Dynamin-related protein 1 mediates low glucose-induced endothelial dysfunction in human arterioles.

Intensive glycemic regulation has resulted in an increased incidence of hypoglycemia. Hypoglycemic burden correlates with adverse cardiovascular complications and contributes acutely and chronically to endothelial dysfunction. Prior data indicate that mitochondrial dysfunction contributes to hypoglycemia-induced endothelial dysfunction, but the mechanisms behind this linkage remain unknown. We attempt to determine whether clinically relevant low-glucose (LG) exposures acutely induce endothelial dysfunction through activation of the mitochondrial fission process. Characterization of mitochondrial morphology was carried out in cultured endothelial cells by using confocal microscopy. Isolated human arterioles were used to explore the effect LG-induced mitochondrial fission has on the formation of detrimental reactive oxygen species (ROS), bioavailability of nitric oxide (NO), and endothelial-dependent vascular relaxation. Fluorescence microscopy was employed to visualize changes in mitochondrial ROS and NO levels and videomicroscopy applied to measure vasodilation response. Pharmacological disruption of the profission protein Drp1 with Mdivi-1 during LG exposure reduced mitochondrial fragmentation among vascular endothelial cells (LG: 0.469; LG+Mdivi-1: 0.276; P = 0.003), prevented formation of vascular ROS (LG: 2.036; LG+Mdivi-1: 1.774; P = 0.005), increased the presence of NO (LG: 1.352; LG+Mdivi-1: 1.502; P = 0.048), and improved vascular dilation response to acetylcholine (LG: 31.6%; LG+Mdivi-1; 78.5% at maximum dose; P < 0.001). Additionally, decreased expression of Drp1 via siRNA knockdown during LG conditions also improved vascular relaxation. Exposure to LG imparts endothelial dysfunction coupled with altered mitochondrial phenotypes among isolated human arterioles. Disruption of Drp1 and subsequent mitochondrial fragmentation events prevents impaired vascular dilation, restores mitochondrial phenotype, and implicates mitochondrial fission as a primary mediator of LG-induced endothelial dysfunction.NEW & NOTEWORTHY Acute low-glucose exposure induces mitochondrial fragmentation in endothelial cells via Drp1 and is associated with impaired endothelial function in human arterioles. Targeting of Drp1 prevents fragmentation, improves vasofunction, and may provide a therapeutic target for improving cardiovascular complications among diabetics.Listen to this article's corresponding podcast @ http://ajpheart.podbean.com/e/mitochondrial-dynamics-impact-endothelial-function/.

Mineralocorticoid exposure and receptor activity modulate microvascular endothelial function in African Americans with and without hypertension.

Prior work suggests blood pressure in African Americans is more sensitive to the effects of aldosterone than in Caucasians. This mechanism may relate to a negative response of the vascular endothelium to aldosterone, including reduced glucose-6-phosphate dehydrogenase (G6PD) activity. Thirty-three African Americans (11 hypertensives, 22 controls) without evidence of diabetes or metabolic syndrome completed the protocol. The protocol included measurement of in vivo microvascular endothelial function by digital pulse arterial tonometry and ex vivo measurement of endothelial function by videomicroscopy of arterioles obtained from these same subjects with and without exposure to aldosterone or spironolactone. Systemic and arteriolar G6PD activities were also measured. In vivo and ex vivo microvascular endothelial function were impaired in African Americans with hypertension. One-hour exposure with aldosterone impaired endothelium-dependent vasodilation in arterioles from normotensive subjects, while 1 hour of spironolactone exposure reversed endothelial dysfunction in arterioles from hypertensive subjects. G6PD activity was impaired in hypertensive arterioles. Aldosterone-related endothelial dysfunction may be responsible for at least a portion of the greater blood pressure sensitivity to aldosterone in African Americans. This may be in part related to vascular suppression of G6PD activity.

Associations of Reducing Sedentary Time With Vascular Function and Insulin Sensitivity in Older Sedentary Adults.

