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The Frail Renin-Angiotensin System

      Keywords

      The renin-angiotensin system

      The renin-angiotensin system (RAS) is a hormonal system that is of vital importance not only in the regulation of arterial blood pressure and salt balance, but also in many physiologic and pathophysiologic mechanisms in almost every organ system.
      • Wang M.
      • Takagi G.
      • Asai K.
      • et al.
      Aging increases aortic MMP-2 activity and angiotensin II in nonhuman primates.
      • Heymes C.
      • Silvestre J.S.
      • Llorens-Cortes C.
      • et al.
      Cardiac senescence is associated with enhanced expression of angiotensin II receptor subtypes.
      • Min L.J.
      • Mogi M.
      • Iwai M.
      • et al.
      Signaling mechanisms of angiotensin II in regulating vascular senescence.
      The system consists mainly of a 2-step enzymatic cascade catalyzed by renin and angiotensin-converting enzyme (ACE), generating angiotensin II (Ang II), a single bioactive peptide. Ang II, the main RAS effector hormone, acts through 2 receptor subtypes, Ang II types 1 and 2 receptors (AT1R and AT2R) (Fig. 1).
      • Chiu A.T.
      • McCall D.E.
      • Nguyen T.T.
      • et al.
      Discrimination of angiotensin II receptor subtypes by dithiothreitol.
      • Chang R.S.
      • Lotti V.J.
      Two distinct angiotensin II receptor binding sites in rat adrenal revealed by new selective nonpeptide ligands.
      Both the receptor types belong to the G protein–coupled receptor family but differ in terms of tissue distribution and cell signaling pathways. Most of the functions of Ang II are carried through AT1R. The role and biologic functions of AT2R are less studied. It has been documented that AT2R inhibits and antagonizes AT1R-mediated functions,
      • Hein L.
      • Barsh G.S.
      • Pratt R.E.
      • et al.
      Behavioural and cardiovascular effects of disrupting the angiotensin II type-2 receptor in mice.
      • Ichiki T.
      • Labosky P.A.
      • Shiota C.
      • et al.
      Effects on blood pressure and exploratory behaviour of mice lacking angiotensin II type-2 receptor.
      • Masaki H.
      • Kurihara T.
      • Yamaki A.
      • et al.
      Cardiac-specific overexpression of angiotensin II AT2 receptor causes attenuated response to AT1 receptor-mediated pressor and chronotropic effects.
      • AbdAlla S.
      • Lother H.
      • Abdel-tawab A.M.
      • et al.
      The angiotensin II AT2 receptor is an AT1 receptor antagonist.
      and when stimulated by Ang II, AT2R exerts effects that are the opposite of AT1R, including antiinflammatory,
      • Matsubara H.
      Pathophysiological role of angiotensin II type 2 receptor in cardiovascular and renal diseases.
      antiproliferative,
      • Matsubara H.
      Pathophysiological role of angiotensin II type 2 receptor in cardiovascular and renal diseases.
      and antiapoptotic actions (Table 1).
      • Bascands J.L.
      • Girolami J.P.
      • Troly M.
      • et al.
      Angiotensin II induces phenotype-dependent apoptosis in vascular smooth muscle cells.
      Hence, AT2R may play an important role in vascular aging.
      Figure thumbnail gr1
      Fig. 1The steps in the biochemical pathway that is involved in the formation of the most biologically potent angiotensin peptide Ang II and its interaction with angiotensin receptors. The enzymes renin converts angiotensinogen to angiotensin I, which in turn is converted via angiotensin converting enzyme to Angiotensin II. Other enzymes that facilitate alternative pathways for the formation of Ang II are tPA, cathepsin G, and tonin. tPA, tissue plasminogen activator.
      Table 1Opposing functions of AT1R and AT2R, which might be linked to aging
      AT1RAT2R
      VasoconstrictionVasodilatation
      Cell growthAntigrowth
      Cell proliferationCell differentiation
      AntinatriuresisNatriuresis
      Production of O2Production of nitric oxide
      Stimulation of fibroblast proliferation and collagen synthesisInhibition of fibroblast proliferation
      ApoptosisAntiapoptosis
      Evidence suggests that virtually every organ system in the human body possesses a local RAS. The components of RAS are present in peripheral tissues such as vasculature, kidneys, adrenal glands, heart, and immune cells, all of which locally produce Ang II.
      • Peach M.J.
      Renin-angiotensin system: biochemistry and mechanisms of action.
      • Nahmod K.A.
      • Vermeulen M.E.
