Mechanism of Hypercholesterolemia-Induced Atherosclerosis.

Hypercholesterolemia is involved in the development of atherosclerosis and is a risk factor for coronary artery disease, stroke, and peripheral vascular disease. This paper deals with the mechanism of development of hypercholesterolemic atherosclerosis. Hypercholesterolemia increases the formation of numerous atherogenic biomolecules including reactive oxygen species (ROS), proinflammatory cytokines [interleukin (IL)-1, IL-2, IL-6, IL-8, tumor necrosis factor-alpha (TNF- α )], expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), E-selectin, monocyte chemoattractant protein-1 (MCP-1), granulocyte macrophage-colony stimulating factor (GM-CSF) and numerous growth factors [insulin-like growth factor-1 (IGF-1), platelet-derived growth factor-1 (PDGF-1) and transforming growth factor-beta (TGF- ß )]. ROS mildly oxidizes low-density lipoprotein-cholesterol (LDL-C) to form minimally modified LDL (MM-LDL) which is further oxidized to form oxidized LDL (OX-LDL). Hypercholesterolemia also activates nuclear factor-kappa-B (NF- κ B). The above atherogenic biomolecules are involved in the development of atherosclerosis which has been described in detail. Hypercholesterolemia also assists in the development of atherosclerosis through AGE (advanced glycation end-products)-RAGE (receptor for AGE) axis and C-reactive protein (CRP). Hypercholesterolemia is associated with increases in AGE, oxidative stress [AGE/sRAGE (soluble receptor for AGE)] and C-reactive protein, and decreases in the sRAGE, which are known to be implicated in the development of atherosclerosis. In conclusion, hypercholesterolemia induces atherosclerosis through increases in atherogenic biomolecules, AGE-RAGE axis and CRP.

AGE-RAGE stress play a role in aortic aneurysm: A comprehensive review and novel potential therapeutic target.

Aortic aneurysms are mostly asymptomatic but have high rates of mortality when there is rupture or dissection. Matrix metalloproteinases is involved in the evolution of aortic aneurysms. Advanced glycation end products and its cell receptor RAGE (receptor for AGE) and sRAGE (soluble receptor of AGE) have been suggested to be involved in the pathogenesis of numerous diseases. This review addresses the role of AGE, RAGE and AGE-RAGE stress (AGE/sRAGE) in the pathogenesis of abdominal aortic aneurysm and thoracic aortic aneurysm in humans. AGERAGE interaction not only increases the generation of reactive oxygen species and inflammatory cytokines, but also activates NF-kB. There are increases in the levels of AGE in aortic tissue, skin and serum in patients with thoracic aortic aneurysm and abdominal aortic aneurysm. Levels of RAGE in tissue are elevated in abdominal aortic aneurysm. AGE-RAGE stress is elevated in patients with thoracic aortic aneurysm. The serum levels of cytokines and Matrix metalloproteinases are elevated in patients with thoracic aortic aneurysm and abdominal aortic aneurysm. The levels of AGE and AGE-RAGE stress correlate positively with cytokines and Matrix metalloproteinases, but the serum levels of sRAGE correlate negatively with cytokines and Matrix metalloproteinases. Cytokines levels are positively correlated with the levels of Matrix metalloproteinases in patients with thoracic aortic aneurysm. In conclusion, elevated levels of AGE, RAGE and AGE-RAGE stress, and reduced levels of sRAGE increase the levels of cytokines that in turn increase the production of Matrix metalloproteinases resulting in formation of aortic aneurysms. The data suggest that AGE-RAGE stress is involved in the pathogenesis of aortic aneurysms. Treatment options have also been discussed.

Is there any evidence that AGE/sRAGE is a universal biomarker/risk marker for diseases?

