Involvement of AGE and Its Receptors in the Pathogenesis of Hypertension in Elderly People and Its Treatment

Abstract

Both systolic and diastolic blood pressures increase with age up to 50 to 60 years of age. After 60 years of age systolic pressure rises to 84 years of age but diastolic pressure remains stable or even decreases. In the oldest age group (85–99 years), the systolic blood pressure (SBP) is high and diastolic pressure (DBP) is the lowest. Seventy percent of people older than 65 years are hypertensive. This paper deals with the role of advanced glycation end products (AGE) and its cell receptor (RAGE) and soluble receptor (sRAGE) in the development of hypertension in the elderly population. Plasma/serum levels of AGE are higher in older people as compared with younger people. Serum levels of AGE are positively correlated with age, arterial stiffness, and hypertension. Low serum levels of sRAGE are associated with arterial stiffness and hypertension. Levels of sRAGE are negatively correlated with age and blood pressure. Levels of sRAGE are lower in patients with arterial stiffness and hypertension than patients with high levels of sRAGE. AGE could induce hypertension through numerous mechanisms including, cross-linking with collagen, reduction of nitric oxide, increased expression of endothelin-1, and transforming growth factor-β (TGF-β). Interaction of AGE with RAGE could produce hypertension through the generation of reactive oxygen species, increased sympathetic activity, activation of nuclear factor-kB, and increased expression of cytokines, cell adhesion molecules, and TGF- β. In conclusion, the AGE–RAGE axis could be involved in hypertension in elderly people. Treatment for hypertension in elderly people should be targeted at reduction of AGE levels in the body, prevention of AGE formation, degradation of AGE in vivo, downregulation of RAGE expression, blockade of AGE–RAGE interaction, upregulation of sRAGE expression, and use of antioxidants.

Hypertension (HTN) is defined as systolic blood pressure ≥130mm Hg or diastolic pressure ≥80mm Hg. ¹ Twenty-four percent of males and 23% of females aged 20 to 79 have hypertension which increases significantly with age. ² DeGuire et al have reported that the prevalence of HTN increases with age, the increase is 71% in males and 69% in females with hypertension threshold of 140/90mm Hg in the age group of 70 to 79 years, and 25% in male and 21% in female in the age group of 40 to 59%. ² Seventy percent of patients older than 65 years are hypertensive. ^{3 4} Prevalence of hypertension in people in the age group of 65 to 94 years was reported to be 73.8% in males and 73% in females. ⁵ These investigators also reported that the frequency of HTN gradually increases with increasing age up to 84 years of age, then declines with increasing age. In the oldest age group (85–99 years), the systolic blood pressure (SBP) is high and diastolic pressure (DBP) is the lowest. Incidence of HTN increases with age. ⁶ The mortality risk in older people is increased by 100 folds for stroke and chronic lung disease and 90 folds for heart diseases, pneumonia, and influenza, and 40 folds for cancers as compared with people of 25 to 44 years of age. ⁷ Pathophysiology of hypertension includes arterial stiffness, neurohumoral, autonomic dysregulation, and aging of the kidney. ^{8 9} Advanced glycation end (AGE) products and its cell receptor RAGE (receptor for AGE) have been implicated in the pathophysiology of numerous diseases including, end-stage renal disease, ¹⁰ restenosis following percutaneous coronary intervention, ¹¹ hyperthyroidism, ¹² and aortic aneurysm. ¹³ Very little attention has been given on the role of the AGE–RAGE axis in the pathophysiology of hypertension in elderly people. This review focuses on the changes in the blood pressures during aging, AGE–RAGE axis, AGE–RAGE stress, serum/plasma levels of AGE and soluble receptor for AGE (sRAGE), mechanism of AGE–RAGE axis in the development of elderly hypertension, and management of elderly hypertension in brief.

Blood Pressure Changes with Aging

Some of the parameters for hypertension have been described by Prasad et al. ¹⁴ Systolic blood pressure (SBP) increases with increases in stroke volume, peak systolic ejection rate, and increase in the arterial compliance. Systolic blood pressure rises approximately 1mm Hg/year from 110mm Hg at the age of 15 years. This could be due to a progressive reduction in compliance of the artery. Diastolic pressure rises approximately 0.4mm Hg/year after the age of 15 years. And this may be due to elevation of total peripheral resistance, heart rate, systolic pressure, and arterial elastic recoil. Loss of elastic recoil in the arterial wall with aging decreases diastolic pressure. Wide pulse pressure (PP) which is the difference between systolic and diastolic pressure reflects systolic hypertension and an increased central arterial stiffness.