      • Raiden S.
      • et al.
      Control of dendritic cell differentiation by angiotensin II.
      • Jurewicz M.
      • McDermott D.H.
      • Sechler J.M.
      • et al.
      Human T and natural killer cells possess a functional renin-angiotensin system: further mechanisms of angiotensin II-induced inflammation.
      These local systems seem to be independently regulated and compartmentalized from the plasma circulation.
      • Velez J.C.
      The importance of the intrarenal renin-angiotensin system.
      Binding of Ang II to AT1R or AT2R activates various complex signal transduction pathways. Through AT1R, Ang II activates various intracellular protein kinases. These intracellular signaling cascades include receptor- and non-receptor–mediated tyrosine kinases, serine/threonine kinases, mitogen-activated protein kinase (MAPK) family (extracellular signal-regulated kinase, c-Jun N terminal kinase, and p38MAPK), p70 S6 kinase, Akt/PKB (protein kinase B), and various protein kinase C isoforms.
      • Griendling K.K.
      • Ushio-Fukai M.
      • Lassegue B.
      • et al.
      Angiotensin II signaling in vascular smooth muscle. New concepts.
      • Eguchi S.
      • Frank G.D.
      • Mifune M.
      • et al.
      Metalloprotease-dependent ErbB ligand shedding in mediating EGFR transactivation and vascular remodelling.
      • Yin G.
      • Yan C.
      • Berk B.C.
      Angiotensin II signaling pathways mediated by tyrosine kinases.
      • Suzuki H.
      • Motley E.D.
      • Frank G.D.
      • et al.
      Recent progress in signal transduction research of the angiotensin II type-1 receptor: protein kinases, vascular dysfunction and structural requirement.
      These intracellular signals have been linked to vascular remodeling through induction of hypertrophy, hyperplasia, and migration of vascular smooth muscle cells.
      • Griendling K.K.
      • Ushio-Fukai M.
      • Lassegue B.
      • et al.
      Angiotensin II signaling in vascular smooth muscle. New concepts.
      • Eguchi S.
      • Frank G.D.
      • Mifune M.
      • et al.
      Metalloprotease-dependent ErbB ligand shedding in mediating EGFR transactivation and vascular remodelling.
      • Yin G.
      • Yan C.
      • Berk B.C.
      Angiotensin II signaling pathways mediated by tyrosine kinases.
      • Suzuki H.
      • Motley E.D.
      • Frank G.D.
      • et al.
      Recent progress in signal transduction research of the angiotensin II type-1 receptor: protein kinases, vascular dysfunction and structural requirement.
      In contrast, AT2R signals through 3 major transduction pathways that seem to oppose the actions of AT1R: (1) activation of various protein phosphatases causing protein dephosphorylation, (2) activation of the nitric oxide/cyclic GMP system, and (3) stimulation of phospholipase A2, with subsequent release of arachidonic acid.
      • Steckelings U.M.
      • Kaschina E.
      • Unger T.
      The AT2 receptor–a matter of love and hate.
      Of these pathways, MAPK and phosphotyrosine phosphatase (PTP) have been the most studied classic signaling cascade of AT1R and AT2R.
      • Dechend R.
      • Fiebler A.
      • Lindschau C.
      • et al.
      Modulating angiotensin II-induced inflammation by HMG co-A reductase inhibition.
      • Touyz R.M.
      • Schiffrin E.L.
      Signal transduction mechanisms mediating the physiological and pathophysiological actions of angiotensin II in vascular smooth muscle cells.
      • Kambayashi Y.
      • Bardhan S.
      • Takahashi K.
      • et al.
      Molecular cloning of a novel angiotensin II receptor isoform involved in phosphotyrosine phosphatase inhibition.
      • Bedecs K.
      • Elbaz N.
      • Sutren M.
      • et al.
      Angiotensin II type 2 receptors mediate inhibition of mitogen-activated protein kinase cascade and functional activation of SHP-1 tyrosine phosphatase.
      • Horiuchi M.
      • Hayashida W.
      • Kambe T.
      • et al.
      Angiotensin type 2 receptor dephosphorylates Bcl-2 by activating mitogen-activated protein kinase phosphatase-1 and induces apoptosis.
      AT1R activates MAPK cascade, whereas AT2R inhibits MAPK and activates PTP.
      • Bedecs K.
      • Elbaz N.
      • Sutren M.
      • et al.
      Angiotensin II type 2 receptors mediate inhibition of mitogen-activated protein kinase cascade and functional activation of SHP-1 tyrosine phosphatase.
      The influence of cross talk between AT1R and AT2R on activation of these signaling pathways is still largely unknown.

