scholarly journals Role of peroxisome proliferators-activated receptor-gamma in advanced glycation end product-mediated functional loss of voltage-gated potassium channel in rat coronary arteries

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
W Li ◽  
S.D Gao ◽  
B Hua ◽  
Q.B Liu ◽  
H.R Liu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Coronary Artery ◽  
Coronary Arteries ◽  
Funding Source ◽  
Peroxisome Proliferators ◽  
Advanced Glycation ◽  
Coronary Vasodilation ◽  
Voltage Gated ◽  
Kv Channel ◽  
Ppar Γ

Abstract Background Voltage-gated K+ (Kv) channels in coronary artery smooth muscle cells (CSMCs), especially the major specific Kv1 subfamily, contribute to coronary artery vasodilation. Advanced glycation end products (AGEs) have been strongly implicated in diabetes-related cardiovascular complications. Our previous study showed AGEs can impair Kv channel-mediated coronary vasodilation by reducing Kv channel activity. However, its underlying mechanism remains unclear. Purpose Here, we used isolated rat small coronary arteries (RSCAs) and primary CSMCs to investigate the effect of AGEs on Kv channel-mediated coronary vasodilation and the possible involvement of peroxisome proliferators-activated receptor (PPAR)-γ pathway. Methods RSCAs and primary CSMCs were isolated, cultured and treated with bovine serum albumin (BSA), AGE-BSA, alagrebrium (ALA, AGE cross-linking breaker), pioglitazone (PIO) and/or GW9662, and then divided into the following groups: DMEM, BSA, AGE, AGE+ALA, AGE+PIO, and AGE+PIO+GW9662. Kv channel-mediated coronary vasodilation was analyzed using wire myograph. Histology and immunohistochemistry of RSCAs were performed. Western blot was used to detect the protein expression of RAGE, the major Kv1 channel subunits expressed in CSMCs (Kv1.2/1.5), PPAR-γ, and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-2 (NOX-2). Results AGEs markedly reduced forskolin-induced Kv channel-mediated vasodilation of RSCAs by interacting with the receptor for AGEs (RAGE), and ALA or PIO significantly reversed this effect. In both RSCAs and primary CSMCs, AGEs decreased Kv1.2 and Kv1.5 channel protein expression, inhibited PPAR-γ expression, increased RAGE and NOX-2 expression. Treatment with ALA or PIO partially reversed the effects of AGEs on Kv1.2/Kv1.5 expression, accompanied by elevation of PPAR-γ level and diminished oxidative stress. Conclusion AGE/RAGE axis-induced inhibition of PPAR-γ pathway and enhancement of oxidative stress may contribute to AGEs-mediated Kv channel dysfunction and coronary vasodilation in RSCAs. Our results may provide new insights into developing therapeutic strategies to manage diabetic vasculature. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): National Natural Science Foundation of China; Natural Science Foundation of Beijing (7172059)

Role of peroxisome proliferator–activated receptor-gamma activation on visfatin, advanced glycation end products, and renal oxidative stress in obesity-induced type 2 diabetes mellitus

2018 ◽  
Vol 37 (11) ◽  
pp. 1187-1198 ◽  
Author(s):  
A Tabassum ◽  
T Mahboob
Keyword(s):  
Oxidative Stress ◽  
Renal Damage ◽  
Peroxisome Proliferator ◽  
Advanced Glycation ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Glycation End Products ◽  
End Products

The present study focused on the role of peroxisome proliferator–activated receptor-gamma (PPAR-γ) activation on renal oxidative damages, serum visfatin, and advanced glycation end products (AGEs) in high-fat diet (HFD)-induced type 2 diabetes mellitus. Following the institutional animal ethics committee guidelines, Wistar rats were categorized into five groups: group 1: fed on a normal rat diet; group 2: HFD-induced obese rats (HFD for 8 weeks); group 3: HFD-fed rats treated with rosiglitazone (RSG; 3 mg/kg orally for 7 days); group 4: T2DM rats induced by HFD and low dose of streptozotocin (i.p. 35 mg/kg); group 5: T2DM rats treated with RSG (3 mg/kg orally for 7 days). Serum levels of AGEs and visfatin, renal damage, and oxidative stress were analyzed. Results showed that HFD-induced obesity and T2DM caused an elevated blood glucose, serum AGEs, visfatin, insulin, urea, creatinine, and tissue malondialdehyde, whereas a decreased catalase and superoxide dismutase activity were observed. The PPAR-γ activation via agonist restored these changes. Our findings suggest that AGEs and visfatin possess an important role in the progression of renal oxidative stress, which can be reduced by the PPAR-γ agonist that impede deleterious effects of HFD and HFD-induced T2DM on renal damage.