The major cause of elevated systolic blood pressure and pulse pressure, and lower diastolic pressure in older people is the arterial stiffness. These age-related changes in BP are powerful determinants of major cardiovascular disease events and all-cause mortality. ^{15 16} Both systolic and diastolic pressures increase up to the age of 50 to 60 years. After the age of 60 years, systolic pressure increases with age but diastolic pressure remains stable or even decreases. These changes are because of progressive increases in stiffness in the arterial wall. ^{15 16}

Mechanism of Hypertension in Elderly People

The mechanism of hypertension in elderly adults includes mechanical hemodynamic changes, arterial stiffness, neurohumoral and autonomic dysregulation, and aging of the kidney. ⁸ Arterial stiffness is due to various changes in the arterial wall including wall hypertrophy; calcification; atheromatous lesions; and changes in the extracellular matrix such as increases in collagen and fibronectin, fragmentation, and disorganization of elastin. ^{17 18 19 20} Arterial stiffness is due to thickening of the arterial wall, increased collagen content, cross-linking and increased elastin fragmentation, and decreased elastin content. Aging is characterized by decreased turnover of collagen and elastin and increased cross-links. Elastic fibers undergo lysis and disorganization subsequent to their replacement with collagen and other matrix components resulting in loss of elasticity and an increase in stiffness. ²¹ In experimental rat model, it has been shown that angiotensin II (Ang II) produces structural, biochemical, and functional changes in aging. ²² The above investigators have shown that Ang II increases matrix-metalloproteinase (MMP)-2 and transforming growth factor-β1 (TGF-β1), causing both structural and molecular changes in aging arteries. Upregulation of MMPs may be involved in aging-associated elastin fragmentation and collagen deposition. ²³

There is an elevation of endothelin-1 (vasoconstrictor), and a decrease in the bioavailability of nitric oxide (NO) a vasodilator in elderly adults. ²⁴ Aging-related endothelial dysfunction and resultant vascular remodeling and stiffening could be due to decreased NO bioavailability. There is endothelial NO-synthase dysfunction and endothelial NO synthase uncoupling. ^{25 26} There is a decline in renin–angiotensin–aldosterone system. ²⁷ Production of superoxide anion in blood vessels and the presence of oxidative stress prior to the elevation of blood pressure may contribute to hypertension. ^{28 29} Superoxide anion and hydrogen peroxide (H ₂ O ₂ ) concentration in vascular smooth muscle cells are elevated in patients with essential hypertension. ³⁰ Oxidative stress has been implicated in hypertension. ^{31 32} Superoxide anion ³³ and H ₂ O ₂ ³⁴ produce contraction of isolated rabbit aorta. Baroreceptor reflex sensitivity is reduced with aging. ³⁵ The activity of the sympathetic nervous system is increased with aging. ³⁶ Aging increases the sensitivity in the kidney which induces vasoconstriction and vascular resistance. ³⁷

In summary, hypertension in elderly people could be due to arterial stiffness, reduction in NO production and baroreceptor reflex sensitivity, increase in endothelin-1 levels, the activity of the sympathetic nervous system, and oxidative stress.

