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      Vascular Fibrosis in Aging and Hypertension: Molecular Mechanisms and Clinical Implications

      , PhD, , PhD, , MSc, , PhD, , MBBCh, PhD
      The Canadian Journal of Cardiology
      Pulsus Group

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          Aging is the primary risk factor underlying hypertension and incident cardiovascular disease. With aging, the vasculature undergoes structural and functional changes characterized by endothelial dysfunction, wall thickening, reduced distensibility, and arterial stiffening. Vascular stiffness results from fibrosis and extracellular matrix (ECM) remodelling, processes that are associated with aging and are amplified by hypertension. Some recently characterized molecular mechanisms underlying these processes include increased expression and activation of matrix metalloproteinases, activation of transforming growth factor-β1/SMAD signalling, upregulation of galectin-3, and activation of proinflammatory and profibrotic signalling pathways. These events can be induced by vasoactive agents, such as angiotensin II, endothelin-1, and aldosterone, which are increased in the vasculature during aging and hypertension. Complex interplay between the “aging process” and prohypertensive factors results in accelerated vascular remodelling and fibrosis and increased arterial stiffness, which is typically observed in hypertension. Because the vascular phenotype in a young hypertensive individual resembles that of an elderly otherwise healthy individual, the notion of “early” or “premature” vascular aging is now often used to describe hypertension-associated vascular disease. We review the vascular phenotype in aging and hypertension, focusing on arterial stiffness and vascular remodelling. We also highlight the clinical implications of these processes and discuss some novel molecular mechanisms of fibrosis and ECM reorganization.


          Le vieillissement constitue le principal facteur de risque d’apparition de l’hypertension et de la maladie cardiovasculaire. En vieillissant, le système vasculaire subit des modifications structurelles et fonctionnelles caractérisées par une dysfonction endothéliale ainsi que l’épaississement, la rigidification et la perte d’élasticité des parois vasculaires. La rigidité vasculaire est causée par la fibrose et le remodelage de la matrice extracellulaire, des processus qui sont associés au vieillissement et qui sont amplifiés en présence d’hypertension. Parmi les mécanismes moléculaires sous-jacents du vieillissement récemment identifiés, on retrouve l’augmentation de l’expression et de l’activation des métalloprotéinases matricielles, l’activation des voies de signalisation du facteur de croissance transformant bêta 1 impliquant les protéines SMAD, la régulation positive de la galectine-3 et l’activation des voies de signalisation pro-inflammatoires et profibrotiques. Ces mécanismes peuvent être induits par divers agents vasoactifs comme l’angiotensine II, l’endothéline-1 et l’aldostérone dont la présence s’accroît au fil du processus de vieillissement et en présence d’hypertension. Cette interaction complexe entre le « processus de vieillissement » et les facteurs pro-hypertensifs entraîne un remodelage et une fibrose accélérée ainsi que la rigidification des artères qu’on observe habituellement avec l’hypertension. Puisque le phénotype vasculaire de l’hypertendu jeune ressemble à celui de la personne âgée par ailleurs en bonne santé, on fait désormais de plus en plus souvent appel au vocable de vieillissement vasculaire « précoce » ou « prématuré » pour désigner la maladie vasculaire liée à l’hypertension. Nous passons ici en revue le phénotype vasculaire du vieillissement et de l’hypertension en mettant l’accent sur la rigidité artérielle et le remodelage vasculaire. Nous traitons également de l’incidence clinique de ces processus, en plus d’aborder quelques-uns des mécanismes moléculaires de la fibrose et de la réorganisation de la matrice extracellulaire.

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          Most cited references79

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          2003 World Health Organization (WHO)/International Society of Hypertension (ISH) statement on management of hypertension.

