Diabetes and Atherosclerosis

Beckman, Joshua A.; Creager, Mark A.; Libby, Peter

doi:10.1001/jama.287.19.2570

Cited by 2,276 publications

(631 citation statements)

References 156 publications

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“…Patients admitted with an acute coronary syndrome (ACS) are at increased risk of subsequent cardiovascular events, especially those with type 2 diabetes mellitus,1, 2 who constitute ≈30% of all ACS patients 3. Determining the predictors of death, myocardial infarction (MI), heart failure (HF), and stroke among these patients is important as it assists in identifying the individuals at highest risk of these various outcomes.…”

Section: Introductionmentioning

confidence: 99%

Role of B‐Type Natriuretic Peptide and N‐Terminal Prohormone BNP as Predictors of Cardiovascular Morbidity and Mortality in Patients With a Recent Coronary Event and Type 2 Diabetes Mellitus

Wolsk

Claggett

Pfeffer

et al. 2017

JAHA

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BackgroundNatriuretic peptides are recognized as important predictors of cardiovascular events in patients with heart failure, but less is known about their prognostic importance in patients with acute coronary syndrome. We sought to determine whether B‐type natriuretic peptide (BNP) and N‐terminal prohormone B‐type natriuretic peptide (NT‐proBNP) could enhance risk prediction of a broad range of cardiovascular outcomes in patients with acute coronary syndrome and type 2 diabetes mellitus.Methods and ResultsPatients with a recent acute coronary syndrome and type 2 diabetes mellitus were prospectively enrolled in the ELIXA trial (n=5525, follow‐up time 26 months). Best risk models were constructed from relevant baseline variables with and without BNP/NT‐proBNP. C statistics, Net Reclassification Index, and Integrated Discrimination Index were analyzed to estimate the value of adding BNP or NT‐proBNP to best risk models. Overall, BNP and NT‐proBNP were the most important predictors of all outcomes examined, irrespective of history of heart failure or any prior cardiovascular disease. BNP significantly improved C statistics when added to risk models for each outcome examined, the strongest increments being in death (0.77–0.82, P<0.001), cardiovascular death (0.77–0.83, P<0.001), and heart failure (0.84–0.87, P<0.001). BNP or NT‐proBNP alone predicted death as well as all other variables combined (0.77 versus 0.77).ConclusionsIn patients with a recent acute coronary syndrome and type 2 diabetes mellitus, BNP and NT‐proBNP were powerful predictors of cardiovascular outcomes beyond heart failure and death, ie, were also predictive of MI and stroke. Natriuretic peptides added as much predictive information about death as all other conventional variables combined.Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT01147250.

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Section: Introductionmentioning

confidence: 99%

Role of B‐Type Natriuretic Peptide and N‐Terminal Prohormone BNP as Predictors of Cardiovascular Morbidity and Mortality in Patients With a Recent Coronary Event and Type 2 Diabetes Mellitus

Wolsk

Claggett

Pfeffer

et al. 2017

JAHA

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“…Unsaturated membrane lipids have a high propensity for oxidation and increased lipid peroxidation is frequently associated with tissue injury due to several etiologically unrelated diseases (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12). Moreover, adducts derived from lipid peroxidation products are the most common background DNA lesions in humans and rodents (54,55), suggesting that there may be continuous peroxidation of membrane lipids although at low levels are difficult to detect in healthy tissues.…”

Section: Discussionmentioning

confidence: 99%

“…When generated in high concentrations, the reactive oxygen species (ROS) 2 cause tissue injury and cell death. Excessive ROS production has been linked to a number of degenerative diseases including atherosclerosis (1-3), Alzheimer disease (4,5), and heart failure (6 -8), as well as tissue injury and dysfunction associated with myocardial ischemia and reperfusion (9,10) and diabetes (11,12). Additionally, recent evidence suggests that ROS are physiological regulators and mediators of cell signaling due to cytokines and growth factors (13)(14)(15)(16).…”

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confidence: 99%

Mitogenic Responses of Vascular Smooth Muscle Cells to Lipid Peroxidation-derived Aldehyde 4-Hydroxy-trans-2-nonenal (HNE)