Advanced glycation end products (AGE) and its cell-bound receptor called receptor for AGE (RAGE) are implicated in the pathogenesis of numerous diseases. Soluble receptor for AGE (sRAGE) counteracts the adverse effects of AGE-RAGE interaction by competing with RAGE for binding with AGE. Low levels of serum sRAGE have been proposed as a biomarker for diseases. However, the serum levels of sRAGE in diabetes and end-stage renal disease (ESRD) are elevated. Thus, low levels of sRAGE cannot be a universal biomarker. An elevated ratio of AGE/sRAGE was then proposed as a universal biomarker. However, evidence was not provided for this new biomarker. The objective of this paper is to provide evidence in support of elevated AGE/sRAGE being a universal biomarker. The data for serum levels of AGE, sRAGE, and ratio of AGE/sRAGE were collected from patients with low serum sRAGE [non-ST-elevation myocardial infarction (NSTEMI), hyperthyroidism (HT), thoracic aortic aneurysm (TAA),and hypercholesterolemia (HC)], and with high serum levels of sRAGE [type-2 diabetes (T2D) and ESRD], and control subjects. The serum levels of AGE and ratio of AGE/sRAGE were higher in all types of patients irrespective of low or high serum sRAGE as compared to control subjects. Reasons are provided as to why AGE or sRAGE individually cannot be considered as a universal biomarker. In conclusion, the evidence supports the validity of the high ratio AGE/sRAGE as a universal biomarker/risk marker for diseases.

AGE-RAGE stress: a changing landscape in pathology and treatment of Alzheimer's disease.

Numerous hypotheses including amyloid cascade, cholinergic, and oxidative have been proposed for pathogenesis of Alzheimer's disease (AD). The data suggest that advanced glycation end products (AGEs) and its receptor RAGE (receptor for AGE) are involved in the pathogenesis of AD. AGE-RAGE stress, defined as a balance between stressors (AGE, RAGE) and anti-stressors (sRAGE, AGE degraders) in favor of stressors, has been implicated in pathogenesis of diseases. AGE and its interaction with RAGE-mediated increase in the reactive oxygen species (ROS) damage brain because of its increased vulnerability to ROS. AGE and ROS increase the synthesis of amyloid ß (Aß) leading to deposition of Aß and phosphorylation of tau, culminating in formation of plaques and neurofibrillary tangles. ROS increase the synthesis of Aß, high-mobility group box 1(HMGB1), and S100 that interacts with RAGE to produce additional ROS resulting in enhancement of AD pathology. Elevation of ROS precedes the Aß plaques formation. Because of involvement of AGE and RAGE in AD pathology, the treatment should be targeted at lowering AGE levels through reduction in consumption and formation of AGE, and lowering expression of RAGE, blocking of RAGE ligand binding, increasing levels of soluble RAGE (sRAGE), and use of antioxidants. The above treatment aspect of AD is lacking. In conclusion, AGE-RAGE stress initiates, and Aß, HMGB1, and S100 enhance the progression of AD. Reduction of levels of AGE and RAGE, elevation of sRAGE, and antioxidants would be beneficial therapeutic modalities in the prevention, regression, and slowing of progression of AD.

Advanced glycation end products (AGEs) and its receptors in the pathogenesis of hyperthyroidism.

Oxidative stress has been implicated in the pathogenesis of hyperthyroidism and its complications. Interaction of advanced glycation end products (AGEs) with receptor RAGE (receptor for AGEs) generates reactive oxygen species. Soluble receptor for AGEs (sRAGE) competes with RAGE for binding with AGEs and attenuates the generation of ROS. Low levels sRAGE and high levels AGEs would generate more ROS leading to hyperthyroidism and its complications. The objectives are to determine if levels of serum sRAGE are low and the levels of AGEs and AGEs/sRAGE are high in patients with hyperthyroidism. The study subjects comprised of 33 patients with hyperthyroidism and 20 controls. Levels of serum sRAGE were lower, while that of AGEs and AGEs/sRAGE were higher in patients compared to controls, being significant only for sRAGE and AGEs/sRAGE. When the levels of sRAGE, AGEs, and AGEs/sRAGE were assessed for hyperthyroidism associated with different diseases, the levels of sRAGE were lower in Hashimoto disease, and levels of AGEs were higher in patients with Graves' disease compared to control. The levels of AGEs/sRAGE were elevated in an all except patients with Hashimoto disease. The levels of AGEs, sRAGE, or AGEs/RAGE were not correlated with age, weight, and blood pressures except systolic pressure which was inversely correlated with sRAGE. The levels of sRAGE were negatively correlated with AGEs and AGEs/sRAGE. The levels of AGEs/sRAGE were positively correlated with AGEs. In conclusion, low levels of sRAGE, and high levels of AGEs and AGEs/sRAGE are risk biomarkers in the pathogenesis hyperthyroidism and its complications.

