Oxidative stress and vascular dysfunction: Potential therapeutic targets and therapies in peripheral artery disease.

Peripheral artery disease (PAD) is the manifestation of atherosclerosis characterized by the accumulation of plaques in the arteries of the lower limbs. Interestingly, growing evidence suggests that the pathology of PAD is multifaceted and encompasses both vascular and skeletal muscle dysfunctions, which contributes to blunted physical capabilities and diminished quality of life. Importantly, it has been suggested that many of these pathological impairments may stem from blunted reduction-oxidation (redox) handling. Of note, in those with PAD, excessive production of reactive oxygen species (ROS) outweighs antioxidant capabilities resulting in oxidative damage, which may have systemic consequences. It has been suggested that antioxidant supplementation may be able to assist in handling ROS. However, the activation of various ROS production sites makes it difficult to determine the efficacy of these antioxidant supplements. Therefore, this review focuses on the common cellular mechanisms that facilitate ROS production and discusses how excessive ROS may impair vascular and skeletal muscle function in PAD. Furthermore, we provide insight for current and potential antioxidant therapies, specifically highlighting activation of the Kelch-like ECH-associated protein 1 (Keap1) - Nuclear Factor Erythroid 2-related factor 2 (Nrf2) pathway as a potential pharmacological therapy to combat ROS accumulation and aid in vascular function, and physical performance in patients with PAD. Altogether, this review provides a better understanding of excessive ROS in the pathophysiology of PAD and enhances our perception of potential therapeutic targets that may improve vascular function, skeletal muscle function, walking capacity, and quality of life in patients with PAD.

Attenuated reactive hyperemia after prolonged sitting is associated with reduced local skeletal muscle metabolism: insight from artificial intelligence.

Blunted post-occlusive reactive hyperemia (PORH) after prolonged sitting (PS) has been used as evidence of microvascular dysfunction. However, it has not been determined if confounding variables are responsible for the reduction in PORH after PS. Therefore, the purpose of this study was to examine the PS-mediated changes in cardiovascular and metabolic factors that affect PORH using artificial intelligence (AI). We hypothesized that calf muscle metabolic rate (MMR) is attenuated after PS, which may reduce tissue hypoxia during an arterial occlusion (i.e., oxygen deficit) and PORH. Thirty-one subjects (male = 13, female = 18) sat for 2.5 h. A rapid-inflation cuff was placed around the thigh above the knee to generate an arterial occlusion. PORH was represented by the reoxygenation rate (RR) of the near-infrared spectroscopy (NIRS) tissue oxygenation index (TOI) after 5-min of arterial occlusion. An artificial intelligence model (AI) defined the stimulus-response relationship between the oxygen deficit (i.e., ΔTOI and TOI deficit), and RR with 65 previous PORH recordings. If the AI predicts the experimental RRs, then the change in RR is related to the change in the oxygen deficit. RR (Δ -0.27 ± 0.55 lnTOI%·s-1, P = 0.001), MMR (Δ -0.46 ± 0.61 lnTOI%·s-1, P < 0.001), ΔTOI (Δ -0.34 ± 0.62 lnTOI%, P < 0.001), and the TOI deficit (Δ -0.42 ± 0.68 lnTOI%·s, P < 0.001) were reduced after PS. In addition, strong linear associations were found between MMR and the TOI deficit (r2 = 0.900, P < 0.001) and ΔTOI (r2 = 0.871, P < 0.001). Furthermore, the AI accurately predicted the RRs pre- and post-PS (P = 0.471, P = 0.328, respectively). Therefore, blunted PORH after PS may be caused by attenuated MMR and not microvascular dysfunction.NEW & NOTEWORTHY Prolonged sitting reduces lower leg skeletal muscle metabolic rate in healthy individuals. Artificial intelligence revealed that impaired post-occlusive reactive hyperemia after prolonged sitting is related to a reduced stimulus for vasodilation and may not be evidence of microvascular dysfunction. Current post-occlusive reactive hyperemia protocols may be insufficient to assess micro- and macrovascular function after prolonged sitting.