2-Deoxyglucose-induced vasodilation and hyperpolarization in rat coronary artery are reversed by glibenclamide

1994 ◽  
Vol 266 (4) ◽  
pp. H1322-H1326 ◽  
Author(s):  
M. A. Conway ◽  
M. T. Nelson ◽  
J. E. Brayden
Keyword(s):  
Coronary Artery ◽  
Potassium Channels ◽  
Coronary Arteries ◽  
Significant Role ◽  
Hypoglycemic Agents ◽  
Myogenic Tone ◽  
Coronary Vasodilation ◽  
Oral Hypoglycemic Agents ◽  
Intracellular Atp ◽  
Independent Mechanism

The mechanisms responsible for coronary vasodilation during ischemia or hypoxia are poorly understood. It has recently been suggested that alterations in intracellular ATP may play a role in this response. We examined whether dilation of isolated coronary arteries in response to metabolic blockade by 2-deoxyglucose, which competitively inhibits glycolysis and glycogenolysis, was sensitive to glibenclamide, an inhibitor of ATP-sensitive potassium channels. Pressurized rat coronary arteries with myogenic tone dilated in response to 2-deoxyglucose by an endothelium-independent mechanism. The dilation was accompanied by a substantial hyperpolarization. Addition of glibenclamide partially reversed this vasodilation and abolished the hyperpolarization. We propose that ATP-sensitive potassium channels play a significant role in the dilator response to 2-deoxyglucose. This may have implications both for ischemia-induced coronary vasodilation and for the use of oral hypoglycemic agents in general.

Myocardial energetic efficiency is depressed in ischemia with non-obstructive coronary arteries

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
I Eskerud ◽  
C Mancusi ◽  
I Khan ◽  
C.A Berge ◽  
T Larsen ◽  
...  
Keyword(s):  
Regression Analysis ◽  
Coronary Artery ◽  
Myocardial Ischemia ◽  
Coronary Arteries ◽  
Plaque Burden ◽  
Energetic Efficiency ◽  
Funding Source ◽  
Coronary Artery Plaque ◽  
Lv Mass ◽  
Lv Ejection Fraction

Abstract Background Ischemia with non-obstructive coronary arteries (INOCA) is incompletely understood. Depressed myocardial energetic efficiency index (MEEi), the ratio between external work and myocardial oxygen consumption, has been shown in heart failure. However, MEEi in INOCA has not been explored. Purpose To test whether MEEi is associated with INOCA. Methods We included 125 patients (56% women, age 62±9 years) with exercise-induced chest pain and non-obstructive coronary arteries (stenosis <50%) by coronary computed tomography angiography (CCTA). Stroke volume (SV) and left ventricular (LV) mass were assessed by echocardiography. MEEi was calculated as (systolic blood pressure (SBP) x SV) / (SBP x heart rate) and normalized for LV mass. LV hypertrophy was defined as LV mass index >46.7 g/m2.7 in women and >49.2 g/m2.7 in men. Myocardial ischemia was detected by myocardial contrast stress echocardiography. Coronary artery plaque burden was measured as plaque volume by CCTA. Results In univariable regression analysis, stress-induced ischemia, male sex, diabetes, hypertension, LV hypertrophy, lower LV ejection fraction and higher SBP were associated with MEEi (all p<0.05). There were no associations with age, obesity or coronary artery plaque burden. MEEi was lower in patients with stress-induced ischemia (n=66) compared to patients without ischemia (0.47±0.16 vs. 0.54±0.21 ml/sec x g–1, p=0.026). In multivariable linear regression analysis, MEEi remained associated with stress-induced myocardial ischemia after adjustment for cardiovascular risk factors, SBP, LV hypertrophy, LV ejection fraction and coronary artery plaque burden (R2 0.26, p<0.001, Table). Conclusion MEEi is depressed in patients with INOCA. Our results suggest that myocardial ischemia negatively influences MEEi in patients with non-obstructive coronary arteries. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Western Norway Regional Health Authority, University of Bergen