AGEs/sRAGE, a novel risk factor in the pathogenesis of end-stage renal disease.

Interaction of advanced glycation end products (AGEs) with its cell-bound receptor (RAGE) results in cell dysfunction through activation of nuclear factor kappa-B, increase in expression and release of inflammatory cytokines, and generation of oxygen radicals. Circulating soluble receptors, soluble receptor (sRAGE), endogenous secretory receptor (esRAGE) and cleaved receptor (cRGAE) act as decoy for RAGE ligands and thus have cytoprotective effects. Low levels of sRAGE and esRAGE have been proposed as biomarkers for many diseases. However sRAGE and esRAGE levels are elevated in diabetes and chronic renal diseases and still tissue injury occurs. It is possible that increases in levels of AGEs are greater than increases in the levels of soluble receptors in these two diseases. Some new parameters have to be used which could be an universal biomarkers for cell dysfunction. It is hypothesized that increases in serum levels of AGEs are greater than the increases in the soluble receptors, and that the levels of AGEs is correlated with soluble receptors and that the ratios of AGEs/sRAGE, AGEs/esRAGE and AGEs/cRAGE are elevated in patients with end-stage renal disease (ESRD) and would serve as an universal risk marker for ESRD. The study subject comprised of 88 patients with ESRD and 20 healthy controls. AGEs, sRAGE and esRAGE were measured using commercially available enzyme linked immune assay kits. cRAGE was calculated by subtracting esRAGE from sRAGE. The data show that the serum levels of AGEs, sRAGE, cRAGE are elevated and that the elevation of AGEs was greater than those of soluble receptors. The ratios of AGEs/sRAGE, AGEs/esRAGE and AGEs/cRAGE were elevated and the elevation was similar in AGEs/sRAGE and AGEs/cRAGE but greater than AGEs/esRAGE. The sensitivity, specificity, accuracy, and positive and negative predictive value of AGEs/sRAGE and AGEs/cRAGE were 86.36 and 84.88 %, 86.36 and 80.95 %, 0.98 and 0.905, 96.2 and 94.8 %, and 61.29 and 56.67 % respectively. There was a positive correlation of sRAGE with esRAGE and cRAGE, and AGEs with esRAGE; and negative correlation between sRAGE and AGEs/sRAGE, esRAGE and AGES/esRAGE, and cRAGE and AGES/cRAGE. In conclusion, AGEs/sRAGE, AGEs/cRAGE and AGEs/esRAGE may serve as universal risk biomarkers for ESRD and that AGEs/sRAGE and AGEs/cRAGE are better risk biomarkers than AGEs/esRAGE.

Vitamin E and regression of hypercholesterolemia-induced oxidative stress in kidney.

Hypercholesterolemia (HC) is an independent risk factor for the onset and progression of renal disease. HC induces oxidative stress (OS) in the kidney; Vitamin E (Vit.E), an antioxidant, slows the progression of OS in the kidney. This study was to investigate if Vit.E regresses the HC-induced OS, and the regression is associated with an increase in the antioxidant reserve (AR). The studies were carried out in four groups of rabbits. The kidneys were removed under anesthesia. OS and AR in the renal tissue were assessed by measuring malondialdetyde (MDA) and chemiluminescent (CL) activity, respectively. High-cholesterol diet elevated the serum total cholesterol (TC), and the regular diet with or without Vit.E following a high-cholesterol diet reduced the serum TC to control levels. HC increased the MDA levels of kidney by 5.54-fold compared to control. The MDA contents of the kidneys in groups on regular diet with or without Vit.E were, respectively, 56 and 53 % lower than the control group. The CL activity in the control group was 12.15 ± 0.73 × 10(6) RLU/mg protein. The CL activity in HC group was 45.26 % lower than that in control, indicating an increase in AR. The regular diet with or without Vit.E following high-cholesterol diet normalized the CL activity/AR. In conclusion, HC increases OS in the kidney; reduction of serum cholesterol by regular diet regresses the renal OS but Vit.E does not regress HC-induced OS in kidney.

