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Division of Geriatric Medicine and Gerontology, Johns Hopkins University School of Medicine, John R. Burton Pavilion, 5505 Hopkins Bayview Circle, Baltimore, MD 21224, USA
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.
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).
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,
Hence, AT2R may play an important role in vascular aging.
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.
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.
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.
Recent progress in signal transduction research of the angiotensin II type-1 receptor: protein kinases, vascular dysfunction and structural requirement.
Curr Med Chem Cardiovasc Hematol Agents.2005; 3: 305-322
These intracellular signals have been linked to vascular remodeling through induction of hypertrophy, hyperplasia, and migration of vascular smooth muscle cells.
Recent progress in signal transduction research of the angiotensin II type-1 receptor: protein kinases, vascular dysfunction and structural requirement.
Curr Med Chem Cardiovasc Hematol Agents.2005; 3: 305-322
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.
Angiotensin II type 2 receptors mediate inhibition of mitogen-activated protein kinase cascade and functional activation of SHP-1 tyrosine phosphatase.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
The inflammatory cytokine IL-6, total white blood cells, neutrophils, and monocytes have also been identified as significant correlates of frailty in older populations.
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.
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).
Blockade of the angiotensin II type 1 receptor stabilizes atherosclerotic plaques in humans by inhibiting prostaglandin E2-dependent matrix metalloproteinase activity.
Expression of angiotensin II and interleukin 6 in human coronary atherosclerotic plaques: potential implications for inflammation and plaque instability.
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.
Angiotensin II induces interleukin-6 transcription in vascular smooth muscle cells through pleiotropic activation of nuclear factor-kappa B transcription factors.
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.
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).
STAT3 is a key signal transduction protein that mediates cell differentiation, proliferation, apoptosis, inflammation, and tumor cell evasion of the immune system.
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.
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.
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.
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,
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.
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.
Cardiovascular morbidity and mortality in the losartan intervention for endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol.
Cardiovascular morbidity and mortality in patients with diabetes in the losartan intervention for endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol.
Regression of hypertensive left ventricular hypertrophy by losartan compared with atenolol: the losartan intervention for endpoint reduction in hypertension (LIFE) trial.
Cardiovascular morbidity and mortality in hypertensive patients with a history of atrial fibrillation: the losartan intervention for end point reduction in hypertension (LIFE) study.
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.
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.
Cardiovascular morbidity and mortality in the losartan intervention for endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol.
Effect of baseline cognitive function and antihypertensive treatment on cognitive and cardiovascular outcomes: Study on COgnition and Prognosis in the Elderly (SCOPE).
Possible pathophysiologic mechanisms supporting the superior stroke protection of angiotensin receptor blockers compared to angiotensin-converting enzyme inhibitors: clinical and experimental evidence.
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.
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.
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.
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.
Effect of quinapril, quinapril-hydrochlorothiazide, and enalapril on the bone mass of hypertensive subjects: relationship with angiotensin converting enzyme polymorphisms.
Treatment with beta-blockers, ACE inhibitors, and calcium-channel blockers is associated with a reduced fracture risk: a nationwide case-control study.
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.
References
Wang M.
Takagi G.
Asai K.
et al.
Aging increases aortic MMP-2 activity and angiotensin II in nonhuman primates.
Recent progress in signal transduction research of the angiotensin II type-1 receptor: protein kinases, vascular dysfunction and structural requirement.
Curr Med Chem Cardiovasc Hematol Agents.2005; 3: 305-322
Angiotensin II type 2 receptors mediate inhibition of mitogen-activated protein kinase cascade and functional activation of SHP-1 tyrosine phosphatase.
Increased NADH-oxidase-mediated superoxide production in the early stages of atherosclerosis: evidence for involvement of the renin-angiotensin system.
Proinflammatory cytokine-induced cellular senescence of biliary epithelial cells is mediated via oxidative stress and activation of ATM pathway: a culture study.
Frailty and activation of the inflammation and coagulation systems with and without clinical comorbidities: results from the Cardiovascular Health Study.
Blockade of the angiotensin II type 1 receptor stabilizes atherosclerotic plaques in humans by inhibiting prostaglandin E2-dependent matrix metalloproteinase activity.
Expression of angiotensin II and interleukin 6 in human coronary atherosclerotic plaques: potential implications for inflammation and plaque instability.
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.
Angiotensin II induces interleukin-6 transcription in vascular smooth muscle cells through pleiotropic activation of nuclear factor-kappa B transcription factors.
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.
Cardiovascular morbidity and mortality in the losartan intervention for endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol.
Cardiovascular morbidity and mortality in patients with diabetes in the losartan intervention for endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol.
Regression of hypertensive left ventricular hypertrophy by losartan compared with atenolol: the losartan intervention for endpoint reduction in hypertension (LIFE) trial.
Cardiovascular morbidity and mortality in hypertensive patients with a history of atrial fibrillation: the losartan intervention for end point reduction in hypertension (LIFE) study.
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.
Effect of baseline cognitive function and antihypertensive treatment on cognitive and cardiovascular outcomes: Study on COgnition and Prognosis in the Elderly (SCOPE).
Possible pathophysiologic mechanisms supporting the superior stroke protection of angiotensin receptor blockers compared to angiotensin-converting enzyme inhibitors: clinical and experimental evidence.
Effect of quinapril, quinapril-hydrochlorothiazide, and enalapril on the bone mass of hypertensive subjects: relationship with angiotensin converting enzyme polymorphisms.
Treatment with beta-blockers, ACE inhibitors, and calcium-channel blockers is associated with a reduced fracture risk: a nationwide case-control study.