Moderate dose of dietary nitrate improves skeletal muscle microvascular function in patients with peripheral artery disease.

Peripheral artery disease (PAD) is an atherosclerotic disease characterized by compromised lower-extremity blood flow that impairs walking ability. We showed that a moderate dose of dietary nitrate in the form of beetroot juice (BRJ, 0.11 mmol/kg) can improve macrovascular function and maximal walking distance in patients with PAD. However, its impacts on the microcirculation and autonomic nervous system have not been examined. Therefore, we investigated the impacts of this dose of dietary nitrate on skeletal muscle microvascular function and autonomic nervous system function and further related these measurements to 6-min walking distance, pain-free walking distance, and exercise recovery in patients with PAD. Patients with PAD (n = 10) ingested either BRJ or placebo in a randomized crossover design. Heart rate variability, skeletal muscle microvascular function, and 6-min walking distance were performed pre- and post-BRJ and placebo. There were significant group × time interactions (P < 0.05) for skeletal muscle microvascular function, 6-min walking distance, and exercise recovery, but no changes (P > 0.05) in heart rate variability or pain-free walking distance were noted. The BRJ group demonstrated improved skeletal muscle microvascular function (∆ 22.1 ± 7.5 %·min-1), longer 6-min walking distance (Δ 37.5 ± 9.1 m), and faster recovery post-exercise (Δ -15.3 ± 4.2 s). Furthermore, changes in skeletal muscle microvascular function were positively associated with changes in 6-min walking distance (r = 0.5) and pain-free walking distance (r = 0.6). These results suggest that a moderate dose of dietary nitrate may support microvascular function, which is related to improvements in walking distance and claudication in patients with PAD.

Impaired microcirculatory function, mitochondrial respiration, and oxygen utilization in skeletal muscle of claudicating patients with peripheral artery disease.

Peripheral artery disease (PAD) is an atherosclerotic disease that impairs blood flow and muscle function in the lower limbs. A skeletal muscle myopathy characterized by mitochondrial dysfunction and oxidative damage is present in PAD; however, the underlying mechanisms are not well established. We investigated the impact of chronic ischemia on skeletal muscle microcirculatory function and its association with leg skeletal muscle mitochondrial function and oxygen delivery and utilization capacity in PAD. Gastrocnemius samples and arterioles were harvested from patients with PAD (n = 10) and age-matched controls (Con, n = 11). Endothelium-dependent and independent vasodilation was assessed in response to flow (30 µL·min-1), acetylcholine, and sodium nitroprusside (SNP). Skeletal muscle mitochondrial respiration was quantified by high-resolution respirometry, microvascular oxygen delivery, and utilization capacity (tissue oxygenation index, TOI) were assessed by near-infrared spectroscopy. Vasodilation was attenuated in PAD (P < 0.05) in response to acetylcholine (Con: 71.1 ± 11.1%, PAD: 45.7 ± 18.1%) and flow (Con: 46.6 ± 20.1%, PAD: 29.3 ± 10.5%) but not SNP (P = 0.30). Complex I + II state 3 respiration (P < 0.01) and TOI recovery rate were impaired in PAD (P < 0.05). Both flow and acetylcholine-mediated vasodilation were positively associated with complex I + II state 3 respiration (r = 0.5 and r = 0.5, respectively, P < 0.05). Flow-mediated vasodilation and complex I + II state 3 respiration were positively associated with TOI recovery rate (r = 0.8 and r = 0.7, respectively, P < 0.05). These findings suggest that chronic ischemia attenuates skeletal muscle arteriole endothelial function, which may be a key mediator for mitochondrial and microcirculatory dysfunction in the PAD leg skeletal muscle. Targeting microvascular dysfunction may be an effective strategy to prevent and/or reverse disease progression in PAD.NEW & NOTEWORTHY Ex vivo skeletal muscle arteriole endothelial function is impaired in claudicating patients with PAD, and this is associated with attenuated skeletal muscle mitochondrial respiration. In vivo skeletal muscle oxygen delivery and utilization capacity is compromised in PAD, and this may be due to microcirculatory and mitochondrial dysfunction. These results suggest that targeting skeletal muscle arteriole function may lead to improvements in skeletal muscle mitochondrial respiration and oxygen delivery and utilization capacity in claudicating patients with PAD.