T1 mapping for myocardial tissue evaluation in patients with ischemia and stable coronary artery disease: MASS V-Trial Study Group

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
M Ribeiro ◽  
W Hueb ◽  
P.C Rezende ◽  
C.E Rochitte ◽  
C.H Nomura ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Coronary Arteries ◽  
Structural Changes ◽  
T1 Mapping ◽  
Ischemic Myocardium ◽  
Myocardial Tissue ◽  
Funding Source ◽  
Chronic Coronary Artery Disease ◽  
Artery Disease

Abstract Background T1 mapping is a magnetic resonance imaging (MRI) technique that enables the identification of myocardial structural changes during acute ischemic injury. However, it is not known whether these structural changes are present in patients with chronic effort induced ischemia.Thus, we sought to document the possible T1 mapping changes in chronic coronary artery disease (CAD) patients with documented myocardial ischemia. Methods Multivessel CAD patients from MASS V Trial with indication of myocardial revascularization, were evaluated for the presence of ischemia by myocardial scintigraphy. MRI with T1 mapping was performed in all patients. Based on the results of the scintigraphy, the myocardial segments were identified as ischemic and non-ischemic segments. The corresponding segments of scintigraphy and MRI were compared in relation to native T1 map (NT1), post-contrast T1 (CAT1) and extracellular volume (ECV). Results Of the 720 myocardial segments analyzed, there were 161 ischemic and 559 non-ischemic segments. Comparing ischemic vs non-ischemic segments, respectively, NT1 was 1022.7 (980.0–1052.0) versus 1029.3 (985.0–1066.3), p=0.57, ECV results were 25.4 (24.0–28.1) versus 26.4 (25.3–29.9), p=0.75 and CAT1 results were 492 (461.9–515.4) versus 488 (469.2–521.7), p=0.09. Myocardial segments supplied by obstructive coronary arteries were compared to those supplied by non-obstructive coronary arteries in relation to NT1 and ECV. NT1 values in obstructive and non-obstructive territories were, respectively, 1024.7 (998.5–1043.5) versus 1036.8 (1008.6–1046.9), p=0.30 and ECV results were 26.8 (24.4–29.9) versus 26.8 (24.4–30.0), p=0.90. Conclusion In this study, MRI identified structural similarities between chronic ischemic myocardium compared to the non-ischemic myocardium. This finding supports myocardial tissue stability in the presence of stress induced ischemia. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Zerbini Foundation and also by the FAPESP (2011/ 20876-2)

H2O2 activates redox- and 4-aminopyridine-sensitive Kv channels in coronary vascular smooth muscle

2007 ◽  
Vol 292 (3) ◽  
pp. H1404-H1411 ◽  
Author(s):  
Paul A. Rogers ◽  
William M. Chilian ◽  
Ian N. Bratz ◽  
Robert M. Bryan ◽  
Gregory M. Dick
Keyword(s):  
Hydrogen Peroxide ◽  
Smooth Muscle ◽  
Coronary Artery ◽  
Alkylating Agent ◽  
Dependent Manner ◽  
Coronary Vasodilation ◽  
Concentration Dependent Manner ◽  
Voltage Gated ◽  
Kv Channels ◽  
Whole Cell Patch Clamp

