Tyler D. Bammert

Passive heat stress reduces circulating endothelial and platelet microparticles

What is the central question of this study? Does passive heat stress of +2°C oesophageal temperature change concentrations of circulating arterial endothelial‐ and platelet‐derived microparticles in healthy adults? What is the main finding and its importance? Concentrations of circulating endothelial‐ and platelet‐derived microparticles were markedly decreased in heat stress. Reductions in circulating microparticles might indicate favourable vascular changes associated with non‐pathological hyperthermia.

Chronic Nebivolol Treatment Suppresses Endothelin-1–Mediated Vasoconstrictor Tone in Adults With Elevated Blood Pressure

Abstract—Endothelin-1 (ET-1) plays a major role in the pathophysiology of hypertension and its associated cardiovascular risk. We tested the hypothesis that chronic nebivolol treatment reduces ET-1–mediated vasoconstrictor tone in adult humans with elevated blood pressure (BP). Furthermore, reducing ET-1 vasoconstrictor activity contributes to the improvement in endothelial vasodilator function associated with nebivolol treatment. Forty-two middle-aged adults with elevated BP (systolic BP ≥130 mm Hg or diastolic BP ≥85 mm Hg) completed a 3-month, double-blind, randomized, placebo controlled trial: 14 received nebivolol (8 men/6 women; 5 mg per day); 14 received metoprolol succinate (9 men/5 women; 100 mg per day); and 14 received placebo (9 men/5 women). Forearm blood flow (plethysmography) responses to selective (BQ-123: 100 nmol/min; 60 minutes) and nonselective (BQ-123+BQ-788 [50 nmol/min]; 60 minutes) ET-1 receptor blockade, as well as acetylcholine (4.0, 8.0, and 16.0 &mgr;g per 100 mL of tissue per minute) in the absence and presence of nonselective ET-1 receptor blockade were determined before and after each treatment intervention. Forearm blood flow responses to BQ-123 and BQ-123+BQ-788 were similarly and significantly elevated (≈30% and 60%, respectively) from baseline in all 3 groups. Nebivolol, but not metoprolol or placebo, therapy resulted in a marked (≈25% and 45%; P<0.05) reduction in forearm blood flow response to BQ-123 and BQ-123+BQ-788. Moreover, after nebivolol therapy only, vasodilator response to acetylcholine was not significantly increased by ET-1 receptor blockade. These results demonstrate that nebivolol, but not metoprolol, treatment reduces ET-1–mediated vasoconstrictor tone in adult humans with elevated BP. In addition, nebivolol-induced reduction in ET-1–mediated vasoconstrictor tone underlies the favorable effects of this &bgr;-blocker on endothelial vasodilation. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT01395329.

Carbohydrate restriction with postmeal walking effectively mitigates postprandial hyperglycemia and improves endothelial function in type 2 diabetes

Postprandial hyperglycemia has deleterious effects on endothelial function. Restricting carbohydrate intake and postmeal walking have each been shown to reduce postprandial hyperglycemia, but their combination and subsequent effects on endothelial function have not been investigated. Here, we sought to examine the effect of blunting postprandial hyperglycemia by following a low-carbohydrate diet, with or without postmeal walking exercise, on markers of vascular health in type 2 diabetes (T2D). In a randomized crossover design, individuals with T2D ( n = 11) completed three 4-day controlled diet interventions consisting of 1) low-carbohydrate diet alone (LC), 2) low-carbohydrate diet with 15-min postmeal walks (LC + Ex), and 3) low-fat control diet (CON). Fasting blood samples and brachial artery flow-mediated dilation (%FMD) were measured before and after each intervention. Total circulating microparticles (MPs), endothelial MPs, platelet MPs, monocyte-platelet aggregates, and adhesion molecules were assessed as biomarkers of vascular health. There was a significant condition × time interaction for %FMD ( P = 0.01), with post hoc tests revealing improved %FMD after LC + Ex (+0.8 ± 1.0%, P = 0.02), with no change after LC or CON. Endothelial MPs were significantly reduced with the LC diet by ~45% (from 99 ± 60 to 44 ± 31 MPs/μl, P = 0.02), with no change after LC + Ex or CON (interaction: P = 0.04). Total MPs were lower (main effect time: P = 0.02), whereas monocyte-platelet aggregates were higher (main effect time: P < 0.01) after all interventions. Plasma adhesion molecules and C-reactive protein were unaltered. Attenuating postprandial hyperglycemic excursions using a low-carbohydrate diet combined with postmeal walking appears to be an effective strategy to improve endothelial function in individuals with T2D. NEW & NOTEWORTHY Carbohydrate restriction and postmeal walking lower postprandial hyperglycemia in individuals with type 2 diabetes. Here, we show that the combination significantly improved endothelial function and that carbohydrate restriction alone reduced circulating endothelial microparticles in individuals with type 2 diabetes. Listen to this articles corresponding podcast at http://ajpheart.podbean.com/e/low-carb-diet-and-exercise-improve-endothelial-health/ .