      Changes in RAS with aging

      Most of the studies on the effect of aging on RAS have been done in animal models. The effects of aging on RAS have been studied in tissues and in circulation. There seems to be a differential regulation of the circulating and intrarenal RAS during aging.
      • Kobori H.
      • Nangaku M.
      • Navar L.G.
      • et al.
      The intrarenal renin-angiotensin system: from physiology to the pathobiology of hypertension and kidney disease.
      On the tissue-specific level, renal Ang II content increases in older animals.
      • Thompson M.M.
      • Oyama T.T.
      • Kelly F.J.
      • et al.
      Activity and responsiveness of the renin-angiotensin system in the aging rat.
      In contrast, aging is associated with a decline in the concentration of the components of the circulating RAS in animals, including reduction in renal tissue renin messenger RNA levels, juxtaglomerular cell renin content, responsiveness of renin release to various challenges, and plasma renin and Ang II levels.
      • Thompson M.M.
      • Oyama T.T.
      • Kelly F.J.
      • et al.
      Activity and responsiveness of the renin-angiotensin system in the aging rat.
      • Anderson S.
      Ageing and the renin-angiotensin system.
      • Anderson S.
      • Rennke H.G.
      • Zatz R.
      Glomerular adaptations with normal aging and with long-term converting enzyme inhibition in rats.
      • Baylis C.
      Renal responses to acute angiotensin II inhibition and administered angiotensin II in the aging, conscious, chronically catheterized rat.
      • Baylis C.
      • Corman B.
      The aging kidney: insights from experimental studies.
      • Masilamani S.
      • Zhang X.Z.
      • Baylis C.
      Blunted pressure natriuretic response in the old rat: participation of the renal nerves.
      • Reckelhoff J.F.
      • Baylis C.
      Proximal tubular metalloprotease activity is decreased in the senescent rat kidney.
      The decline in the concentration of the components of the circulating RAS during aging may be a consequence of the age-related increase in pressure, because plasma Ang II levels do not decline in rats without increased pressure during aging.
      • Kobori H.
      • Nangaku M.
      • Navar L.G.
      • et al.
      The intrarenal renin-angiotensin system: from physiology to the pathobiology of hypertension and kidney disease.
      The reduction in the levels of the circulating RAS components may also have predisposed to the increased renal vasoconstrictor responses to exogenously administered Ang II in older animals.
      • Thompson M.M.
      • Oyama T.T.
      • Kelly F.J.
      • et al.
      Activity and responsiveness of the renin-angiotensin system in the aging rat.
      Upregulation of AT1R has been observed in both the heart and the vasculature,
      • Wang M.
      • Takagi G.
      • Asai K.
      • et al.
      Aging increases aortic MMP-2 activity and angiotensin II in nonhuman primates.
      • Heymes C.
      • Silvestre J.S.
      • Llorens-Cortes C.
      • et al.
      Cardiac senescence is associated with enhanced expression of angiotensin II receptor subtypes.
      suggesting an important role of RAS in senescence. On the other hand, AT2R is expressed in large quantities in fetal tissues but its expression decreases in the neonatal period and reaches a comparatively low level in the adult animal.
      • Carey R.M.
      • Siragy H.M.
      Newly recognized components of the renin-angiotensin system: potential roles in cardiovascular and renal regulation.
      However, the capacity for AT2R reexpression is retained in the adult, because upregulation is a common response to circumstances of cardiovascular tissue damage, such as myocardial infarction, heart failure, and hypertension.
      • Thompson M.M.
      • Oyama T.T.
      • Kelly F.J.
      • et al.
      Activity and responsiveness of the renin-angiotensin system in the aging rat.
      • Jones E.S.
      • Vinh A.
      • McCarthy C.A.
      • et al.
      AT2 receptors: functional relevance in cardiovascular disease.
      • Widdop R.E.
      • Vinh A.
      • Henrion D.
      • et al.
      Vascular angiotensin AT2 receptors in hypertension and ageing.
      • Savoia C.
      • Touyz R.M.
      • Volpe M.
      • et al.
      Angiotensin type 2 receptor in resistance arteries of type 2 diabetic hypertensive patients.
      The only available studies on microvascular AT2R expression and action in humans demonstrate that AT2R expression can be induced chronically in hypertensive diabetic subjects by AT1R blockade and, under these circumstances, mediates vasodilation.
      • Thompson M.M.
      • Oyama T.T.
      • Kelly F.J.
      • et al.
      Activity and responsiveness of the renin-angiotensin system in the aging rat.
      • Savoia C.
      • Touyz R.M.
      • Volpe M.
      • et al.
      Angiotensin type 2 receptor in resistance arteries of type 2 diabetic hypertensive patients.
      However, the interpretation of these studies and their applicability in human studies is still an area of debate.
      There is evidence that an altered ratio between AT1R and AT2R levels may result in elevated blood pressure and induction of inflammation.
      • Warnholtz A.
      • Nickenig G.
      • Schulz E.
      • et al.
      Increased NADH-oxidase-mediated superoxide production in the early stages of atherosclerosis: evidence for involvement of the renin-angiotensin system.
      The contribution of changes in the expression of AT1R and AT2R to the increased production of inflammatory cytokines observed in older individuals is yet to be explored. It also seems that the use of AT1R blockade increases AT2R activity in vivo.
      • Weber M.A.
      Clinical experience with the angiotensin II receptor antagonist losartan. A preliminary report.
      • Guan H.
      • Cachofeiro V.
      • Pucci M.L.
      • et al.
      Nitric oxide and the depressor response to angiotensin blockade in hypertension.
      Beneficial actions of AT1R blockers on remodeling and cardiac fibrosis were completely abolished by simultaneous AT2R blockade, suggesting that such beneficial effects are because of AT2R activation rather than AT1R blockade.
      • Siragy H.M.
      • de Gasparo M.
      • Carey R.M.
      Angiotensin type 2 receptor mediates valsartan-induced hypotension in conscious rats.
      • Oishi Y.
      • Ozono R.
      • Yoshizumi M.
      • et al.
      AT2 receptor mediates the cardioprotective effects of AT1 receptor antagonist in post-myocardial infarction remodeling.
      • Carey R.M.
      • Howell N.L.
      • Jin X.H.
      • et al.
      Angiotensin type 2 receptor-mediated hypotension in angiotensin type-1 receptor-blocked rats.
      How aging might influence RAS is still largely unknown. Genetic and environmental factors may contribute
      • Staessen J.A.
      • Wang J.
      • Bianchi G.
      • et al.
      Essential hypertension.
      but fail to account entirely for any changes with age. There is evidence from human monozygotic twin studies that methylation patterns can change with aging.
      • Fraga M.F.
      • Ballestar E.
      • Paz M.F.
      • et al.
      Epigenetic differences arise during the lifetime of monozygotic twins.
      The process of aging and development is accompanied by selective methylation of genes that are not needed for function of the differentiated cell. Evidence from animal and human studies suggests that in utero expression of the angiotensin receptors is regulated by methylation of the angiotensin receptor genes.
      • Gilbert J.S.
      • Lang A.L.
      • Nijland M.J.
      Maternal nutrient restriction and the fetal left ventricle: decreased angiotensin receptor expression.
      • Bogdarina I.
      • Welham S.
      • King P.J.
      • et al.
      Epigenetic modification of the renin-angiotensin system in the fetal programming of hypertension.
      However, no studies are available on the effect of aging on the regulation of AT1R and AT2R and their genes in humans. Given the importance of these receptors in performing the major functions of RAS and the gap in knowledge related to how aging triggers and affects these systems, studies as proposed here may have important implications for human health.