AGE–RAGE Axis and AGE–RAGE Stress

Nonenzymatic interaction of reducing sugars (Glucose, fructose, maltose, and lactose) with proteins, lipids, and nucleic acids results in the formation of heterogenous group of irreversible adducts, called AGE products. ^{38 39} AGE includes four important compounds: N€-carboxymethyl-lysine (CML), N€-carboxyethyl-lysine (CEL), pentosidine, and pyrraline. AGE interacts with three main receptors: full-length multiligand cell receptor RAGE (receptor for AGE), C-truncated RAGE which has two isoforms, cleaved RAGE (cRAGE), and endogenous secretory RAGE (esRAGE). cRAGE is proteolytically cleaved from full-length RAGE, ⁴⁰ while esRAGE is formed from alternative splicing of mRNA of full-length RAGE. ⁴¹ sRAGE is composed of both cRAGE and esRAGE. Serum levels of esRAGE are 20 to 30% of the serum levels of sRAGE. ^{10 42} sRAGE and esRAGE lack cytosolic and transmembrane domain and circulate in the blood while RAGE is cell-bound. AGE–RAGE axis comprises of AGE, RAGE, and sRAGE. AGE interacts with RAGE and generates ROS ⁴³ which activates NF-kB. ⁴⁴ Activated NF-kB in turn activates numerous proinflammatory genes of cytokines (tumor necrosis factor-α [TNF-α], interleukin [IL]-1, IL-2, IL-6, IL-8, and IL-9). ^{45 46} Nuclear factor (NF)-kB increases the production of MMPs. ⁴⁷ Low levels of sRAGE have been reported to elevate the levels of cytokines that in turn increase the levels of MMPs in patients with aortic aneurysms. ¹³ AGE has been reported to enhance the activity of MMP-2 and ROS generation. ⁴⁸ Proinflammatory cytokines upregulate nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase ⁴⁹ and generate ROS. ⁵⁰

Interaction of AGE with RAGE increases the expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin through NF-kB. ⁵¹ AGE increases the expression of monocyte chemoattractant protein-1 (MCP-1) and vascular endothelial growth factor in human-cultured mesangial cells. ⁵² Expression and secretion of granulocyte macrophage-colony stimulating factor (GM-CSF) by macrophages is enhanced with AGE. ⁵³ AGE–RAGE binding in smooth muscle cells enhances chemotactic migration, cellular proliferation and fibrinogen generation. ⁵⁴ AGE–RAGE interaction enhances the expression of insulin-like growth factor (IGF-1) and platelet-derived growth factor (PDGF). ^{55 56} AGE increases the expression of TGF-β. ⁵⁷ AGE increases the synthesis of extracellular matrix ⁵⁸ and cross-binds with collagen. ⁵⁹ AGE reduces nitric oxide (NO) production. ⁶⁰ AGE quenches NO. ⁶¹ Matrix-bound AGE decreases NO production, ⁶² decreases the half-life of nitric oxide synthase, ⁶³ quenches and inactivates NO, ⁶⁴ and inhibits the antiproliferative activity of NO. ⁶⁵ Matrix-bound AGE increases the expression of endothelin-1. ⁶⁶

Interaction of sRAGE or esRAGE with AGE does not activate intracellular signaling. ⁶⁷ sRAGE and esRAGE act as a protective endogenous decoy for RAGE by binding with AGE. ^{68 69} sRAGE and esRAGE protect the body from the adverse effects of AGE–RAGE interaction.

Prasad and Mishra ⁷⁰ have coined three terminologies, stressors (AGE and RAGE), antistressors (sRAGE and enzymatic- and receptor-mediated degraders of AGE), and AGE–RAGE stress. AGE–RAGE stress has been coined as a shift in the balance between stressors and antistressors in favor of stressors. They have developed equations for the assessment of AGE–RAGE stress and have suggested that the ratio of AGE/sRAGE is a simple and feasible measure of AGE–RAGE stress. A high-ratio indicates the presence of AGE–RAGE stress, suggesting the presence of disease and progression of the disease.

Serum/Plasma Levels of AGE in Elderly People

Plasma levels of AGEs have been reported to be higher in hypertensive patients than in normotensive patients (7.84±0.94 vs 2.97±0.94 µg/mL). ⁷¹ They also showed that aortic stiffness was strongly associated with the plasma levels of AGEs, CML, and CEL in hypertensive patients but not in normotensive patients. This association was not dependent on age. Plasma levels of methyl glyoxal (MG), a precursor of AGE, were elevated in spontaneous hypertensive rats as compared with normotensive Wistar–Kyoto rats. ⁷² Uribarri et al ⁷³ have reported that serum levels of CML and MG were higher in patients aged 60 to 80 years than in patients aged 18 to 45 years.