Vitamin E does not regress hypercholesterolemia-induced oxidative stress in heart.

Vitamin E suppresses the hypercholesterolemia-induced cardiac oxidative stress. The objectives were to investigate: if vitamin E regresses the hypercholesterolemia-induced oxidative stress in hearts and if regression is associated with decreases in the antioxidant reserve. The rabbits were assigned to 4 groups: I, regular diet (2-months); II, 0.25% cholesterol diet (2-months); III, 0.25% cholesterol diet (2-months) followed by regular diet (2-months); and IV, 0.25% cholesterol diet (2-months) followed by regular diet with vitamin E (2-months). Blood samples were collected before and at the end of protocol for the measurement of total cholesterol (TC). Hearts were removed at the end of the protocol under anesthesia for the assessment of oxidative stress parameters, malondialdehyde (MDA), and tissue chemiluminescent (CL) activity. High cholesterol diet increased the serum levels of TC, and regular diet with or without vitamin E reduced the TC levels to a similar extent. The MDA content of the heart in groups I, II, III, and IV were 0.074 ± 0.015, 0.234 ± 0.016, 0.183 ± 0.028 and 0.169 ± 0.016 nmol/mg protein, respectively. Regular diet following high cholesterol diet reduced the MDA levels (0.234 ± 0.016 vs. 0.183 ± 0.028 nmol/mg protein but vitamin E did not reduce the MDA levels. The cardiac-CL activities were similar in groups' I, II, and III (30.11 ± 0.7 × 10(6), 32.9 ± 1.43, and 37.92 ± 8.35 × 10(6) RLU/mg protein). The activity decreased in group IV, suggesting that vitamin E increased the antioxidant reserve while lowering serum cholesterol did not increase antioxidant reserve. In conclusion, hypercholesterolemia increases cardiac oxidative stress and regular diet regresses hypercholesterolemia-induced oxidative stress but vitamin E does not further regress hypercholesterolemia-induced cardiac oxidative stress. Vitamin E reduces oxidative stress in the heart tissue in spite of a decrease in CL activity (increase in antioxidant reserve).

Outcomes and biochemical parameters following cardiac surgery: effects of transfusion of residual blood using centrifugation and multiple-pass hemoconcentration.

OBJECTIVES: To determine whether or not there was a significant difference between the methods of centrifugation (CF) and multiple-pass hemoconcentration (MPH) of the residual cardiopulmonary-bypass volume in relation to biochemical measurements and patient outcomes. DESIGN: Prospective, randomized, and controlled. SETTING: Conducted at a western Canadian tertiary care hospital. PARTICIPANTS: Consisted of 61 consecutive male and female patients from ages 40 to 80 who were scheduled for cardiac surgery with cardiopulmonary bypass. INTERVENTIONS: Either the centrifugation or multiple-pass hemoconcentration method was used to process the residual blood from the cardiopulmonary bypass circuit. RESULTS: The 12-hour postoperative levels of serum hemoglobin were not significantly different in the centrifugation group as compared to the multiple-pass hemoconcentration group. However, the serum levels of total protein and albumin were significantly higher in the multiple-pass hemoconcentration group as compared to the centrifugation group. Additionally, after 12-hours postoperatively, the serum fibrinogen and platelet counts were significantly higher in the multiple-pass hemoconcentration group as compared to those of the centrifugation group. The allogeneic product transfusion index and the chest-tube blood drainage indices were lower in the multiple-pass hemoconcentration group as compared to the centrifugation group. CONCLUSION: Although the CF method provided a product in a shorter turnaround time, with consistent clearance of heparin, the MPH method trended towards enhanced biochemical and clinical patient outcomes over the 12-hour postoperative period.