      RAS and its role in chronic inflammation and frailty in older adults

      Inappropriate, chronic, low-grade inflammation is implicated in the pathogenesis of many common and disabling diseases in older adults. Most of these diseases are slowly progressive and have a clear association with advancing age.
      • Ershler W.B.
      • Keller E.T.
      Age-associated increased interleukin-6 gene expression, late-life diseases, and frailty.
      • Fujita J.
      • Tsujinaka T.
      • Ebisui C.
      • et al.
      Role of interleukin-6 in skeletal muscle protein breakdown and cathepsin activity in vivo.
      • Maggio M.
      • Guralnik J.M.
      • Longo D.L.
      • et al.
      Interleukin-6 in aging and chronic disease: a magnificent pathway.
      In addition, chronic inflammation is associated with functional decline, frailty, and increased mortality.
      • Fried L.P.
      • Tangen C.M.
      • Walston J.
      • et al.
      Frailty in older adults: evidence for a phenotype.
      • Walston J.
      • Fried L.P.
      Frailty and the older man.
      The clinical criteria for frailty include weight loss, low levels of activity, muscle weakness, exhaustion, and slow walking speed.
      • Fried L.P.
      • Tangen C.M.
      • Walston J.
      • et al.
      Frailty in older adults: evidence for a phenotype.
      The causes that trigger chronic inflammatory activation in older adults are likely heterogeneous and include multiple chronic disease states, redox imbalance, senescent cells, and increased body fat.
      • Chung H.Y.
      • Cheng K.Q.
      • Chung G.J.
      • Chung H.Y.
      • Sung B.
      • Jung K.J.
      • et al.
      The molecular inflammatory process in aging.
      • Kim H.J.
      • Jung K.J.
      • Yu B.P.
      • et al.
      Modulation of redox-sensitive transcription factors by calorie restriction during aging.
      • Ren J.L.
      • Pan J.S.
      • Lu Y.P.
      • et al.
      Inflammatory signaling and cellular senescence.
      • Sasaki M.
      • Ikeda H.
      • Sato Y.
      • et al.
      Proinflammatory cytokine-induced cellular senescence of biliary epithelial cells is mediated via oxidative stress and activation of ATM pathway: a culture study.
      These triggers act through nuclear factor κB signal transduction, which leads to increased expression of multiple inflammatory mediators including tumor necrosis factor (TNF) α, interleukin (IL) 1b, IL-6, cyclooxygenase 2, and inducible nitric oxide synthase.
      • Chung H.Y.
      • Cheng K.Q.
      • Chung G.J.
      • Chung H.Y.
      • Sung B.
      • Jung K.J.
      • et al.
      The molecular inflammatory process in aging.
      • Kim H.J.
      • Jung K.J.
      • Yu B.P.
      • et al.
      Modulation of redox-sensitive transcription factors by calorie restriction during aging.
      The inflammatory cytokine IL-6, total white blood cells, neutrophils, and monocytes have also been identified as significant correlates of frailty in older populations.
      • Leng S.X.
      • Xue Q.L.
      • Tian J.
      • et al.
      Inflammation and frailty in older women.
      • Walston J.
      • McBurnie M.A.
      • Newman A.
      • et al.
      Frailty and activation of the inflammation and coagulation systems with and without clinical comorbidities: results from the Cardiovascular Health Study.
      Although the cause cannot be proven from these studies, the consistent and reproducible associations between increased expression of markers of inflammation and frailty in older adults suggest that inflammatory pathways are more active in frail older adults than in nonfrail adults and that chronic inflammation worsens disease status, leading to muscle strength decline and stem cell failure.
      • Ershler W.B.
      • Keller E.T.
      Age-associated increased interleukin-6 gene expression, late-life diseases, and frailty.
      • Cohen H.J.
      • Harris T.
      • Pieper C.F.
      Coagulation and activation of inflammatory pathways in the development of functional decline and mortality in the elderly.
      Hence, chronic inflammation may play an important role in late life decline. Frailty status provides an important in vivo model for chronic inflammation and etiology of inflammation and for RAS change.
      Substantial evidence confirms the role of RAS in activation of inflammatory pathways. Most of the functions of Ang II are carried through AT1R. The role and biologic functions of AT2R are less studied. It has been reported that AT2R inhibits and antagonizes AT1R-mediated functions (see Table 1).
      • Hein L.
      • Barsh G.S.
      • Pratt R.E.
      • et al.
      Behavioural and cardiovascular effects of disrupting the angiotensin II type-2 receptor in mice.
      • Ichiki T.
      • Labosky P.A.
      • Shiota C.
      • et al.
      Effects on blood pressure and exploratory behaviour of mice lacking angiotensin II type-2 receptor.
      • Masaki H.
      • Kurihara T.
      • Yamaki A.
      • et al.
      Cardiac-specific overexpression of angiotensin II AT2 receptor causes attenuated response to AT1 receptor-mediated pressor and chronotropic effects.
      • AbdAlla S.
      • Lother H.
      • Abdel-tawab A.M.
      • et al.
      The angiotensin II AT2 receptor is an AT1 receptor antagonist.
      The activation of AT1R has a powerful proinflammatory effect.
      • Suzuki Y.
      • Ruiz-Ortega M.
      • Lorenzo O.
      • et al.
      Inflammation and angiotensin II.
      AT1R actions include induction of reactive oxygen species,
      • Nickenig G.
      • Harrison D.G.
      The AT(1)-type angiotensin receptor in oxidative stress and atherogenesis: part I: oxidative stress and atherogenesis.
      hypertrophy and apoptosis,
      • Bascands J.L.