Body mass-normalized moderate dose of dietary nitrate intake improves endothelial function and walking capacity in patients with peripheral artery disease.

Peripheral artery disease (PAD) is characterized by the accumulation of atherosclerotic plaques in the lower extremity conduit arteries, which impairs blood flow and walking capacity. Dietary nitrate has been used to reduce blood pressure (BP) and improve walking capacity in PAD. However, a standardized dose for PAD has not been determined. Therefore, we sought to determine the effects of a body mass-normalized moderate dose of nitrate (0.11 mmol nitrate/kg) as beetroot juice on serum nitrate/nitrite, vascular function, walking capacity, and tissue oxygen utilization capacity in patients with PAD. A total of 11 patients with PAD received either nitrate supplement or placebo in a randomized crossover design. Total serum nitrate/nitrite, resting BP, brachial and popliteal artery endothelial function (flow-mediated dilation, FMD), arterial stiffness (pulse-wave velocity, PWV), augmentation index (AIx), maximal walking distance and time, claudication onset time, and skeletal muscle oxygen utilization were measured pre- and postnitrate and placebo intake. There were significant group × time interactions (P < 0.05) for serum nitrate/nitrite, FMD, BP, walking distance and time, and skeletal muscle oxygen utilization. The nitrate group showed significantly increased serum nitrate/nitrite (Δ1.32 µM), increased brachial and popliteal FMD (Δ1.3% and Δ1.7%, respectively), reduced peripheral and central systolic BP (Δ-4.7 mmHg and Δ-8.2 mmHg, respectively), increased maximal walking distance (Δ92.7 m) and time (Δ56.3 s), and reduced deoxygenated hemoglobin during walking. There were no changes in PWV, AIx, or claudication (P > 0.05). These results indicate that a body-mass normalized moderate dose of nitrate may be effective and safe for reducing BP, improving endothelial function, and improving walking capacity in patients with PAD.

Acute high-intensity exercise and skeletal muscle mitochondrial respiratory function: role of metabolic perturbation.

Recently it was documented that fatiguing, high-intensity exercise resulted in a significant attenuation in maximal skeletal muscle mitochondrial respiratory capacity, potentially due to the intramuscular metabolic perturbation elicited by such intense exercise. With the utilization of intrathecal fentanyl to attenuate afferent feedback from group III/IV muscle afferents, permitting increased muscle activation and greater intramuscular metabolic disturbance, this study aimed to better elucidate the role of metabolic perturbation on mitochondrial respiratory function. Eight young, healthy males performed high-intensity cycle exercise in control (CTRL) and fentanyl-treated (FENT) conditions. Liquid chromatography-mass spectrometry and high-resolution respirometry were used to assess metabolites and mitochondrial respiratory function, respectively, pre- and postexercise in muscle biopsies from the vastus lateralis. Compared with CTRL, FENT yielded a significantly greater exercise-induced metabolic perturbation (PCr: -67% vs. -82%, Pi: 353% vs. 534%, pH: -0.22 vs. -0.31, lactate: 820% vs. 1,160%). Somewhat surprisingly, despite this greater metabolic perturbation in FENT compared with CTRL, with the only exception of respiratory control ratio (RCR) (-3% and -36%) for which the impact of FENT was significantly greater, the degree of attenuated mitochondrial respiratory capacity postexercise was not different between CTRL and FENT, respectively, as assessed by maximal respiratory flux through complex I (-15% and -33%), complex II (-36% and -23%), complex I + II (-31% and -20%), and state 3CI+CII control ratio (-24% and -39%). Although a basement effect cannot be ruled out, this failure of an augmented metabolic perturbation to extensively further attenuate mitochondrial function questions the direct role of high-intensity exercise-induced metabolite accumulation in this postexercise response.