Previously, we demonstrated that coronary vasodilation in response to hydrogen peroxide (H2O2) is attenuated by 4-aminopyridine (4-AP), an inhibitor of voltage-gated K+ (KV) channels. Using whole cell patch-clamp techniques, we tested the hypothesis that H2O2 increases K+ current in coronary artery smooth muscle cells. H2O2 increased K+ current in a concentration-dependent manner (increases of 14 ± 3 and 43 ± 4% at 0 mV with 1 and 10 mM H2O2, respectively). H2O2 increased a conductance that was half-activated at −18 ± 1 mV and half-inactivated at −36 ± 2 mV. H2O2 increased current amplitude; however, the voltages of half activation and inactivation were not altered. Dithiothreitol, a thiol reductant, reversed the effect of H2O2 on K+ current and significantly shifted the voltage of half-activation to −10 ± 1 mV. N-ethylmaleimide, a thiol-alkylating agent, blocked the effect of H2O2 to increase K+ current. Neither tetraethylammonium (1 mM) nor iberiotoxin (100 nM), antagonists of Ca2+-activated K+ channels, blocked the effect of H2O2 to increase K+ current. In contrast, 3 mM 4-AP completely blocked the effect of H2O2 to increase K+ current. These findings lead us to conclude that H2O2 increases the activity of 4-AP-sensitive KV channels. Furthermore, our data support the idea that 4-AP-sensitive KV channels are redox sensitive and contribute to H2O2-induced coronary vasodilation.

Intracoronary acetylcholine spasm testing: differences in epicardial coronary artery response between smooth and atherosclerotic coronary arteries

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
R Gollwitzer ◽  
V Martinez Pereyra ◽  
A Seitz ◽  
R Bekeredjian ◽  
U Sechtem ◽  
...  
Keyword(s):  
Coronary Artery ◽  
Myocardial Ischemia ◽  
Coronary Arteries ◽  
Univariate Analysis ◽  
Coronary Artery Spasm ◽  
Signs And Symptoms ◽  
Funding Source ◽  
Epicardial Coronary Artery ◽  
Microvascular Spasm ◽  
Test Result

Abstract Background Coronary artery spasm is an established cause for angina pectoris. Epicardial coronary spasm may occur in patients with obstructed as well as unobstructed coronary arteries. Previous studies have suggested that epicardial plaque/atherosclerosis is a prerequisite for the development of epicardial spasm. The aim of the present study was to compare the results of intracoronary acetylcholine (ACh) testing in patients with signs and symptoms of myocardial ischemia with completely smooth versus atherosclerotic yet unobstructed epicardial arteries. Methods Between 2008 and 2016 a total number of 617 patients with signs and symptoms of myocardial ischemia yet unobstructed epicardial arteries (<50% epicardial stenosis) was included in the present study (mean age 61±11, 61% female). All patients underwent invasive diagnostic coronary angiography followed by intracoronary ACh testing according to a standardized protocol. The ACh-test was considered “positive” in the presence of (a) angina, ischemic ECG shifts during the test and ≥75% focal or diffuse coronary diameter reduction (“epicardial coronary artery spasm”) or (b) ischemic ST-shifts and angina in the absence of epicardial spasm (“microvascular spasm”). All angiograms were assessed regarding any visible epicardial plaque/atherosclerosis in a blinded fashion and patients were categorized into those with completely smooth versus those with atherosclerotic coronary arteries. The analysis included 179 patients (29%) with epicardial spasm and 172 patients with microvascular spasm (28%). The remaining 266 patients (43%) had an uneventful or an inconclusive ACh-test result. Results There were 389 patients (63%) with completely smooth epicardial arteries. The remaining 228 patients (37%) had non-obstructive epicardial plaques <50%. Patients with smooth arteries developed epicardial spasm in 24%, microvascular spasm in 32% and a negative/inconclusive test result in 44% of cases. Patients with atherosclerotic arteries developed epicardial spasm in 38%, microvascular spasm in 21% and an inconclusive/negative test result in 41% of cases. On univariate analysis the presence of epicardial atherosclerosis was associated with epicardial spasm (p=0.006) whereas this was not the case for microvascular spasm (p=0.094). Multivariate analysis revealed the presence of epicardial atherosclerosis (OR 1.921, CI 1.285–2.871, p=0.001) as well as female sex (OR 1.526, CI 1.024–2.274, p=0.038) as independent predictors for epicardial spasm. Conclusion In patients with signs and symptoms of myocardial ischemia yet unobstructed coronary arteries the presence of epicardial atherosclerosis is an independent predictor for the occurrence of epicardial spasm but not microvascular spasm on acetylcholine testing. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Robert-Bosch-Stiftung, Berthold-Leibinger-Stiftung

scholarly journals Advanced Glycation End Products Impair Voltage-Gated K+ Channels-Mediated Coronary Vasodilation in Diabetic Rats