      • Girolami J.P.
      • Troly M.
      • et al.
      Angiotensin II induces phenotype-dependent apoptosis in vascular smooth muscle cells.
      and stimulation of fibroblast proliferation and collagen synthesis.
      • Cipollone F.
      • Fazia M.
      • Iezzi A.
      • et al.
      Blockade of the angiotensin II type 1 receptor stabilizes atherosclerotic plaques in humans by inhibiting prostaglandin E2-dependent matrix metalloproteinase activity.
      AT1R antagonists exert cardiovascular protection, in part through their vascular antiinflammatory effects.
      • Navalkar S.
      • Parthasarathy S.
      • Santanam N.
      • et al.
      Irbesartan, an angiotensin type 1 receptor inhibitor, regulates markers of inflammation in patients with premature atherosclerosis.
      AT1R activation affects cytokine levels by increasing IL-6,
      • Schieffer B.
      • Schieffer E.
      • Hilfiker-Kleiner D.
      • et al.
      Expression of angiotensin II and interleukin 6 in human coronary atherosclerotic plaques: potential implications for inflammation and plaque instability.
      TNF-α,
      • Siragy H.M.
      • Awad A.
      • Abadir P.
      • et al.
      The angiotensin II type 1 receptor mediates renal interstitial content of tumor necrosis factor-alpha in diabetic rats.
      • Tsutamoto T.
      • Wada A.
      • Maeda K.
      • et al.
      Angiotensin II type 1 receptor antagonist decreases plasma levels of tumor necrosis factor alpha, interleukin-6 and soluble adhesion molecules in patients with chronic heart failure.
      • Beasley D.
      Phorbol ester and interleukin-1 induce interleukin-6 gene expression in vascular smooth muscle cells via independent pathways.
      • Han Y.
      • Runge M.S.
      • Brasier A.R.
      Angiotensin II induces interleukin-6 transcription in vascular smooth muscle cells through pleiotropic activation of nuclear factor-kappa B transcription factors.
      • Hahn A.W.
      • Jonas U.
      • Buhler F.R.
      • et al.
      Activation of human peripheral monocytes by angiotensin II.
      and interferon gamma production
      • Weidanz J.A.
      • Jacobson L.M.
      • Muehrer R.J.
      • et al.
      ATR blockade reduces IFN-gamma production in lymphocytes in vivo and in vitro.
      and decreasing nitric oxide and cyclic GMP production.
      • Abadir P.M.
      • Carey R.M.
      • Siragy H.M.
      Angiotensin AT2 receptors directly stimulate renal nitric oxide in bradykinin B2-receptor-null mice.
      AT1R expression seems to be limiting for the effect of Ang II. Upregulation of AT1R expression enhances the action of Ang II in vitro as well as in vivo.
      • Nickenig G.
      • Sachinidis A.
      • Michaelsen F.
      • et al.
      Upregulation of vascular angiotensin II receptor gene expression by low-density lipoprotein in vascular smooth muscle cells.
      The molecular mechanisms through which angiotensin receptors manipulate cytokines production and chronic inflammation remain unclear (Fig. 2). Ang II activates the signal transducer and activator of transcription proteins 3 (STAT3).
      • Omura T.
      • Yoshiyama M.
      • Takeuchi K.
      • et al.
      Angiotensin blockade inhibits SIF DNA binding activities via STAT3 after myocardial infarction.
      STAT3 is a key signal transduction protein that mediates cell differentiation, proliferation, apoptosis, inflammation, and tumor cell evasion of the immune system.
      • Costantino L.
      • Barlocco D.
      STAT 3 as a target for cancer drug discovery.
      Binding sites have been identified for STAT3 within the promoter region of TNF-α.
      • Chappell V.L.
      • Le L.X.
      • LaGrone L.
      • et al.
      Stat proteins play a role in tumor necrosis factor alpha gene expression.
      Mutation of the 3 base pairs of the STAT3 binding site had considerable effects on the promoter activity, demonstrating that STAT3 upregulates TNF-α expression.
      • Chappell V.L.
      • Le L.X.
      • LaGrone L.
      • et al.
      Stat proteins play a role in tumor necrosis factor alpha gene expression.
      Figure thumbnail gr2
      Fig. 2A hypothetical model for changes in the angiotensin receptors with aging and/or frailty, resulting in increased production of cytokines, pathologic changes, and development/worsening of diseases. Note that with robust aging, the balance is maintained between the angiotensin receptors despite decrease in both AT1R (blue circles) and AT2R (red circles). With development of frailty that balance is tipped toward more expression of AT1R and less AT2R predisposing to increased cytokine production, which further widens the gap by increasing the expression of AT1R and reducing expression of AT2R. ACEi, ACE inhibitor; ARBs, Ang II receptor blockers.
      To date, few have studies examined the influence of increased inflammation on RAS. In animal models IL-6, released locally, contributes substantially to the vascular dysfunction produced by Ang II.
      • Schrader L.I.
      • Kinzenbaw D.A.
      • Johnson A.W.
      • et al.
      IL-6 deficiency protects against angiotensin II induced endothelial dysfunction and hypertrophy.
      Treatment of mice with IL-6 for 18 days increased vascular AT1R expression.
      • Wassmann S.
      • Stumpf M.
      • Strehlow K.
      • et al.
      Interleukin-6 induces oxidative stress and endothelial dysfunction by overexpression of the angiotensin II type 1 receptor.
      Because the upregulation of AT1R expression in vitro and in vivo is involved in IL-6–induced propagation of oxidative stress and endothelial dysfunction, the interaction of the proinflammatory cytokine IL-6 with RAS may represent an important pathogenetic mechanism in inflammatory diseases in older population.

