Impairment Of Nitric Oxide Signaling Research Articles

A rare genetic variant of BPIFB4 predisposes to high blood pressure via impairment of nitric oxide signaling

BPIFB4 is associated with exceptional longevity: four single-nucleotide polymorphisms distinguish the wild-type form from a longevity-associated variant conferring positive effects on blood pressure. The effect of a rare variant (RV; allele frequency, 4%) on blood pressure is unknown. Here, we show that overexpression of RV-BPIFB4 in ex-vivo mouse vessels impairs phosphorylation of endothelial nitric oxide synthase (eNOS), blunting acetylcholine-evoked vasorelaxation; in vivo, virally mediated overexpression of RV-BPIFB4 increases blood pressure, an action absent in eNOS-deficient mice. In humans, we found RV carriers to have increased diastolic blood pressure, a finding that was more marked in subjects on anti-hypertensive medication; moreover, recombinant RV-BPIFB4 protein impaired eNOS function in ex-vivo human vessels. Thus, RV-BPIFB4 acts directly on blood pressure homeostasis and may represent a novel biomarker of vascular dysfunction and hypertension.

Pentraxin 3 Induces Vascular Endothelial Dysfunction Through a P-selectin/Matrix Metalloproteinase-1 Pathway.

Pentraxin 3 (PTX3), the prototype of long pentraxins, has been described to be associated with endothelial dysfunction in different cardiovascular disorders. No study has yet evaluated the possible direct effect of PTX3 on vascular function. Through in vitro experiments of vascular reactivity and ultrastructural analyses, we demonstrate that PTX3 induces dysfunction and morphological changes in the endothelial layer through a P-selectin/matrix metalloproteinase-1 pathway. The latter hampered the detachment of endothelial nitric oxide synthase from caveolin-1, leading to an impairment of nitric oxide signaling. In vivo studies showed that administering PTX3 to wild-type mice induced endothelial dysfunction and increased blood pressure, an effect absent in P-selectin-deficient mice. In isolated human umbilical vein endothelial cells, PTX3 significantly blunted nitric oxide production through the matrix metalloproteinase-1 pathway. Finally, using ELISA, we found that hypertensive patients (n=31) have higher plasma levels of PTX3 and its mediators P-selectin and matrix metalloproteinase-1 than normotensive subjects (n=21). Our data show for the first time a direct role of PTX3 on vascular function and blood pressure homeostasis, identifying the molecular mechanisms involved. The findings in humans suggest that PTX3, P-selectin, and matrix metalloproteinase-1 may be novel biomarkers that predict the onset of vascular dysfunction in hypertensive patients.

Reversal of Hyperglycemia: Effects on Nitric Oxide Signaling

BackgroundHyperglycemia in patients with acute coronary syndromes is associated with poor outcomes, and its rapid correction with insulin infusion has been shown to restore platelet responsiveness to nitric oxide and to suppress superoxide (O2−) generation. Thioredoxin-interacting protein has emerged recently as a pivotal modulator of hyperglycemia-induced inflammation, O2− production, and impairment of nitric oxide signaling, but it is not known whether its expression in platelets can be downregulated rapidly. MethodsIn 12 hyperglycemic patients with acute coronary syndrome, we evaluated the putative role of thioredoxin-interacting protein suppression in the platelet nitric oxide response after reversal of hyperglycemia with insulin infusion. ResultsInsulin infusion for 13.0 ± 0.8 (standard error of the mean) hours decreased blood glucose level from 16.6 ± 1.6 mmol/L to 8.7 ± 1.4 mmol/L (P = .002). This induced (1) sensitization of antiaggregatory response to nitric oxide (from 6.5% ± 7.7% to 39.7% ± 7.0%, P < .0001); (2) improved endothelial progenitor cell function (from a median of 45 to 180 colony-forming units, P < .05); and (3) decreases of whole blood reactive oxygen species content (P < .05). However, there was no significant suppression of platelet thioredoxin-interacting protein expression (mean decrease, 59 arbitrary units; 95% confidence interval, −193 to +74). ConclusionsCorrection of hyperglycemia in patients with acute coronary syndrome rapidly reverses oxidative stress, restoring both platelet nitric oxide responsiveness and endothelial progenitor cell function, but this process is largely or entirely independent of thioredoxin-interacting protein.