Clinical features of early-onset pediatric traumatic glaucoma and predictive factors for the need of early glaucoma surgery.

Purpose: To assess the clinical presentation of pediatric patients having early traumatic glaucoma and to analyze early predictors for the need of filtration surgery. Methods: Patients with early traumatic glaucoma after close globe injury (CGI) from January 2014 to December 2020 were retrospectively reviewed. Clinical features, treatment provided (medical and surgical), and visual outcomes were documented. Patients were divided into two groups based on the management required: group A- trabeculectomy and group B- medication + minor surgery. Results: A total of 85 patients were studied after applying the necessary inclusion and exclusion criteria. Out of these, 46 underwent trabeculectomy for the control of intraocular pressure (IOP) and the remaining 39 were managed with antiglaucoma medications. Significant male predominance of 9.6:1 was observed. Patients presented to the hospital after a mean duration of 8.5 days posttrauma. Wooden objects were most commonly responsible for trauma. Mean best corrected visual acuity at presentation was 1.91 log of minimum angle of resolution (logMAR). Mean IOP at presentation was 40 mmHg. The common anterior segment finding were severe anterior chamber (AC) reaction (63.5%), followed by angle recession (56.4%). Severe AC reaction (P = 0.0001) and corneal microcystic edema (P = 0.04) were significant predictive factors for early need of trabeculectomy. Conclusion: Need of trabeculectomy was higher in patients with severe AC reaction and corneal microcystic edema. The threshold to perform trabeculectomy should be lower, as glaucoma is often relentless, severe, and may result in irreversible vision loss.

Vitamin E slows the progression of hypercholesterolemia-induced oxidative stress in heart, liver and kidney.

Vitamin E suppresses the hypercholesterolemia-induced oxidative stress in the heart. The objectives were to investigate if: (a) hypercholesterolemia-induced oxidative stress is similar in heart, liver, and kidney, and is dependent upon duration of hypercholesterolemia; and (b) vitamin E slows the progression of oxidative stress in these organs. The rabbits were assigned to 4 groups: I, regular diet (2 months); II, 0.25 % cholesterol diet (2 months); III, 0.25 % cholesterol diet (4 months); and IV, 0.25 % cholesterol diet (2 months) followed by 0.25 % cholesterol diet plus vitamin E (2 months). Blood samples were collected before and at the end of protocol for the measurement of total cholesterol (TC). Hearts, livers, and kidneys were removed at the end of the protocol under anesthesia for the measurement of oxidative parameters, malondialdehyde (MDA), and chemiluminescence (CL). The basal MDA levels in the heart, liver, and kidney of rabbits in Group I were similar, but increased to 14.65-, 3.18-, and 10.35-fold, respectively, with hypercholesterolemia. The increases in MDA levels were dependent upon the duration of hypercholesterolemia. Vitamin E did not alter the TC levels, but reduced the MDA levels in all organs. Hypercholesterolemia and vitamin E had variable effects on CL activity. In conclusion, (i) hypercholesterolemia induces oxidative stress in heart, liver, and kidney, the heart being the most and the liver the least susceptible to oxidative stress; (ii) oxidative stress is positively associated with duration of hypercholesterolemia; and (iii) vitamin E slows the progression of oxidative stress in these organs.

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

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-ß (TGF-ß). 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- ß. 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.

Does AGE-RAGE Stress Play a Role in the Development of Coronary Artery Disease in Obesity?