      Aging RAS—disease interactions culminating in the development of frailty

      RAS contributes to the pathogenesis of several human diseases that have a clear association with advanced aging, including hypertension, myocardial infarction, congestive heart failure, stroke, atrial fibrillation, coronary artery disease, diabetes, and nephropathy. Large population studies have clearly demonstrated that both ACE inhibitors and Ang II receptor blockers (ARB) have been shown to be effective in preventing or regressing some of the age-associated effects of these diseases in humans and animals.
      • Burrell L.M.
      • Johnston C.I.
      Angiotensin II receptor antagonists. Potential in elderly patients with cardiovascular disease.
      • Basso N.
      • Paglia N.
      • Stella I.
      • et al.
      Protective effect of the inhibition of the renin-angiotensin system on aging.
      • Schmieder R.E.
      • Hilgers K.F.
      • Schlaich M.P.
      • et al.
      Renin-angiotensin system and cardiovascular risk.

      Myocardial Infarction

      The expression of both AT1R and AT2R is upregulated in cardiac tissue after myocardial infarction. Induction of myocardial infarction in mice lacking AT2Rs caused significant damage to the heart as compared with the wild-type mice,
      • Oishi Y.
      • Ozono R.
      • Yoshizumi M.
      • et al.
      AT2 receptor mediates the cardioprotective effects of AT1 receptor antagonist in post-myocardial infarction remodeling.
      • Xu J.
      • Carretero O.A.
      • Liu Y.H.
      • et al.
      Role of AT2 receptors in the cardioprotective effect of AT1 antagonists in mice.
      demonstrating that the beneficial effects of AT1R blockade after myocardial infarction may be partially mediated by the AT2R.
      • Jugdutt B.I.
      • Menon V.
      AT2 receptor and apoptosis during AT1 receptor blockade in reperfused myocardial infarction in the rat.