BACKGROUND: We previously reported increased moderate-intensity (3-6 metabolic equivalents (METs)) physical activity (PA) reverses aging-associated vascular endothelial dysfunction, a surrogate marker of cardiovascular risk. Whether reductions in sedentary time alone contribute to this improvement is unknown. METHODS: Data from 96 adults (aged ≥50 years) enrolled in a randomized control trial evaluating a 12-week intervention to increase PA in sedentary individuals were analyzed. Amount and intensity of activity were measured pre- and post-intervention by step count and accelerometry. Subjects were divided into 3 categories based on change in sedentary activity (<1. 5 METs): (i) ≥5% reduction in sedentary time, (ii) 0-4.99% reduction, and (iii) increase sedentary time. Vascular endothelial function was measured by brachial artery flow-mediated dilation (FMD%) pre- and post-intervention. RESULTS: Sedentary time decreased overall (P = 0.001), with a 101-minute decrease in category 1 (N = 27, P < 0.001), a 42-minute decrease in category 2 (N = 29, P = 0.003), and a 44-minute increase in category 3 (N = 40, P = 0.02). While FMD% increased in the entire study population (P = 0.008) over 12 weeks, no differences were observed between the categories (P = 0.73). In category 1, FMD% improvement was associated achievement of ≥20 minutes/day of moderate intensity PA in bouts ≥ 10 minutes in length. CONCLUSIONS: Reductions of up to 100 minutes of sedentary time per day over 12 weeks was not significantly associated with improved vascular endothelial function in older adults. FMD% was significantly higher among those with lower sedentary behavior and concomitant moderate-intensity PA of ≥20 minutes/day in bouts.

The Impact of Moderate Intensity Physical Activity on Cardiac Structure and Performance in Older Sedentary Adults.

BACKGROUND: Sedentary aging leads to adverse changes in vascular function and cardiac performance. We published improvements in vascular function with moderate intensity physical activity (PA) in continuous bouts. Whether moderate intensity PA also impacts cardiac structure and cardiovascular performance of the aging left ventricle (LV) is unknown. METHODS: We recruited and analyzed results from 102 sedentary older adults ages ≥ 50 from a randomized controlled trial with 3 study groups: control (group 1), a pedometer-only intervention (group 2), or a pedometer with an interactive website employing strategies to increase habitual physical activity (PA, group 3) for 12 weeks. Transthoracic echocardiograms were performed prior to and following the 12 week intervention period to assess cardiac morphology, left ventricular (LV) systolic performance, LV diastolic function, arterial and LV ventricular elastance. Step count and PA intensity/distribution were measured by pedometer and accelerometer. RESULTS: We found no significant changes in cardiac morphology. Further, we found no improvement in the aforementioned cardiac functional parameters. Comparing those who achieved the following benchmarks to those who did not showed no significant changes in cardiac structure or performance: 1)10,000 steps/day, 2) ≥ 30 minutes/day of moderate intensity physical activity, or 3) moderate intensity PA in bouts ≥ 10 minutes for ≥ 20 minutes/day. CONCLUSIONS: In sedentary older adults, increasing moderate intensity PA to currently recommend levels does not result in favorable changes in LV morphology or performance over 12 weeks. More prolonged exposure, higher PA intensity, or earlier initiation of PA may be necessary to see benefits.

Relative importance of step count, intensity, and duration on physical activity's impact on vascular structure and function in previously sedentary older adults.

BACKGROUND: Age-related endothelial dysfunction and vascular stiffening are associated with increased cardiovascular (CV) risk. Many groups have encouraged goals of ≥10 000 steps/day or ≥30 min/day of moderate intensity physical activity (MPA) to reduce age-related CV risk. The impact of MPA on the vasculature of older adults remains unclear. METHODS AND RESULTS: We randomized 114 sedentary older adults ages ≥50 to 12 weeks of either no intervention (group 1), a pedometer-only intervention (group 2), or a pedometer with an interactive website employing strategies to increase the adoption of habitual physical activity (PA, group 3). Endothelial function by brachial flow-mediated dilation (FMD%), vascular stiffness by tonometry, step-count by pedometer, and PA intensity/distribution by accelerometer were measured. Step-count increased in groups 2 (5136±1554 to 9596±3907, P<0.001) and 3 (5474±1512 to 8167±3111, P<0.001) but not in group 1 (4931±1667 to 5410±2410). Both groups 2 and 3 increased MPA ≥30 min/day. Only group 3 increased MPA in continuous bouts of ≥10 minutes (P<0.001) and improved FMD% (P=0.001). Neither achievement of ≥10 000 steps/day nor ≥30 min/day of MPA resulted in improved FMD%. However, achieving ≥20 min/day in MPA bouts resulted in improved FMD%. No changes in vascular stiffness were observed. CONCLUSIONS: MPA reverses age-related endothelial dysfunction, but may require MPA to be performed in bouts of ≥10 minutes duration for ≥20 min/day to be effective. Commonly encouraged PA goals do not guarantee improved endothelial function and may not be as effective in reducing CV risk. CLINICAL TRIAL REGISTRATION URL: Clinicaltrials.gov. UNIQUE IDENTIFIER: NCT-01212978.