This article deals with the role of AGE (advanced glycation end products)-RAGE (receptor for AGE) stress (AGE/sRAGE) in the development of coronary artery disease (CAD) in obesity. CAD is due to atherosclerosis in coronary artery. The serum/plasma levels of AGE and sRAGE are reduced, while AGE-RAGE stress and expression of RAGE are elevated in obese individuals. However, the levels of AGE are elevated in obese individuals with more than one metabolic syndrome. The increases in the AGE-RAGE stress would elevate the expression and production of atherogenic factors, including reactive oxygen species, nuclear factor-kappa B, cytokines, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, endothelial leukocyte adhesion molecules, monocyte chemoattractant protein-1, granulocyte-macrophage colony-stimulating factor, and growth factors. Low levels of sRAGE would also increase the atherogenic factors. The increases in the AGE-RAGE stress and decreases in the levels of sRAGE would induce development of atherosclerosis, leading to CAD. The therapeutic regimen for AGE-RAGE stress-induced CAD in obesity would include lowering of AGE intake, prevention of AGE formation, degradation of AGE in vivo, suppression of RAGE expression, blockade of AGE-RAGE interaction, downregulation of sRAGE expression, and use of antioxidants. In conclusion, the data suggest that AGE-RAGE stress is involved in the development of CAD in obesity, and the therapeutic interventions to reduce AGE-RAGE would be helpful in preventing, regressing, and slowing the progression of CAD in obesity.

Outcomes and risk factors for failure of trabeculectomy with mitomycin C in children with traumatic glaucoma - A retrospective study.

PURPOSE: To determine surgical outcomes and risk factors for failure of trabeculectomy with mitomycin C (TMMC) in pediatric traumatic glaucoma. METHODS: Children who underwent TMMC post trauma from January 2014 to December 2019 were reviewed. Demographic features, ocular findings, and surgery details were noted. Surgical success was defined as achieving intraocular pressure (IOP) within 6-21 mm Hg. RESULTS: Seventy-one eyes of seventy patients underwent TMMC. The mean age of the patients was 11.28 ± 3.63 years with a male/female ratio of 13:1. The median time from trauma to IOP rise was 13 days. The majority of the patients (n = 64, 90.1%) had close globe injury. Baseline IOP was 39.3 ± 10.5 mm Hg. Results of the surgery were noted at the last visit. Cumulative success was noted in 51 (71.8%) eyes, while 20 (28.2%) eyes were labeled failures. Mean IOP reduced from 39.3 ± 10.5 to 14.5 ± 8.1 mm Hg. Mean visual acuity improved from 2.3 ± 0.93 to 1.19 ± 1.08 logMAR. Post surgery, the mean follow-up of the patients was 20.3 ± 11.4 months. Age <6 years (RR 3.6), elevated IOP at 1 month after TMMC (RR 2.19), and hypotony within a week of surgery (RR 1.81) were found as independent risk factors of surgical failure. CONCLUSION: TMMC is effective in reducing IOP in traumatic glaucoma. Young age and inability to control IOP within normal ranges in the immediate period after surgery are important risk factors of failure.

Attenuated combined action of cyclosporine a and hyperlipidemia on atherogenesis in rabbits by thymoquinone.

This descriptive study investigates in a rabbit model of atherosclerosis (i) the extent of atherogenesis induced by cyclosporine A (CsA) or hyperlipidemia alone or in combination and (ii) whether thymoquinone (TQ), a known herbal antioxidant, offers protection against these effects. New Zealand White female rabbits were assigned to five groups of six animals each: Group I, control; Group II, CsA [25 mg kg(-1) day(-1) orally (PO)]; Group III, 1% cholesterol; Group IV, 1% cholesterol + CsA (25 mg kg(-1) day(-1) PO); and Group V, 1% cholesterol + CsA (25 mg kg(-1) day(-1) PO) + TQ (10 mg kg(-1) day(-1) PO). Lipids and oxidative stress parameters [Malondialdehyde (MDA) and protein carbonyl] and aortic atherosclerosis were compared. CsA alone did not show a significant effect on either serum lipids and did not induce atherosclerosis. High-cholesterol diet induced atherosclerosis (45 ± 11% of the intimal surface of aorta was covered with atherosclerotic plaques). CsA and high-cholesterol diet increased atherosclerosis severity as measured from intimal and media lesions, but did not affect the extent of atherosclerosis. TQ decreased aortic MDA by 83%. It was also associated with reduced aortic atherosclerosis extend by 52% compared with Group IV. We concluded that (i) CsA aggravates hyperlipidemia-induced atherosclerosis and (ii) TQ attenuates the oxidative stress and atherogenesis induced by the combined effect of CsA and hyperlipidemia.