Combined anthocyanins and bromelain supplement improves endothelial function and skeletal muscle oxygenation status in adults: a double-blind placebo-controlled randomised crossover clinical trial.

Anthocyanins and bromelain have gained significant attention due to their antioxidative and anti-inflammatory properties. Both have been shown to improve endothelial function, blood pressure (BP) and oxygen utility capacity in humans; however, the combination of these two and the impacts on endothelial function, BP, total antioxidant capacity (TAC) and oxygen utility capacity have not been previously investigated. The purpose of this study was to investigate the impacts of a combined anthocyanins and bromelain supplement (BE) on endothelial function, BP, TAC, oxygen utility capacity and fatigability in healthy adults. Healthy adults (n 18, age 24 (sd 4) years) received BE or placebo in a randomised crossover design. Brachial artery flow-mediated dilation (FMD), BP, TAC, resting heart rate, oxygen utility capacity and fatigability were measured pre- and post-BE and placebo intake. The BE group showed significantly increased FMD, reduced systolic BP and improved oxygen utility capacity compared with the placebo group (P < 0·05). Tissue saturation and oxygenated Hb significantly increased following BE intake, while deoxygenated Hb significantly decreased (P < 0·05) during exercise. Additionally, TAC was significantly increased following BE intake (P < 0·05). There were no significant differences for resting heart rate, diastolic BP or fatigability index. These results suggest that BE intake is an effective nutritional therapy for improving endothelial function, BP, TAC and oxygen utility capacity, which may be beneficial to support vascular health in humans.

Functional, proteomic and bioinformatic analyses of Nrf2- and Keap1- null skeletal muscle.

KEY POINTS: Nrf2 is a master regulator of endogenous cellular defences, governing the expression of more than 200 cytoprotective proteins, including a panel of antioxidant enzymes. Nrf2 plays an important role in redox haemostasis of skeletal muscle in response to the increased generation of reactive oxygen species during contraction. Employing skeletal muscle-specific transgenic mouse models with unbiased-omic approaches, we uncovered new target proteins, downstream pathways and molecular networks of Nrf2 in skeletal muscle following Nrf2 or Keap1 deletion. Based on the findings, we proposed a two-way model to understand Nrf2 function: a tonic effect through a Keap1-independent mechanism under basal conditions and an induced effect through a Keap1-dependent mechanism in response to oxidative and other stresses. ABSTRACT: Although Nrf2 has been recognized as a master regulator of cytoprotection, its functional significance remains to be completely defined. We hypothesized that proteomic/bioinformatic analyses from Nrf2-deficient or overexpressed skeletal muscle tissues will provide a broader spectrum of Nrf2 targets and downstream pathways than are currently known. To this end, we created two transgenic mouse models; the iMS-Nrf2flox/flox and iMS-Keap1flox/flox , employing which we demonstrated that selective deletion of skeletal muscle Nrf2 or Keap1 separately impaired or improved skeletal muscle function. Mass spectrometry revealed that Nrf2-KO changed expression of 114 proteins while Keap1-KO changed expression of 117 proteins with 10 proteins in common between the groups. Gene ontology analysis suggested that Nrf2 KO-changed proteins are involved in metabolism of oxidoreduction coenzymes, purine ribonucleoside triphosphate, ATP and propanoate, which are considered as the basal function of Nrf2, while Keap1 KO-changed proteins are involved in cellular detoxification, NADP metabolism, glutathione metabolism and the electron transport chain, which belong to the induced effect of Nrf2. Canonical pathway analysis suggested that Keap1-KO activated four pathways, whereas Nrf2-KO did not. Ingenuity pathway analysis further revealed that Nrf2-KO and Keap1-KO impacted different signal proteins and functions. Finally, we validated the proteomic and bioinformatics data by analysing glutathione metabolism and mitochondrial function. In conclusion, we found that Nrf2-targeted proteins are assigned to two groups: one mediates the tonic effects evoked by a low level of Nrf2 at basal condition; the other is responsible for the inducible effects evoked by a surge of Nrf2 that is dependent on a Keap1 mechanism.