Ramana

Bhatnagar

Srivastava

et al. 2006

Journal of Biological Chemistry

132

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Products of lipid peroxidation such as 4-hydroxy-trans-2-nonenal (HNE) trigger multiple signaling cascades that variably affect cell growth, differentiation, and apoptosis. Because glutathiolation is a significant metabolic fate of these aldehydes, we tested the possibility that the bioactivity of HNE depends upon its conjugation with glutathione. Addition of HNE or the cell-permeable esters of glutathionyl-4-hydroxynonenal (GS-HNE) or glutathionyl-1,4-dihydroxynonene (GS-DHN) to cultures of rat aortic smooth muscle cells stimulated protein kinase C, NF-B, and AP-1, and increased cell growth. The mitogenic effects of HNE, but not GS-HNE or GS-DHN, were abolished by glutathione depletion. Pharmacological inhibition or antisense ablation of aldose reductase (which catalyzes the reduction of GS-HNE to GS-DHN) prevented protein kinase C, NF-B, and AP-1 stimulation and the increase in cell growth caused by HNE and GS-HNE, but not GS-DHN. The growth stimulating effect of GS-DHN was enhanced in cells treated with antibodies directed against the glutathione conjugate transporters RLIP76 (Ral-binding protein) or the multidrug resistance protein-2. Overexpression of RLIP76 abolished the mitogenic effects of HNE and its glutathione conjugates, whereas ablation of RLIP76 using RNA interference promoted the mitogenic effects. Collectively, our findings suggest that the mitogenic effects of HNE are mediated by its glutathione conjugate, which has to be reduced by aldose reductase to stimulate cell growth. These results raise the possibility that the glutathione conjugates of lipid peroxidation products are novel mediators of cell signaling and growth.Incomplete reduction of oxygen leads to the generation of highly reactive species. When generated in high concentrations, the reactive oxygen species (ROS) 2 cause tissue injury and cell death. Excessive ROS production has been linked to a number of degenerative diseases including atherosclerosis (1-3), Alzheimer disease (4, 5), and heart failure (6 -8), as well as tissue injury and dysfunction associated with myocardial ischemia and reperfusion (9, 10) and diabetes (11,12). Additionally, recent evidence suggests that ROS are physiological regulators and mediators of cell signaling due to cytokines and growth factors (13-16). Under physiological conditions, the biological effects of ROS are tightly regulated by chemical and enzymatic antioxidant defenses. However, when these defenses are overwhelmed by disease or injury, ROS attack many cell constituents, with unsaturated lipids being the main target. Unsaturated lipids provide a readily extractable proton to oxygen-free radicals. The resultant lipid radical is stabilized by the bis-allylic double bond system and rapidly accepts molecular oxygen to form peroxyl radicals. This initiates a series of complex, autocatalytic reactions that generate a variety of carbonyl compounds as their end products (17). Of these, aldehydes, such as 4-hydroxy-trans-2-nonenal (HNE) are the most abundant and hence of greater biological significance (...

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“…Macrovascular and microvascular complications contribute to morbidity and mortality in diabetes mellitus 1, 2, 3. Endothelial dysfunction and abnormal platelet function represent the main determinants of the vascular accidents in diabetic patients, contributing to high incidence of thrombotic events 4.…”

Section: Introductionmentioning

confidence: 99%

Rac1 Modulates Endothelial Function and Platelet Aggregation in Diabetes Mellitus

Schiattarella

Carrizzo

Ilardi

et al. 2018

JAHA

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BackgroundVascular complications and abnormal platelet function contribute to morbidity and mortality in diabetes mellitus. We hypothesized that the Rho‐related GTPase protein, Rac1, can influence both endothelial and platelet function and might represent a potential novel therapeutic target in diabetes mellitus.Methods and ResultsWe used both in vitro and ex vivo approaches to test the effects of pharmacological inhibition of Rac1 during hyperglycemic condition. We evaluated the effect of NSC23766, a pharmacological inhibitor of Rac1, on vascular function in diabetic mice and platelet aggregation in diabetic subjects. We demonstrated that the administration of NSC23766 protects from hyperglycemia‐induced endothelial dysfunction, restoring NO levels, and reduces oxidative stress generated by nicotinamide adenine dinucleotide phosphate oxidase. Mechanistically, we identified Rho‐associated coiled‐coil serine/threonine kinase‐1 as a downstream target of Rac1. Moreover, we reported that during hyperglycemic conditions, human platelets showed hyperactivation of Rac1 and impaired NO release, which were both partially restored after NSC23766 treatment. Finally, we characterized the antiplatelet effect of NSC23766 during hyperglycemic conditions, demonstrating the additional role of Rac1 inhibition in reducing platelet aggregation in diabetic patients treated with common antiplatelet drugs.ConclusionsOur data suggest that the pharmacological inhibition of Rac1 could represent a novel therapeutic strategy to reduce endothelial dysfunction and platelet hyperaggregation in diabetes mellitus.

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Diabetes and Atherosclerosis

Abstract: Since most patients with diabetes die from complications of atherosclerosis, they should receive intensive preventive interventions proven to reduce their cardiovascular risk.

Cited by 2,276 publications

References 156 publications

Role of B‐Type Natriuretic Peptide and N‐Terminal Prohormone BNP as Predictors of Cardiovascular Morbidity and Mortality in Patients With a Recent Coronary Event and Type 2 Diabetes Mellitus

Role of B‐Type Natriuretic Peptide and N‐Terminal Prohormone BNP as Predictors of Cardiovascular Morbidity and Mortality in Patients With a Recent Coronary Event and Type 2 Diabetes Mellitus

Mitogenic Responses of Vascular Smooth Muscle Cells to Lipid Peroxidation-derived Aldehyde 4-Hydroxy-trans-2-nonenal (HNE)

Rac1 Modulates Endothelial Function and Platelet Aggregation in Diabetes Mellitus

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