Loose cholesterol, get stiff! Focus on “oxLDL-induced decrease in lipid order of membrane domains is inversely correlated with endothelial stiffness and network formation”

increased levels of oxidized LDL (oxLDL) accumulate in atherosclerotic lesions, promote atherosclerotic process, and may cause endothelial dysfunction including disruption of endothelial barrier, impairment of nitric oxide signaling, and decreased endothelial cell migration. In addition, oxLDL

Vascular NAD(P)H oxidase mediates endothelial dysfunction in basilar arteries from Otsuka Long-Evans Tokushima Fatty (OLETF) rats

We examined the responses of basilar arteries taken from Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a type 2 diabetes model. Both the nitric oxide (NO)-mediated relaxation and the cyclic 3′,5′-guanosine monophosphate (cGMP) production elicited by acetylcholine (ACh) were much weaker in OLETF rats than in age-matched control Long Evans Tokushima Otsuka (LETO) rats. The contraction induced by an NO synthase (NOS) inhibitor [ N G-nitro- l-arginine ( l-NNA)] was weaker in the OLETF group. In that group, application of apocynin, an NAD(P)H oxidase inhibitor, normalized (i) ACh-induced relaxation, (ii) l-NNA-induced contraction, and (iii) ACh-induced cGMP production to the LETO levels. Superoxide anion production was greater in basilar arteries from OLETF rats than in those from LETO rats. The protein expression of gp91 phox, an NAD(P)H oxidase subunit, was upregulated in the OLETF arteries (versus LETO ones). These results suggest that the existence of endothelial dysfunction in basilar arteries in type 2 diabetes is related to increased oxidative stress mediated via NAD(P)H oxidase. Possibly, an impairment of NO-dependent relaxation responses and a basal impairment of NO signaling may be responsible for the increased risk of adverse cerebrovascular events in type 2 diabetes.

Modifying cardiovascular risk in diabetes mellitus.

DIABETES mellitus affects an estimated 35 million people in the United States, and the disease prevalence is predicted to increase by nearly 200% in the next several decades. As a result, anesthesiologists will be confronted with an increasing population of patients undergoing anesthesia and surgery who are at risk for ischemic heart disease. Hyperglycemia Predicts Cardiovascular Risk Diabetes is a significant predictor of perioperative cardiovascular morbidity and mortality, but few studies have evaluated methods to modify this risk. Compelling evidence indicates that aggressive management of diabetes may substantially decrease the adverse consequences of myocardial ischemia and infarction. The direct impact of hyperglycemia on cardiovascular mortality in patients with and without diabetes is a central theme of current research, and several investigations conducted during the past 20 yr demonstrated that mortality resulting from acute myocardial infarction (AMI) is increased if blood glucose concentration is elevated at the time of hospital admission. 1 These findings were confirmed in a recent prospective analysis of 336 consecutive patients admitted with AMI. 2 One-year mortality was 9% for patients with AMI and normal admission blood glucose values. In contrast, patients with hyperglycemia (blood glucose concentrations of 121 15, 168 13, and 282 65 mg/dl) on admission demonstrated substantial increases (P 0.005) in mortality to 13, 30, and 44%, respectively. 2 The Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) trial addressed the prognostic significance of hyperglycemia in patients with type 1 and 2 diabetes and AMI. 3 A nearly linear relationship between blood glucose concentration on admission and long-term mortality was observed in conventionally treated patients in this randomized clinical trial (mortality rates of 35, 40, and 55% at blood glucose concentrations of 235, 235–298, and 298 mg/dl, respectively). A direct relationship between fasting blood glucose concentration and the risk of sustaining a cardiovascular event (e.g., sudden cardiac death, AMI, or cerebrovascular accident) has been demonstrated in a meta-regression analysis of data from 20 studies involving more than 95,000 patients. 4 The risk associated with fasting blood glucose concentrations was linear and extended below the threshold used to define diabetes. A fasting blood glucose value of only 110 mg/dl was associated with an increased relative risk of a cardiovascular event. Similarly, the odds ratio of AMI was increased to 1.5, 3.4, and 6.0 at fasting blood glucose concentrations of approximately 90, 110, and greater than 115 mg/dl, respectively. 5 Another large cohort study indicated that glycosylated hemoglobin (HbA1c) concentration, but not the presence of diabetes, predicted an increase in mortality. 6 The risk of all-cause mortality increased by a factor of 1.46 for every 1% increase in HbA 1c when male patients with diabetes, those with HbA 1c concentrations greater than 7%, or patients with a history of heart disease or stroke were excluded from the multivariate regression model. Similarly, creatinine kinase concentrations were higher in patients with hyperglycemia admitted with AMI compared with those with normal blood glucose levels. 2 These data demonstrate a striking relationship