Inverse Association between Cardiac Troponin-I and Soluble Receptor for Advanced Glycation End Products in Patients with Non-ST-Segment Elevation Myocardial Infarction.

Interaction of advanced glycation end products (AGEs) with the receptor for advanced AGEs (RAGE) results in activation of nuclear factor kappa-B, release of cytokines, expression of adhesion molecules, and induction of oxidative stress. Oxygen radicals are involved in plaque rupture contributing to thromboembolism, resulting in acute coronary syndrome (ACS). Thromboembolism and the direct effect of oxygen radicals on myocardial cells cause cardiac damage that results in the release of cardiac troponin-I (cTnI) and other biochemical markers. The soluble RAGE (sRAGE) compete with RAGE for binding with AGE, thus functioning as a decoy and exerting a cytoprotective effect. Low levels of serum sRAGE would allow unopposed serum AGE availability for binding with RAGE, resulting in the generation of oxygen radicals and proinflammatory molecules that have deleterious consequences and promote myocardial damage. sRAGE may stabilize atherosclerotic plaques. It is hypothesized that low levels of sRAGE are associated with high levels of serum cTnI in patients with ACS. The main objective of the study was to determine whether low levels of serum sRAGE are associated with high levels of serum cTnI in ACS patients. The serum levels of sRAGE and cTnI were measured in 36 patients with non-ST-segment elevation myocardial infarction (NSTEMI) and 30 control subjects. Serum levels of sRAGE were lower in NSTEMI patients (802.56 ± 39.32 pg/mL) as compared with control subjects (1311.43 ± 66.92 pg/mL). The levels of cTnI were higher in NSTEMI patients (2.18 ± 0.33 µg/mL) as compared with control subjects (0.012 ± 0.001 µg/mL). Serum sRAGE levels were negatively correlated with the levels of cTnI. In conclusion, the data suggest that low levels of serum sRAGE are associated with high serum levels of cTnI and that there is a negative correlation between sRAGE and cTnI.

Current Status of Primary, Secondary, and Tertiary Prevention of Coronary Artery Disease.

Fifty percent of all death from cardiovascular diseases is due to coronary artery disease (CAD). This is avoidable if early identification is made. Preventive health care has a major role in the fight against CAD. Atherosclerosis and atherosclerotic plaque rupture are involved in the development of CAD. Modifiable risk factors for CAD are dyslipidemia, diabetes, hypertension, cigarette smoking, obesity, chronic renal disease, chronic infection, high C-reactive protein, and hyperhomocysteinemia. CAD can be prevented by modification of risk factors. This paper defines the primary, secondary, and tertiary prevention of CAD. It discusses the mechanism of risk factor-induced atherosclerosis. This paper describes the CAD risk score and its use in the selection of individuals for primary prevention of CAD. Guidelines for primary, secondary, and tertiary prevention of CAD have been described. Modification of risk factors and use of guidelines for prevention of CAD would prevent, regress, and slow down the progression of CAD, improve the quality of life of patient, and reduce the health care cost.

AGE-RAGE Stress and Coronary Artery Disease.

Coronary artery atherosclerosis and atherosclerotic plaque rupture cause coronary artery disease (CAD). Advanced glycation end products (AGE) and its cell receptor RAGE, and soluble receptor (sRAGE) and endogenous secretory RAGE (esRAGE) may be involved in the development of atherosclerosis. AGE and its interaction with RAGE are atherogenic, while sRAGE and esRAGE have antiatherogenic effects. AGE-RAGE stress is a ratio of AGE/sRAGE. A high AGE-RAGE stress results in development and progression of CAD and vice-versa. AGE levels in serum and skin, AGE/sRAGE in patients with CAD, and expression of RAGE in animal model of atherosclerosis were higher, while serum levels of esRAGE were lower in patients with CAD compared with controls. Serum levels of sRAGE in CAD patients were contradictory, increased or decreased. This contradictory data may be due to type of patients used, because the sRAGE levels are elevated in diabetics and end-stage renal disease. AGE/sRAGE ratio is elevated in patients with reduced or elevated levels of serum sRAGE. It is to stress that AGE, RAGE, sRAGE, or esRAGE individually cannot serve as universal biomarker. AGE and sRAGE should be measured simultaneously to assess the AGE-RAGE stress. The treatment of CAD should be targeted at reduction in AGE levels, prevention of AGE formation, degradation of AGE in vivo, suppression of RAGE expression, blockade of RAGE, elevation of sRAGE, and use of antioxidants. In conclusion, AGE-RAGE stress would initiate the development and progression of atherosclerosis. Treatment modalities would prevent, regress, and slow the progression of CAD.