          Hypertension is estimated to cause 4.5% of current global disease burden and is as prevalent in many developing countries, as in the developed world. Blood pressure-induced cardiovascular risk rises continuously across the whole blood pressure range. Countries vary widely in capacity for management of hypertension, but worldwide the majority of diagnosed hypertensives are inadequately controlled. This statement addresses the ascertainment of overall cardiovascular risk to establish thresholds for initiation and goals of treatment, appropriate treatment strategies for non-drug and drug therapies, and cost-effectiveness of treatment. Since publication of the WHO/ISH Guidelines for the Management of Hypertension in 1999, more evidence has become available to support a systolic blood pressure threshold of 140 mmHg for even 'low-risk' patients. In high-risk patients there is evidence for lower thresholds. Lifestyle modification is recommended for all individuals. There is evidence that specific agents have benefits for patients with particular compelling indications, and that monotherapy is inadequate for the majority of patients. For patients without a compelling indication for a particular drug class, on the basis of comparative trial data, availability, and cost, a low dose of diuretic should be considered for initiation of therapy. In most places a thiazide diuretic is the cheapest option and thus most cost effective, but for compelling indications where other classes provide additional benefits, even if more expensive, they may be more cost effective. In high-risk patients who attain large benefits from treatment, expensive drugs may be cost effective, but in low-risk patients treatment may not be cost-effective unless the drugs are cheap.
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              Role of reactive oxygen species in TGF-beta1-induced mitogen-activated protein kinase activation and epithelial-mesenchymal transition in renal tubular epithelial cells.

              Epithelial-mesenchymal transition (EMT) plays an important role in renal tubulointerstitial fibrosis and TGF-beta1 is the key inducer of EMT. Phosphorylation of Smad proteins and/or mitogen-activated protein kinases (MAPK) is required for TGF-beta1-induced EMT. Because reactive oxygen species (ROS) are involved in TGF-beta1 signaling and are upstream signaling molecules to MAPK, this study examined the role of ROS in TGF-beta1-induced MAPK activation and EMT in rat proximal tubular epithelial cells. Growth-arrested and synchronized NRK-52E cells were stimulated with TGF-beta1 (0.2 to 20 ng/ml) or H(2)O(2) (1 to 500 microM) in the presence or absence of antioxidants (N-acetylcysteine or catalase), inhibitors of NADPH oxidase (diphenyleneiodonium and apocynin), mitochondrial electron transfer chain subunit I (rotenone), and MAPK (PD 98059, an MEK [MAP kinase/ERK kinase] inhibitor, or p38 MAPK inhibitor) for up to 96 h. TGF-beta1 increased dichlorofluorescein-sensitive cellular ROS, phosphorylated Smad 2, p38 MAPK, extracellular signal-regulated kinases (ERK)1/2, alpha-smooth muscle actin (alpha-SMA) expression, and fibronectin secretion and decreased E-cadherin expression. Antioxidants effectively inhibited TGF-beta1-induced cellular ROS, phosphorylation of Smad 2, p38 MAPK, and ERK, and EMT. H(2)O(2) reproduced all of the effects of TGF-beta1 with the exception of Smad 2 phosphorylation. Chemical inhibition of ERK but not p38 MAPK inhibited TGF-beta1-induced Smad 2 phosphorylation, and both MAPK inhibitors inhibited TGF-beta1- and H(2)O(2)-induced EMT. Diphenyleneiodonium, apocynin, and rotenone also significantly inhibited TGF-beta1-induced ROS. Thus, this data suggest that ROS play an important role in TGF-beta1-induced EMT primarily through activation of MAPK and subsequently through ERK-directed activation of Smad pathway in proximal tubular epithelial cells.

                Author and article information

                Can J Cardiol
                Can J Cardiol
                The Canadian Journal of Cardiology
                Pulsus Group
                1 May 2016
                May 2016
                : 32
                : 5
                : 659-668
                [1]Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, Scotland
                Author notes
                []Corresponding author: Dr Rhian M. Touyz, Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow G12 8TA, Scotland. Tel.: + 44 (0)141 330 7775/7774; fax: + 44 (0)141 330-3360.Institute of Cardiovascular and Medical SciencesBHF Glasgow Cardiovascular Research CentreUniversity of Glasgow126 University PlaceGlasgowG12 8TAScotland rhian.touyz@ 123456glasgow.ac.uk
                © 2016 The Authors. Canadian Cardiovascular Society. Published by Elsevier Inc.

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                : 10 February 2016
                : 18 February 2016


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