Impacts of prolonged sitting with mild hypercapnia on vascular and autonomic function in healthy recreationally active adults.

Prolonged sitting, which is known to impair peripheral vascular function, often occurs in spaces (e.g., offices) with mild hypercapnic atmospheres. However, the effects of prolonged sitting in hypercapnic conditions on vascular function are unknown. Therefore, the purpose of this study was to investigate the effects of prolonged sitting in mild hypercapnic conditions on vascular and autonomic function in humans. Twelve healthy young adults participated in two experimental visits that consisted of sitting for 2.5 h in a control condition [normal atmospheric conditions sitting (PSIT)] or a mild hypercapnic condition (HCAP; CO2 = 1,500 ppm). During each visit, heart rate variability (HRV), blood pressure (BP), pulse wave velocity (PWV), augmentation index (AIx), brachial and popliteal artery flow-mediated dilation (FMD), and near-infrared spectroscopy (NIRS) were assessed before and after prolonged sitting. Sitting significantly decreased AIx in both groups (P < 0.05). Brachial and popliteal FMD were reduced with sitting (P < 0.05), and the reduction in popliteal FMD was amplified by HCAP (P < 0.05). Baseline microvascular oxygenation was decreased following sitting in both groups (P < 0.05). However, microvascular reoxygenation upon cuff release was slower only in HCAP (P < 0.05). HRV, HR, BP, and PWV did not significantly change with sitting in either group (P > 0.05). We conclude that prolonged sitting attenuated both brachial and popliteal endothelial function and was associated with perturbed microcirculation. Additionally, mild hypercapnic conditions further impaired peripheral endothelial and microvascular function. Together, these findings suggest that prolonged sitting is accompanied by a host of deleterious effects on the vasculature, which are exacerbated by mild hypercapnia.NEW & NOTEWORTHY The results of this study reveal that prolonged sitting attenuates endothelial function and microvascular function. Additionally, prolonged sitting with mild hypercapnia, which is similar to everyday environments, further exacerbates peripheral endothelial function and microvascular function.

Acute mitochondrial antioxidant intake improves endothelial function, antioxidant enzyme activity, and exercise tolerance in patients with peripheral artery disease.

Peripheral artery disease (PAD) is a manifestation of atherosclerosis in the leg arteries, which causes claudication. This may be in part due to vascular mitochondrial dysfunction and excessive reactive oxygen species (ROS) production. A mitochondrial-targeted antioxidant (MitoQ) has been shown to improve vascular mitochondrial function that, in turn, led to improved vascular function in older adults and animal models. However, the roles of vascular mitochondria in vascular function including endothelial function and arterial stiffness in patients with PAD are unknown; therefore, with the use of acute MitoQ intake, this study examined the roles of vascular mitochondria in endothelial function, arterial stiffness, exercise tolerance, and skeletal muscle function in patients with PAD. Eleven patients with PAD received either MitoQ or placebo in a randomized crossover design. At each visit, blood samples, brachial and popliteal artery flow-mediated dilation (FMD), peripheral and central pulse-wave velocity (PWV), blood pressure (BP), maximal walking capacity, time to claudication (COT), and oxygen utility capacity were measured pre- and-post-MitoQ and placebo. There were significant group by time interactions (P < 0.05) for brachial and popliteal FMD that both increased by Δ2.6 and Δ3.3%, respectively, and increases superoxide dismutase (Δ0.03 U/mL), maximal walking time (Δ73.8 s), maximal walking distance (Δ49.3 m), and COT (Δ44.2 s). There were no changes in resting heart rate, BP, malondialdehyde, total antioxidant capacity, PWV, or oxygen utility capacity (P > 0.05). MitoQ intake may be an effective strategy for targeting the vascular mitochondrial environment, which may be useful for restoring endothelial function, leg pain, and walking time in patients with PAD.NEW & NOTEWORTHY The results of this study reveal for the first time that acute oral intake of mitochondrial-targeted antioxidant (MitoQ, 80 mg) is effective for improving vascular endothelial function and superoxide dismutase in patients with peripheral artery disease (PAD). Acute MitoQ intake is also effective for improving maximal walking capacity and delaying the onset of claudication in patients with PAD. These findings suggest that the acute oral intake of MitoQ-mediated improvements in vascular mitochondria play a pivotal role for improving endothelial function, the redox environment, and skeletal muscle performance in PAD.