Effects of vitamin E on serum enzymes and electrolytes in hypercholesterolemia.

It is not known if vitamin E in hyperlipidemia and hypercholesterolemia of longer duration has any beneficial or adverse effects on electrolytes, and liver and kidney function. The objectives of this study are to determine (i) if long duration of mild hypercholesterolemia has any adverse effects on serum electrolytes, glucose and enzymes related to liver and kidney functions; (ii) if vitamin E has any effects on serum electrolytes, glucose and enzymes related to liver and kidney function in hypercholesterolemia. Blood samples were collected from the rabbits before and at various intervals during administration of a high cholesterol diet (0.25%) for 2 and 4 months, and while on a high cholesterol diet with vitamin E following a high cholesterol diet. Measurements of serum total cholesterol (TC), glucose, aspartate aminotransferase (AST), alkaline phosphatase (ALP), alanine aminotransferase (ALT), gamma-glutamyltransferase (GGT), albumin, creatinine, electrolytes [sodium (Na), potassium (K), chloride (Cl), and carbon dioxide (CO2)] were made. High cholesterol diet for 2 months produced hypercholesterolemia which was associated with reductions in serum glucose, unaltered serum electrolytes, ALT, ALP, GGT, albumin and creatinine, and increased levels of AST. Hypercholesterolemia for 4 months had effects similar to hypercholesterolemia for 2 months except it lowered serum ALP. Vitamin E did not affect any of the parameters except serum glucose and Cl, which decreased compared to the values at month 2. Hypercholesterolemia for short and long term does not have adverse effects on liver or kidney function, and serum electrolytes. Vitamin E during hypercholesterolemia does not affect serum electrolytes or liver and kidney function.

Effect of chronic administration of vitamin E on the hemopoietic system in hypercholesterolemia.

Hypercholesterolemia induces oxidative stress, which is known to have adverse effects on the integrity of cells. Hence, hypercholesterolemia may have adverse effects on the hemopoietic system. Vitamin E, an antioxidant, is being used by normo- and hypercholesterolemic subjects. It is, however, not known if vitamin E has any beneficial or adverse effects on the hemopoietic system. The objectives of this study are to determine if (i) hypercholesterolemia has any adverse effects on the hemopoietic system [red blood cell (RBC) count, mean corpuscular volume (MCV), red blood cell distribution width (RDW), hematocrit (Hct), hemoglobin (Hb), mean corpuscular hemoglobin (MCH), MCH concentration (MCHC), white blood cell (WBC), and platelet counts, and mean platelet volume (MPV)], and (ii) vitamin E has any effect on the hemopoietic system in hypercholesterolemia. Blood samples were collected before and at various intervals during a high cholesterol diet (0.25% cholesterol) for 2 and 4 months, and while on high cholesterol diet with vitamin E (2 months) following a high cholesterol diet (2 months). Serum cholesterol was measured on an automated Clinical System Analyzer and hemopoietic parameters were measured on an automated Cell-dyn-4000. The results show that hypercholesterolemia decreased RBC count, Hct and Hb, increased MCV, RDW, MCH, and MCHC, and had no effect on WBC and platelet counts, and MPV. Vitamin E did not affect any of the parameters of the hemopoietic system. In conclusion, hypercholesterolemia of short duration has adverse effects on certain elements of the hemopoietic system. Vitamin E does not affect the hemopoietic system during hypercholesterolemia.