      Left Ventricular Hypertrophy

      The extent of left ventricular hypertrophy is aggravated by the activity of RAS,
      • Mancia G.
      • Zanchetti A.
      • Agabiti-Rosei E.
      • et al.
      Ambulatory blood pressure is superior to clinic blood pressure in predicting treatment-induced regression of left ventricular hypertrophy. SAMPLE Study Group. Study on Ambulatory Monitoring of Blood Pressure and Lisinopril Evaluation.
      • Schmieder R.E.
      The role of non-haemodynamic factors of the genesis of LVH.
      independent of, and in addition to, the effect of elevated blood pressure.
      • Mazzolai L.
      • Nussberger J.
      • Aubert J.F.
      • et al.
      Blood pressure-independent cardiac hypertrophy induced by locally activated renin-angiotensin system.
      • Mazzolai L.
      • Pedrazzini T.
      • Nicoud F.
      • et al.
      Increased cardiac angiotensin II levels induce right and left ventricular hypertrophy in normotensive mice.
      At similar blood pressure levels, incidence of left ventricular hypertrophy was greater with the ARB losartan than with the β-blocker atenolol throughout a follow-up of 5 years.
      • Dahlof B.
      • Devereux R.B.
      • Kjeldsen S.E.
      • et al.
      Cardiovascular morbidity and mortality in the losartan intervention for endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol.
      • Lindholm L.H.
      • Ibsen H.
      • Dahlof B.
      • et al.
      Cardiovascular morbidity and mortality in patients with diabetes in the losartan intervention for endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol.
      • Devereux R.B.
      • Dahlof B.
      • Gerdts E.
      • et al.
      Regression of hypertensive left ventricular hypertrophy by losartan compared with atenolol: the losartan intervention for endpoint reduction in hypertension (LIFE) trial.

      Atrial Fibrillation

      Treatment with ARB has been shown to reduce the incidence of atrial fibrillation by 21% in hypertensive patients.
      • Wachtell K.
      • Hornestam B.
      • Lehto M.
      • et al.
      Cardiovascular morbidity and mortality in hypertensive patients with a history of atrial fibrillation: the losartan intervention for end point reduction in hypertension (LIFE) study.
      • Wachtell K.
      • Lehto M.
      • Gerdts E.
      • et al.
      Angiotensin II receptor blockade reduces new-onset atrial fibrillation and subsequent stroke compared to atenolol: the losartan intervention for end point reduction in hypertension (LIFE) study.
      • Schmieder R.E.
      • Kjeldsen S.E.
      • Julius S.
      • et al.
      Reduced incidence of new-onset atrial fibrillation with angiotensin II receptor blockade: the VALUE trial.
      The mechanism underlying this protective effect is related to the prevention of left atrial dilation and atrial fibrosis and to the reduction of conduction velocity.
      • Schmieder R.E.
      • Hilgers K.F.
      • Schlaich M.P.
      • et al.
      Renin-angiotensin system and cardiovascular risk.

      Stroke

      Several clinical trials have demonstrated a prominent effect of ARB treatment on the prevention of stroke.
      • Dahlof B.
      • Devereux R.B.
      • Kjeldsen S.E.
      • et al.
      Cardiovascular morbidity and mortality in the losartan intervention for endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol.
      • Lithell H.
      • Hansson L.
      • Skoog I.
      • et al.
      The Study on COgnition and Prognosis in the Elderly (SCOPE); outcomes in patients not receiving add-on therapy after randomization.
      • Lithell H.
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      • Skoog I.
      • et al.
      The Study on COgnition and Prognosis in the Elderly (SCOPE): principal results of a randomized double-blind intervention trial.
      • Skoog I.
      • Lithell H.
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      Effect of baseline cognitive function and antihypertensive treatment on cognitive and cardiovascular outcomes: Study on COgnition and Prognosis in the Elderly (SCOPE).
      • Chrysant S.G.
      Possible pathophysiologic mechanisms supporting the superior stroke protection of angiotensin receptor blockers compared to angiotensin-converting enzyme inhibitors: clinical and experimental evidence.
      At a similar blood pressure, control ARB had an additional 25% reduction in strokes compared with those on a β-blocker.
      • Dahlof B.
      • Devereux R.B.
      • Kjeldsen S.E.
      • et al.
      Cardiovascular morbidity and mortality in the losartan intervention for endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol.
      A similar result was also observed in the Study on COgnition and Prognosis in the Elderly (SCOPE).

