pressure in aged mice, in contrast to many other studies (9, 26). Therefore, agents that could reverse oxidatively modified proteins to their native state may provide protection against age-related hypertension, whereas antioxidants alone may have limited effectiveness.…”

Section: Introductioncontrasting

confidence: 86%

“…Although human studies have shown that large artery stiffness is a major cause of increased SBP with decreased diastolic blood pressure (DBP) (8, 9) in aging, the temporal relationship between blood pressure and vascular stiffening remains unclear, specifically whether vascular stiffness precedes hypertension (10). Studies have shown correlation of proximal aortic stiffness with the incidence of hypertension (10); higher carotid artery (CA) stiffness was also associated with incidence of hypertension (11).…”

Section: Introductionmentioning

confidence: 99%

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Thioredoxin reverses age-related hypertension by chronically improving vascular redox and restoring eNOS function

et al. 2017

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The incidence of high blood pressure with advancing age is notably high, and it is an independent prognostic factor for the onset or progression of a variety of cardiovascular disorders. Although age-related hypertension is an established phenomenon, current treatments are only palliative but not curative. Thus, there is a critical need for a curative therapy against age-related hypertension, which could greatly decrease the incidence of cardiovascular disorders. We show that overexpression of human thioredoxin (TRX), a redox protein, in mice prevents age-related hypertension. Further, injection of recombinant human TRX (rhTRX) for three consecutive days reversed hypertension in aged wild-type mice, and this effect lasted for at least 20 days. Arteries of wild-type mice injected with rhTRX or mice with TRX overexpression exhibited decreased arterial stiffness, greater endothelium-dependent relaxation, increased nitric oxide production, and decreased superoxide anion (O2•−) generation compared to either saline-injected aged wild-type mice or mice with TRX deficiency. Our study demonstrates a potential translational role of rhTRX in reversing age-related hypertension with long-lasting efficacy.

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Section: Introductioncontrasting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Thioredoxin reverses age-related hypertension by chronically improving vascular redox and restoring eNOS function

et al. 2017

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“…Indeed, Ang-II and TGF-β play similarly important roles in hypertension and aging wherein the wall can thicken to counteract increased pressure-induced wall stress 26,32,91,93 , though not all matrix production need be structurally protective 37,38 . Interestingly, a transcriptional analysis of vascular aging identified altered cell-matrix interactions as particularly important 171 . Mechanical stress and TGF-β signaling are also complementary partners in the differentiation of fibroblasts to myofibroblasts, which enables increased synthesis and organization of matrix 78,81 .…”

Section: A Unifying Hypothesismentioning

confidence: 99%

“…Such maintenance and adaptivity are achieved, in large part, by intramural cells properly sensing their chemo-mechanical environment and actively regulating the ECM to ensure appropriate compliance and structural integrity. However, aging results in diffusely diminished smooth muscle functionality, lost elastic fiber integrity, remodeled collagen, increased glycosaminoglycans, and increased intramural Ang-II and TGF-β 26,171 . These changes can manifest clinically as decreased arterial distensibility, increased pulse wave velocity, and increased central systolic and pulse pressure, all of which feedback to increase the hemodynamic loads 93 .…”

Section: Closurementioning

confidence: 99%

Role of Mechanotransduction in Vascular Biology

Humphrey

Schwartz

Tellides

et al. 2015

Circulation Research

325

224

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Thoracic aortic diseases that involve progressive enlargement, acute dissection, or rupture are influenced by the hemodynamic loads and mechanical properties of the wall. We have only limited understanding, however, of the mechanobiological processes that lead to these potentially lethal conditions. Homeostasis requires that intramural cells sense their local chemo-mechanical environment and establish, maintain, remodel, or repair the extracellular matrix to provide suitable compliance and yet sufficient strength. Proper sensing, in turn, necessitates both receptors that connect the extracellular matrix to intracellular actomyosin filaments and signaling molecules that transmit the related information to the nucleus. Thoracic aortic aneurysms and dissections are associated with poorly controlled hypertension and mutations in genes for extracellular matrix constituents, membrane receptors, contractile proteins, and associated signaling molecules. This grouping of factors suggests that these thoracic diseases result, in part, from dysfunctional mechanosensing and mechanoregulation of the extracellular matrix by the intramural cells, which leads to a compromised structural integrity of the wall. Thus, improved understanding of the mechanobiology of aortic cells could lead to new therapeutic strategies for thoracic aortic aneurysms and dissections.

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“…While rodents and humans share a great deal of similarity in the organization of the immune system (Haley, 2003;Bailey et al, 2013;Cho et al, 2015;Plackett et al, 2003;Gelinas and McLaurin, 2005;Ferrari et al, 2001), a growing body of literature suggests that immune systems of rodents and humans differ in ways that significantly hamper translation of results obtained in preclinical trials in rodents to successful therapeutics in humans (Renshaw et al, 2002;Boehmer et al, 2004;Rhoades and Orne, 1998;Swift et al, 2001;Rammos et al, 2014;Wang et al, 2014;Bruhns, 2012;Rousseaux et al, 1983;Mestas and Hughes, 2004). Rodents and humans respond differently to infectious agents and possess disparate inflammatory responses (Leist and Hartung, 2013;Tuomela and Lahesmaa, 2013).…”

Section: Immunological Considerations: Disparities Between Rodents Anmentioning

confidence: 99%

Advantages of nonhuman primates as preclinical models for evaluating stem cell-based therapies for Parkinson's disease

Grow¹,

McCarrey²,

Navara³

2016

Stem Cell Research

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The derivation of dopaminergic neurons from induced pluripotent stem cells brings new hope for a patient-specific, stem cell-based replacement therapy to treat Parkinson's disease (PD) and related neurodegenerative diseases; and this novel cell-based approach has already proven effective in animal models. However, there are several aspects of this procedure that have yet to be optimized to the extent required for translation to an optimal cell-based transplantation protocol in humans. These challenges include pinpointing the optimal graft location, appropriately scaling up the graft volume, and minimizing the risk of chronic immune rejection, among others. To advance this procedure to the clinic, it is imperative that a model that accurately and fully recapitulates characteristics most pertinent to a cell-based transplantation to the human brain is used to optimize key technical aspects of the procedure. Nonhuman primates mimic humans in multiple ways including similarities in genomics, neuroanatomy, neurophysiology, immunogenetics, and age-related changes in immune function. These characteristics are critical to the establishment of a relevant model in which to conduct preclinical studies to optimize the efficacy and safety of cell-based therapeutic approaches to the treatment of PD. Here we review previous studies in rodent models, and emphasize additional advantages afforded by nonhuman primate models in general, and the baboon model in particular, for preclinical optimization of cell-based therapeutic approaches to the treatment of PD and other neurodegenerative diseases. We outline current unresolved challenges to the successful application of stem cell therapies in humans and propose that the baboon model in particular affords a number of traits that render it most useful for preclinical studies designed to overcome these challenges.

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Age-related vascular gene expression profiling in mice

Cited by 33 publications

References 63 publications

Thioredoxin reverses age-related hypertension by chronically improving vascular redox and restoring eNOS function

Thioredoxin reverses age-related hypertension by chronically improving vascular redox and restoring eNOS function

Role of Mechanotransduction in Vascular Biology

Advantages of nonhuman primates as preclinical models for evaluating stem cell-based therapies for Parkinson's disease

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