Vasodilatory and vascular mitochondrial respiratory function with advancing age: evidence of a free radically mediated link in the human vasculature.

Recognizing the age-related decline in skeletal muscle feed artery (SMFA) vasodilatory function, this study examined the link between vasodilatory and mitochondrial respiratory function in the human vasculature. Twenty-four SMFAs were harvested from young (35 ± 6 yr, n = 9) and old (71 ± 9 yr, n = 15) subjects. Vasodilation in SMFAs was assessed, by pressure myography, in response to flow-induced shear stress, acetylcholine (ACh), and sodium nitroprusside (SNP) while mitochondrial respiration was measured, by respirometry, in permeabilized SMFAs. Endothelium-dependent vasodilation was significantly attenuated in the old, induced by both flow (young: 92 ± 3, old: 45 ± 4%) and ACh (young: 92 ± 3, old: 54 ± 5%), with no significant difference in endothelium-independent vasodilation. Complex I and I + II state 3 respiration was significantly lower in the old (CI young: 10.1 ± 0.8, old: 7.0 ± 0.4 pmol·s-1·mg-1; CI + II young: 12.3 ± 0.6, old: 7.6 ± 0.4 pmol·s-1·mg-1). The respiratory control ratio (RCR) was also significantly attenuated in the old (young: 2.2 ± 0.1, old: 1.1 ± 0.1). Furthermore, state 3 (CI + II) and 4 respiration, as well as RCR, were significantly correlated (r = 0.49-0.86) with endothelium-dependent, but not endothelium-independent, function. Finally, the direct intervention with mitochondrial-targeted antioxidant (MitoQ) significantly improved endothelium-dependent vasodilation in the old but not in the young. Thus, the age-related decline in vasodilatory function is linked to attenuated vascular mitochondrial respiratory function, likely by augmented free radicals.NEW & NOTEWORTHY In human skeletal muscle feed arteries, the well-recognized age-related fall in endothelium-dependent vasodilatory function is strongly linked to a concomitant fall in vascular mitochondrial respiratory function. The direct intervention with the mitochondrial-targeted antioxidant restored vasodilatory function in the old but not in the young, supporting the concept that exacerbated mitochondrial-derived free radical production is linked to age-related vasodilatory dysfunction. Age-related vasodilatory dysfunction in humans is linked to attenuated vascular mitochondrial respiratory function, likely a consequence of augmented free radical production.

Correction to: The effects of a 12-week jump rope exercise program on abdominal adiposity, vasoactive substances, inflammation, and vascular function in adolescent girls with prehypertension.

The Following error was published on page 578. The incorrect IRB number under "Participants" section was accidently reported.

Salt restriction lowers blood pressure at rest and during exercise without altering peripheral hemodynamics in hypertensive individuals.