      Atherosclerosis

      Activation of RAS through AT1R (1) induces vasoconstriction and formation of extracellular matrix and matrix metalloproteinases, (2) enhances migration and proliferation of vascular smooth muscle cells, (3) increases synthesis of plasminogen activator inhibitor (PAI-1), and (4) stimulates release of proinflammatory cytokines, including IL-6 and TNF-α.
      • Farmer J.A.
      • Torre-Amione G.
      The renin angiotensin system as a risk factor for coronary artery disease.

      Diabetes

      In a meta-analysis, treatment with ARBs has been shown to reduce the incidence of diabetes mellitus by 23%, regardless of the presence of cardiovascular disease.
      • Kjeldsen S.E.
      • Julius S.
      • Mancia G.
      • et al.
      Effects of valsartan compared to amlodipine on preventing type 2 diabetes in high-risk hypertensive patients: the VALUE trial.
      • Scheen A.J.
      Renin-angiotensin system inhibition prevents type 2 diabetes mellitus. Part 1. A meta-analysis of randomised clinical trials.
      • Gillespie E.L.
      • White C.M.
      • Kardas M.
      • et al.
      The impact of ACE inhibitors or angiotensin II type 1 receptor blockers on the development of new-onset type 2 diabetes.

      Renal Damage

      Treatment with ARBs improves renal damage in patients with and without diabetes.
      • Parving H.H.
      • Lehnert H.
      • Brochner-Mortensen J.
      • et al.
      The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes.
      • Lewis E.J.
      • Lewis J.B.
      Treatment of diabetic nephropathy with angiotensin II receptor antagonist.
      • Lewis E.J.
      • Hunsicker L.G.
      • Clarke W.R.
      • et al.
      Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes.

      Dementia

      Hypertension induces damage to brain microcirculation, which contributes to the development of dementia. However, evidence on the benefit of RAS blockade on cognitive function has been controversial. The role of angiotensin IV on cognitive function has been described.
      • Gard P.R.
      Cognitive-enhancing effects of angiotensin IV.
      • Wright J.W.
      • Harding J.W.
      The brain RAS and Alzheimer’s disease.
      • Wright J.W.
      • Harding J.W.
      The angiotensin AT4 receptor subtype as a target for the treatment of memory dysfunction associated with Alzheimer’s disease.

      Muscle Strength

      A fully functional RAS exists in the skeletal muscle microvasculature. Studies have also confirmed that skeletal muscles generate Ang II locally.
      • Unger T.
      • Gohlke P.
      • Paul M.
      • et al.
      Tissue renin-angiotensin systems: fact or fiction?.
      • Atlas S.A.
      The renin-angiotensin system revisited: classical and nonclassical pathway of angiotensin formation.
      • Danser A.H.
      Local renin-angiotensin systems.
      The polymorphism of the ACE gene is an important factor in determining physical performance.
      • Montgomery H.
      • Clarkson P.
      • Barnard M.
      • et al.
      Angiotensin-converting-enzyme gene insertion/deletion polymorphism and response to physical training.
      However, clinical studies are needed to confirm a role for blockade of RAS in muscle function.

      Osteoporosis, Fracture Risk, and Bone Marrow Density

      Clinical studies indicate a possible role of RAS in bone metabolism and fracture risk. Patients treated with an ACE inhibitor showed an increased bone mineral density and a reduced fracture risk.
      • Perez-Castrillon J.L.
      • Justo I.
      • Silva J.
      • et al.
      Relationship between bone mineral density and angiotensin converting enzyme polymorphism in hypertensive postmenopausal women.
      • Perez-Castrillon J.L.
      • Silva J.
      • Justo I.
      • et al.
      Effect of quinapril, quinapril-hydrochlorothiazide, and enalapril on the bone mass of hypertensive subjects: relationship with angiotensin converting enzyme polymorphisms.
      • Rejnmark L.
      • Vestergaard P.
      • Mosekilde L.
      Treatment with beta-blockers, ACE inhibitors, and calcium-channel blockers is associated with a reduced fracture risk: a nationwide case-control study.
      In addition, individuals with decreased ACE activity have a higher bone marrow density than individuals with increased ACE activity.
      • Woods D.
      • Onambele G.
      • Woledge R.
      • et al.
      Angiotensin-I converting enzyme genotype-dependent benefit from hormone replacement therapy in isometric muscle strength and bone mineral density.

      Summary

      RAS plays a broad role in vascular regulation, inflammation, oxidative stress, and apoptosis. Each of these molecular realms has been hypothesized to influence the aging phenotype. RAS also clearly influences multiple disease states with increasing age, and pharmaceuticals targeting these pathways are now a mainstay of treatment of many older adults. RAS blockade exerts potent antiatherosclerotic, antihypertensive, antiinflammatory, antiproliferative, and oxidative stress–lowering properties. Given the influence of RAS on frailty-related diseases and traits, and the age-related changes in this system that seem to accelerate these conditions, further evaluation on the causes, multisystemic interactions, and intervention development on RAS regulation is indicated.

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