Effects of HIV‐1 gp120 and tat on endothelial cell sensescence and senescence‐associated microRNAs

The aim of this study was to determine, in vitro, the effects of X4 and R5 HIV‐1 gp120 and Tat on: (1) endothelial cell senescence and (2) endothelial cell microRNA (miR) expression. Endothelial cells were treated with media without and with: R5 gp120 (100 ng/mL), X4 gp120 (100 ng/mL), or Tat (500 ng/mL) for 24 h and stained for senescence‐associated β‐galactosidase (SA‐β‐gal). Cell expression of miR‐34a, miR‐217, and miR‐146a was determined by RT‐PCR. X4 and R5 gp120 and Tat significantly increased (~100%) cellular senescence versus control. X4 gp120 significantly increased cell expression of miR‐34a (1.60 ± 0.04 fold) and miR‐217 (1.52 ± 0.18), but not miR‐146a (1.25 ± 0.32). R5 gp120 significantly increased miR‐34a (1.23 ± 0.07) and decreased miR‐146a (0.56 ± 0.07). Tat significantly increased miR‐34a (1.49 ± 0.16) and decreased miR‐146a (0.55 ± 0.23). R5 and Tat had no effect on miR‐217 (1.05 ± 0.13 and 1.06 ± 0.24; respectively). HIV‐1 gp120 (X4 and R5) and Tat promote endothelial cell senescence and dysregulation of senescence‐associated miRs.

Influence of Overweight and Obesity on Circulating Inflammation-Related Microrna

BACKGROUND Increased cardiovascular disease risk and prevalence associated with overweight and obesity is due, in part, to heightened inflammatory burden. The mechanisms underlying adiposity-related amplification of inflammation are not fully understood. Alterations in regulators of inflammatory processes such as microRNAs (miRs), however, are thought to play a pivotal role. OBJECTIVE The aim of this study was to determine the influence of overweight and obesity, independent of other cardiovascular risk factors, on circulating expression of miR-34a, miR-126, miR-146a, miR-150 and miR-181b. METHODS Forty-five sedentary, middle-aged (47-64 years) adults were studied: 15 were normal weight (8M/7F; BMI: 23.3 ± 0.3 kg/m2); 15 were overweight (8M/7F; 28.2 ± 0.3 kg/m2); and 15 were obese (7M/8F; 32.3 ± 0.5 kg/m2). All subjects were non-smokers, normotensive and free of overt cardiometabolic disease. Circulating levels of the following inflammation-related miRs: miR-34a, miR-126, miR-146a, miR-150 and miR-181b were determined in plasma using standard RT-PCR techniques. miR expression was normalized to exogenous C. elegans miR-39 and reported as relative expression (AU). RESULTS Circulating miR-34a was ~200% higher (P< 0.05) in the obese as compared with normal weight and overweight groups. Whereas, miR-126, miR-146a and miR-150 were significantly lower (~65%) in both the obese and overweight groups than the normal weight group. There were no significant group differences in circulating expression of miR-181b. miR-34a was positively related (r = 0.43; P< 0.05); whereas, miR-126 (r = -0.48), miR-146a (r = -0.33) and miR-150 (r = -0.43) levels were significantly inversely related to BMI. CONCLUSION Overweight and obesity, independent of other cardiometabolic risk factors, negatively influences circulating inflammation-related miRs. Dysregulation of circulating miRs may contribute mechanistically to the heightened inflammatory state associated with overweight and obesity.

Association between hypertension and circulating vascular-related microRNAs

AbstractmicroRNAs (miRNAs) have a key role in regulating inflammation, vascular health and in turn, cardiovascular disease. Specifically, altered circulating expression of miR-17, miR-21, miR-34a, miR-92a, miR-126, miR-145, miR-146a, and miR-150 has been linked with the pathogenesis and progression of cardiovascular disease. The aim of this study was to determine whether the circulating profile of these vascular-related miRNAs is disrupted with hypertension. Thirty sedentary, middle-aged adults were studied: 15 normotensive (10M/5F; age: 56 ± 1 year; BP: 113/71 ± 2/1 mmHg) and 15 hypertensive (10M/5F; 56 ± 2 year; 140/87 ± 2/2 mmHg). All subjects were non-obese and free of other cardiometabolic disorders. Circulating miRNAs were determined in plasma using standard RT-PCR techniques with miRNA primers of interest. Expression was normalized to exogenous C. elegans miR-39 and reported as relative expression in arbitrary units (AU). Circulating expression of miR-34a (9.18 ± 0.94 vs 5.33 ± 0.91 AU) was higher (~170%; P < 0.01) whereas the expression of miR-21 (1.32 ± 0.25 vs 2.50 ± 0.29 AU), miR-126 (0.85 ± 0.10 vs 1.74 ± 0.27 AU) and miR-146a (1.50 ± 0.20 vs 3.10 ± 0.50 AU) were markedly lower (~50%, ~55%, and ~55% respectively; P < 0.05) in the hypertensive vs normotensive groups. Moreover, circulating levels of miR-34a, miR-21, and miR-126 were significantly related to systolic blood pressure (r = 0.48, r = −0.38; r = −0.48); whereas, miR-146a was significantly related to both systolic (r = −0.58) and diastolic (r = −0.55) blood pressure. There were no significant group differences in circulating miR-17, miR-92a, miR-145, and miR-150. In summary, these results suggest that hypertension, independent of other cardiometabolic risk factors, adversely affects the circulating profile of a subset of vascular-related miRNAs that have been link to CVD risk and development.