Dietary salt restriction is a well-established approach to lower blood pressure and reduce cardiovascular disease risk in hypertensive individuals. However, little is currently known regarding the effects of salt restriction on central and peripheral hemodynamic responses to exercise in those with hypertension. Therefore, this study sought to determine the impact of salt restriction on the central and peripheral hemodynamic responses to static-intermittent handgrip (HG) and dynamic single-leg knee extension (KE) exercise in individuals with hypertension. Twenty-two subjects (14 men and 8 women, 51 ± 10 yr, 173 ± 11 cm, 99 ± 23 kg) forewent their antihypertensive medication use for at least 2 wk before embarking on a 5-day liberal salt (LS: 200 mmol/day) diet followed by a 5-day restricted salt (RS: 10 mmol/day) diet. Subjects were studied at rest and during static intermittent HG exercise at 15, 30, and 45% of maximal voluntary contraction and KE exercise at 40, 60, and 80% of maximum KE work rate. Salt restriction lowered resting systolic blood pressure (supine: -12 ± 12 mmHg, seated: -17 ± 12 mmHg) and diastolic blood pressure (supine: -3 ± 9 mmHg, seated: -5 ± 7 mmHg, P < 0.05). Despite an ~8 mmHg lower mean arterial blood pressure during both HG and KE exercise following salt restriction, neither central nor peripheral hemodynamics were altered. Therefore, salt restriction can lower blood pressure during exercise in subjects with hypertension, reducing the risk of cardiovascular events, without impacting central and peripheral hemodynamics during either arm or leg exercise.NEW & NOTEWORTHY This is the first study to examine the potential blood pressure-lowering benefit of a salt-restrictive diet in individuals with hypertension without any deleterious effects of exercising blood flow. While mean arterial pressure decreased by ~8 mmHg following salt restriction, these findings provide evidence for salt restriction to provide protective effects of reducing blood pressure without inhibiting central or peripheral hemodynamics required to sustain arm or leg exercise in subjects with hypertension.

The effects of a 12-week jump rope exercise program on abdominal adiposity, vasoactive substances, inflammation, and vascular function in adolescent girls with prehypertension.

INTRODUCTION: Childhood obesity is strongly associated with cardiovascular disease (CVD) development. It is necessary to combat unfavorable outcomes of obesity at a young age by utilizing effective interventions, such as exercise. PURPOSE: We sought to examine the effects of a jump rope exercise program on CVD risk factors, including body composition, vasoactive substances, inflammation, and vascular function in prehypertensive adolescent girls. METHODS: Forty girls (age 14-16) were recruited and randomly assigned to a jump rope exercise group (EX, n = 20) or control group (CON, n = 20). Body composition, nitrate and nitrite levels, endothelin-1 (ET-1), C-reactive protein (CRP), systolic blood pressure and diastolic blood pressure (SBP, DBP), and arterial stiffness were measured before and after 12 weeks. RESULTS: There were significant group by time interactions following the 12-week program for body composition (from 33.8 ± 3.6 to 30.2 ± 3.1%), central adiposity (from 86.4 ± 4 to 83.3 ± 5 cm), SBP (from 126 ± 3.3 to 120 ± 2.1 mmHg), and brachial-to-ankle pulse wave velocity (from 8.2 ± 1.0 to 7.4 ± 0.2 m/s). Nitrate/nitrite levels increased (from 54.5 ± 5.1 to 57.2 ± 5.2 µmol) along a reduction in CRP levels (from 0.5 ± 0.4 to 0.2 ± 0.1 mg/L). There were no significant changes in ET-1 (P = 0.22). CONCLUSIONS: These findings indicate that jump rope exercise may be an effective intervention to improve these CVD risk factors in prehypertensive adolescent girls. Jumping rope is an easily accessible exercise modality that may have important health implications for CVD prevention in younger populations.

Taekwondo training reduces blood catecholamine levels and arterial stiffness in postmenopausal women with stage-2 hypertension: randomized clinical trial.