Serum levels of CML and MG were reported to be higher in older patients compared with younger patients. ⁷⁴ They also reported that serum levels of CML positively correlated with age and oxidative stress. Elevated serum and plasma AGEs are associated with increased arterial stiffness. ⁷⁵ In patients aged between 26 and 93 years, elevated serum levels of CML were associated with increased arterial stiffness. ⁷⁶ Semba et al ⁷⁷ have reported that elevated serum levels of CML in patients aged 70 to 79 years were associated with arterial stiffness and hypertension. Log10 CML was significantly positively correlated with age in children of 11 to 15 years of age. ⁷⁸ Aging correlates with increased formation and accumulation of AGE. ⁷⁹ Hypertensive patients aged 51 to 66 years with albuminuria had higher serum AGE (2.15 µg/mL) as compared with those without albuminuria (1.71 µg/mL). ⁸⁰ In summary, plasma/serum levels of AGE are elevated in elderly people, and there is a positive significant correlation between age and AGE. In addition, there is a positive correlation between the levels of AGE and arterial stiffness and hypertension.

Serum/Plasma Levels of sRAGE in Elderly People

The serum levels of sRAGE have been shown to be lower in nondiabetic hypertensive patients compared with nonhypertensive patients. ⁸¹ They also reported that low serum levels of sRAGE were independently associated with increased arterial stiffness in a general population. Geroldi et al ⁸² reported that the plasma levels of sRAGE were lower median of 1,206 (879–1,658) pg/mL in patients with essential hypertension than in normotensive control patients median of 1,359 (999–2,198) pg/mL with a similar age group(50±10 or 49±10 years) Plasma level of sRAGE in hypertension was inversely associated with pulse pressure. ⁸² Serum levels of sRAGE were lower in patients with essential hypertension. ⁸³ Serum sRAGE levels were negatively correlated with age and systolic and diastolic blood pressures. ⁸⁴ The patient's age in this study varied from 30 to 83 years. Hypertensive patients aged 51 to 66 years with albuminuria had lower sRAGE (424.5 pg/mL) than those without albuminuria (492.5 pg/mL). ⁸⁰ Dimitriadis et al ⁸⁵ have reported that sRAGE levels were lower in patients with arterial stiffness in essential hypertension than in patients with high s RAGE. ⁸⁵ Patients with low compared with high sRAGE had greater systolic pressure. ⁸⁵

AGE–RAGE Stress in Hypertensive Patients

Hypertensive patients with albuminuria had increased AGE–RAGE stress (AGE/sRAGE; 3.79) as compared with patients without albuminuria (3.29). ⁸⁰

Mechanism of AGE–RAGE Axis-Induced Hypertension in Elderly

It has been established that plasma/serum levels of AGE are elevated in elderly people, and there is a significant positive correlation between age and levels of AGE and hypertension.

AGE could increase hypertension through nonreceptor and receptor-mediated mechanisms.

Non–Receptor-Dependent Mechanisms of AGE-Induced Hypertension

AGE Could induce hypertension through numerous mechanisms including cross-linking with protein, ⁵⁹ reduction of NO production, ⁶⁰ increasing the synthesis of extracellular matrix, ⁵⁸ cross-binding with collagen, ⁵⁹ endothelin-1 expression, and expression of TGF-β. ⁵⁷

AGE Cross-Link and Hypertension

AGE combines with long-lived proteins collagen and elastin and accumulates gradually in life. ²² Long-lived protein (collagen) undergoes continued cross-linking with AGE during aging. ³⁹ Age-associated increases in the stiffness in blood vessels occur with AGE cross-links. ⁸⁶ Vascular stiffness in aging has been described in detail by Vatner et al. ¹⁹ The number of elastic fibers and smooth muscle cells in tunica media decreases but collagen fibers increase with aging. ²⁰ There is a correlation between AGE accumulation and aortic stiffness in the postmortem aorta. ⁸⁷ Serum levels of AGE is associated with aortic stiffness. ⁷¹ Glycated low-density lipoprotein (LDL) is more susceptible to cross-linking with collagen in the arterial wall than nonglycated LDL. ^{87 88} Arterial wall stiffness is a major cause of reduced arterial compliance and increased central-wave velocity and important risk factor for hypertension in the elderly population. ⁸⁹

Reduction of Nitric Oxide Production and Hypertension

AGE reduces the production of NO, ⁹⁰ a vasodilator. Reduction in the production of NO by AGE would increase blood pressure. AGE inhibits the antiproliferative activity of NO in aortic cells. ⁶⁵ This effect of AGE could take part in inducing hypertension in the elderly population.