Short-term low-carbohydrate high-fat diet with or without post-meal walks on glycemic control and inflammation in type 2 diabetes: A randomized trial.

Lowering carbohydrate consumption effectively lowers glucose, but impacts on inflammation are unclear. The objectives of this study were to: 1) determine whether reducing hyperglycemia by following a low-carbohydrate, high-fat (LC) diet could lower markers of innate immune cell activation in type 2 diabetes (T2D) and 2) examine if the combination of an LC diet with strategically timed postmeal walking was superior to an LC diet alone. Participants with T2D ( n = 11) completed a randomized crossover study involving three 4-day diet interventions: 1) low-fat low-glycemic index (GL), 2) and 3) LC with 15-min postmeal walks (LC+Ex). Four-day mean glucose was significantly lower in the LC+Ex group as compared with LC (-5%, P < 0.05), whereas both LC+Ex (-16%, P < 0.001) and LC (-12%, P < 0.001) conditions were lower than GL. A significant main effect of time was observed for peripheral blood mononuclear cells phosphorylated c-Jun N-terminal kinase ( P < 0.001), with decreases in all three conditions (GL: -32%, LC: -45%, and LC+Ex: -44%). A significant condition by time interaction was observed for monocyte microparticles ( P = 0.040) with a significant decrease in GL (-76%, P = 0.035) and a tendency for a reduction in LC (-70%, P = 0.064), whereas there was no significant change in LC+Ex (0.5%, P = 0.990). Both LC (-27%, P = 0.001) and LC+Ex (-35%, P = 0.005) also led to significant reductions in circulating proinsulin. An LC diet improved 4-day glycemic control and fasting proinsulin levels when compared with GL, with added glucose-lowering benefits when LC was combined with postmeal walking.

Nebivolol, But Not Metoprolol, Treatment Improves Endothelial Fibrinolytic Capacity in Adults With Elevated Blood Pressure

Background Vascular endothelial fibrinolytic function is impaired in adults with prehypertension and hypertension and plays a mechanistic role in the development of atherothrombotic events. The influence of β‐blockers on endothelial fibrinolysis is unknown. This study compared the effects of chronic nebivolol and metoprolol treatment on endothelial tissue‐type plasminogen activator (t‐PA) release in adults with elevated blood pressure (BP). Methods and Results Forty‐four middle‐aged adults (36% women) with elevated BP completed a 3‐month, double‐blind, randomized, placebo‐controlled trial comparing nebivolol (5 mg/d), metoprolol succinate (100 mg/d), and placebo. Net endothelial t‐PA release was determined in vivo in response to intrabrachial infusions of bradykinin and sodium nitroprusside before and after each intervention. In a subset, the dose‐response curves to bradykinin and sodium nitroprusside were repeated with a coinfusion of the antioxidant vitamin C. At baseline, resting BP and endothelial t‐PA release were comparable between the 3 groups. BP decreased to a similar extent (≈10 mm Hg) in the nebivolol‐ and metoprolol‐treated groups. There was a substantial increase (≈30%; P<0.05) in the capacity of the endothelium to release t‐PA following chronic treatment with nebivolol but not metoprolol or placebo. Mitigating oxidant stress with vitamin C coinfusion potentiated t‐PA release (90%; P<0.05) at baseline in all groups. However, after the intervention, t‐PA release was unchanged by vitamin C coinfusion in the nebivolol group only. Conclusions Nebivolol but not metoprolol improves endothelial t‐PA release in adults with elevated BP. This may be an important vascular benefit of nebivolol. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT01595516.

Influence of sex on circulating endothelial microparticle number and microRNA expression in middle-aged adults

What is the central question of this study? Are there sex‐related differences in the number of circulating endothelial microparticles (EMPs) and microparticle microRNA expression in middle‐aged adult humans? What is the main finding and its importance? Although the numbers of circulating endothelial microparticles do not differ between middle‐aged men and women, there are sex‐related differences in the expression of miR‐125a in activation‐derived EMPs and miR‐34a in apoptosis‐derived EMPs. Differences in circulating endothelial microparticle microRNA content may provide new insight into the sex‐related disparity in the risk and prevalence of vascular disease in middle‐aged adults.

Influence of sex on the number of circulating endothelial microparticles and microRNA expression in middle‐aged adults

What is the central question of this study? Are there sex‐related differences in the number of circulating endothelial microparticles (EMPs) and microparticle microRNA expression in middle‐aged adult humans? What is the main finding and its importance? Although the numbers of circulating endothelial microparticles do not differ between middle‐aged men and women, there are sex‐related differences in the expression of miR‐125a in activation‐derived EMPs and miR‐34a in apoptosis‐derived EMPs. Differences in circulating endothelial microparticle microRNA content may provide new insight into the sex‐related disparity in the risk and prevalence of vascular disease in middle‐aged adults.