PLoS ONE ◽  
2015 ◽  
Vol 10 (11) ◽  
pp. e0142865 ◽  
Author(s):  
Wen Su ◽  
Weiping Li ◽  
Hui Chen ◽  
Huirong Liu ◽  
Haixia Huang ◽  
...  
Keyword(s):  
Advanced Glycation End Products ◽  
Diabetic Rats ◽  
Advanced Glycation ◽  
Coronary Vasodilation ◽  
K Channels ◽  
Voltage Gated ◽  
Glycation End Products ◽  
End Products

Compositional differences in atherosclerosis between the major epicardial arteries; a secondary analysis from the PARADIGM study

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
A.M Bax ◽  
X Ma ◽  
I.J Van Den Hoogen ◽  
U Gianni ◽  
A.R Van Rosendael ◽  
...  
Keyword(s):  
Coronary Artery ◽  
High Risk ◽  
Coronary Arteries ◽  
Secondary Analysis ◽  
Hounsfield Unit ◽  
Necrotic Core ◽  
Funding Source ◽  
Circumflex Artery ◽  
Left Circumflex Artery ◽  
Calcified Plaque

Abstract Background Atherosclerotic plaques in the left circumflex artery (LCx) are associated with a lower risk of future events than plaques in the right coronary artery (RCA) and left anterior descending artery (LAD). High risk plaque subtypes including necrotic core and fibrofatty plaque can be evaluated on computed coronary tomography angiography (CCTA) by Hounsfield Unit (HU) density. To date, little is known regarding differences in high risk plaque composition between major epicardial vessels. Purpose The aim of this analysis was to compare plaque extent and composition between the three coronary arteries. Methods This is a secondary analysis of baseline scans from the PARADIGM study which enrolled consecutive patients with suspected coronary artery disease undergoing serial CCTA at a scan interval of ≥2 years. Plaque quantification by composition was performed in the three coronary arteries based on fixed HU thresholds: high risk subtypes consisting of necrotic core (<30 HU) and fibrofatty plaque (31–130 HU), and other subtypes including fibrous (131–350 HU) and calcified plaque (≥351 HU). Comparisons between the coronary arteries were made using Generalized Estimating Equations (GEE) models, accounting for within-patient clustering of the coronary arteries and adjusting for ASCVD risk score and diabetes mellitus. Results From 1,271 patients (mean age 60.3±9.3 years; 57% men; median ASCVD score 9.3%), 3,813 vessels were analyzed. The prevalence of any plaque was lowest in the LCx, as was the prevalence of high risk plaque (Figure; P<0.001 for both). The share of total plaque volume made up by high risk plaque subtypes was the lowest in the LCx (17.3% versus 22.5% [RCA] versus 24.4% [LAD]; P<0.001). In contrast, calcified plaque made up the largest proportion in the LCx (44.5% versus 35.6% [RCA] versus 34.9% [LAD]; P<0.001). Conclusion Prevalence of any plaque as well as high risk plaque subtypes was significantly higher in the LAD and RCA than in the LCx. Also, high risk plaque subtypes made up significantly the lowest proportion in the LCx, whereas calcified plaque made up the largest proportion in the LCx. These data support a different atherogenic milieu contributing to the variable risk patterns between the epicardial coronary arteries. Figure 1. Prevalence of (high risk) plaque Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): This work was supported by the Leading Foreign Research Institute Recruitment Program through the National Research Foundation (NRF) of Korea funded by the Ministry of Science and ICT (MSIT) (Grant no. 2012027176).

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