Increased Expression of Endothelin-1

Matrix-bound AGE increases the expression of endothelin-1. ⁶⁶ Endothelin-1, a potent endogenous vasoconstrictor, ⁹¹ would therefore induce hypertension.

Increased Expression of Transforming Growth Factor-β

TGF-β increases extracellular matrix accumulation. ⁹² Matsuki et al ⁹³ have discussed in detail the role of TGF-β in the regulation of blood pressure.

Receptor-Mediated Mechanisms of AGE-Induced Hypertension

Interaction of AGE with RAGE generates ROS ⁴³ and increases the levels of activated NF-kB, ⁴⁴ expression of proinflammatory cytokines, ^{45 46} cell adhesion molecules, ⁵¹ TGF-β, insulin-like growth factor-1, ⁵⁵ and platelet-derived growth factor. ⁵⁷ The attributes of the above biomolecules in the development of hypertension are described below.

Reactive Oxygen Species and Hypertension

Oxidative stress is a key player in the pathophysiology of hypertension. ⁹⁴ Hypertension in diabetes and obesity is associated with oxidative stress. ⁹⁵ Activation of NADPH-oxidase is strongly associated with hypertension. ⁹⁶ Degradation of NO by superoxide anion (oxygen radical) would lead to vasoconstriction and hypertension. ⁹⁷ Hypertension is associated with a reduction in NO bioavailability. ⁹⁸ Superoxide anion interacts with NO in the arterial wall to generate peroxynitrite ⁹⁹ which constricts the cerebral artery ¹⁰⁰ and pulmonary artery. ¹⁰¹ Superoxide anion constricts isolated rabbit aorta and this constriction is endothelium dependent. ³³ H ₂ O ₂ produces constriction in isolated aortic strips. ³⁴ oxidative stress activates collagen synthesis in human pulmonary smooth muscle cells. ¹⁰² ROS increases the synthesis and deposition of collagen in vessels. ^{103 104} AGE cross-linking with collagen produces stiffness in the artery ⁸⁶ resulting in pretension. ⁸⁹

Nuclear Factor-kB and Hypertension

Activated NF-kB generates ROS through the expression of NADPH-oxidase. ¹⁰⁵ ROS is known to produce hypertension. ^{94 95} Activated NF-kB increases the expression of the angiotensin-I receptor ¹⁰⁶ which will constrict the blood vessels to raise the blood pressure. ¹⁰⁷ NF-kB activation increases RAGE expression ¹⁰⁸ which can interact with AGE to produce ROS.

Proinflammatory Cytokines and Hypertension

There are numerous ways in which proinflammatory cytokines could induce hypertension. Proinflammatory cytokines may activate the sympathetic nervous to raise blood pressure. ¹⁰⁹ TNF-α and IL-6 produce structural and functional changes in the endothelial cells resulting in hypertension. ^{110 111} TNF-α increases vascular contraction and inhibits endothelium-dependent NO-cGMP-mediated vascular relaxation in systemic vessels. ¹¹¹ Synthesis of endothelin-1 is enhanced ¹¹² and acetylcholine-induced vascular relaxation is reduced ¹¹¹ by cytokines. Proinflammatory cytokines enhance the formation of angiotensin-converting enzyme which contributes to hypertension. ^{113 114} Cytokines increase ROS production in mitochondria via NADPH-oxidase. ⁵⁰ They also stimulate PMNLs to generate ROS. ¹¹⁵ Increased levels of ROS can increase blood pressure. Increased levels of proinflammatory cytokines are associated with increased blood pressure. ¹¹⁶ The role of cytokines in hypertension has been described in detail by Granger. ¹¹⁷

Cell Adhesion Molecules and Hypertension

DeSouza et al ¹¹⁸ have reported that circulating levels of soluble ICAM-1 and VCAM-1 were higher in older men with uncomplicated essential hypertension compared with normotensive men. They also reported that there was a positive correlation between sICAM-1 and sVCAM-1, and systolic and diastolic pressures. The soluble Cell Adhesion Molecule (sCAM)-1 was positively correlated with age and systolic blood pressures. ICAM-1-mediated monocyte adhesion and migration play a critical role in Ang II–induced arterial hypertension and vascular dysfunction. ¹¹⁹ Blocking ICAM-1 with a neutralizing antibody significantly attenuated Ang II–induced arterial hypertension, vascular hypertrophy, fibrosis, macrophage infiltration, and ROS production, and improved vascular relaxation. Inhibition of ICAM-1 lowers the expression of TGF-β and attenuates cardiac fibrosis which suggests that ICAM-1 plays a profibrotic role in the hypertensive heart. ¹²⁰ In conclusion, ICAM-1-mediated monocyte adhesion and migration play a critical role in Ang II–induced arterial hypertension and vascular dysfunction. ICAM-1 inhibitors may represent a new therapeutic strategy for the treatment of this disease. Yin et al ¹²¹ have reported that Ang II–induced increases in serum VCAM-1 levels and systolic blood pressure were dose dependently reduced in mice with anti CAM-1 neutralizing antibody. These data suggest that cell adhesion molecules are involved in vascular remodeling and hypertension.

Treatment Modalities of Hypertension in Elderly People

Considering the role of the AGE–RAGE axis in the pathophysiology of hypertension in the elderly population, the treatment strategy should include lowering of AGE levels in the body, prevention of AGE formation, degradation of AGE in vivo, downregulation of RAGE expression, blockers of AGE–RAGE interaction, upregulation of sRAGE expression, exogenous administration of sRAGE, and antioxidants. The treatment strategies have been described in detail elsewhere for the AGE–RAGE–induced diseases. ^{122 123 124}

Perspectives

The available information suggests that the AGE–RAGE axis may be involved in the development of hypertension in the elderly population. The increases in the blood pressures correlate with age. Age and blood pressure are positively correlated with serum/plasma levels of AGE and negatively correlated with serum/plasma levels of sRAGE. There are other risk factors including, smoking, alcohol consumption, family history of hypertension, diabetes, race, obesity, use of an excessive amount of common salt and too little potassium, stress, sleep apnea, and renal disease. ^{125 126 127} High serum/plasma levels of AGE and low levels of sRAGE may be one of the many risk factors for hypertension in the elderly population. Interaction of AGE with RAGE produces numerous biomolecules ^{43 44 45 51 64 65 86 87 92} which would increase the stiffness in the blood vessels leading to hypertension. As mentioned earlier, AGE–sRAGE interaction does not activate intracellular signaling and hence has no adverse effects. The protective effect of sRAGE is because when sRAGE combines with AGE, less amount of AGE is left to combine with RAGE. The plasma/serum levels of sRAGE are low in elderly hypertensive patients. ^{81 82 83 84 85} Interaction of a low amount of sRAGE with AGE will leave more amount of AGE to interact with RAGE resulting in greater adverse effects. ROS increases the central and peripheral sympathetic nervous system which could induce hypertension. ¹²⁸ Proinflammatory cytokines could also raise blood pressure through activating the sympathetic nervous system. ¹²⁹ It appears that the AGE–RAGE axis may play a major role in the development of hypertension in the elderly population. The treatment strategies for AGE–RAGE axis-induced hypertension may not be fully effective because there are other risk factors besides the AGE–RAGE axis that are involved in hypertension in the older population. The treatment strategies for AGE–RAGE axis-induced hypertension would supplement the presently used other treatment for hypertension in elderly people.

Conclusion

Elevated levels of AGE and reduced levels of sRAGE could produce hypertension in elderly people in various ways. Nonreceptor-mediated mechanisms of AGE-induced hypertension include cross-linking of AGE with long-lived protein (collagen), increased synthesis of extracellular matrix, reduced production of NO, and increased expression of endothelin-1, and TGF-β. Receptor-mediated mechanisms of AGE-induced elderly hypertension include activation of NF-kB, increased production of ROS, and increased expression of proinflammatory cytokines and cell adhesion molecules. Reduced levels of sRAGE would increase the levels biomolecules produced by AGE–RAGE interaction. Low levels of sRAGE are associated with increased arterial stiffness and hypertension. Treatment modalities of elderly hypertension should include, lowering of AGE consumption, prevention of AGE formation, degradation of AGE in vivo, downregulation of RAGE expression, upregulation of sRAGE expression, blockade of interaction of AGE with RAGE, and administration of sRAGE and antioxidants.