Objective: Menopause is associated with a progressive impairment of vascular function and muscular strength in women. Accordingly, the purpose of this study was to determine if Taekwondo training could improve blood catecholamine levels, arterial stiffness, blood pressure (BP) and skeletal muscle strength in postmenopausal women with stage-2 hypertension. Methods: 20 postmenopausal women (70 ± 4 years old) with stage-2 hypertension were randomly assigned to a 1) Taekwondo training (TT; n = 10) or 2) Control (CON; n = 10) group. Taekwondo training was performed for 60 minutes/day, 3 days/week for 12-weeks. Results: There were significant (P < 0.05) group by time interactions for resting epinephrine (EP) and norepinephrine (NE) levels, with EP decreasing in the TT group and NE increasing in the CON group. Additionally, brachial-ankle pulse wave velocity, resting heart rate, and BP were significantly decreased, while hand grip and leg strength were significantly increased in the TT group compared to CON group. Conclusion: These results suggest that Taekwondo training can be a novel and beneficial mode of exercise for improving cardiovascular function and muscular strength in this population. Abbreviations: TT: Taekwondo training group; CON: control group; EP: epinephrine; NE: norepinephrine; ANS: autonomic nervous system; SNS: sympathetic nervous system; baPWV: brachial-ankle pulse wave velocity.

Vascular mitochondrial respiratory function: the impact of advancing age.

Little is known about vascular mitochondrial respiratory function and the impact of age. Therefore, skeletal muscle feed arteries were harvested from young (33 ± 7 yr, n = 10), middle-aged (54 ± 5 yr, n = 10), and old (70 ± 7 yr, n = 10) subjects, and mitochondrial respiration as well as citrate synthase (CS) activity were assessed. Complex I (CI) and complex I + II (CI+II) state 3 respiration were greater in young (CI: 10.4 ± 0.8 pmol·s-1·mg-1 and CI+II: 12.4 ± 0.8 pmol·s-1·mg-1, P < 0.05) than middle-aged (CI: 7 ± 0.6 pmol·s-1·mg-1 and CI+II: 8.3 ± 0.5 pmol·s-1·mg-1) and old (CI: 7.2 ± 0.4 pmol·s-1·mg-1 and CI+II: 7.6 ± 0.5 pmol·s-1·mg-1) subjects and, as in the case of complex II (CII) state 3 respiration, were inversely correlated with age [ r = -0.56 (CI), r = -0.7 (CI+II), and r = 0.4 (CII), P < 0.05]. In contrast, state 4 respiration and mitochondria-specific superoxide levels were not different across groups. The respiratory control ratio was greater in young (2.2 ± 0.2, P < 0.05) than middle-aged and old (1.4 ± 0.1 and 1.1 ± 0.1, respectively) subjects and inversely correlated with age ( r = -0.71, P < 0.05). As CS activity was inversely correlated with age ( r = -0.54, P < 0.05), when normalized for mitochondrial content, the age-related differences and relationships with state 3 respiration were ablated. In contrast, mitochondrion-specific state 4 respiration was now lower in young (15 ± 1.4 pmol·s-1·mg-1·U CS-1, P < 0.05) than middle-aged and old (23.4 ± 3.6 and 27.9 ± 3.4 pmol·s-1·mg-1·U CS-1, respectively) subjects and correlated with age ( r = 0.46, P < 0.05). Similarly, superoxide/CS levels were lower in young (0.07 ± 0.01) than old (0.19 ± 0.41) subjects and correlated with age ( r = 0.44, P < 0.05). Therefore, with aging, vascular mitochondrial respiratory function declines, predominantly as a consequence of falling mitochondrial content. However, per mitochondrion, aging likely results in greater mitochondrion-derived oxidative stress, which may contribute to age-related vascular dysfunction. NEW & NOTEWORTHY This study determined, for the first time, that vascular mitochondrial oxidative respiratory capacity, oxidative coupling efficiency, and mitochondrial content fell progressively with advancing age. In terms of single mitochondrion-specific respiration, the age-related differences were completely ablated and the likelihood of free radical production increased progressively with advancing age. This study reveals that vascular mitochondrial respiratory capacity declines with advancing age, as a consequence of falling mitochondrial content, as does oxidative coupling efficiency.

Combined resistance and aerobic exercise training reduces insulin resistance and central adiposity in adolescent girls who are obese: randomized clinical trial.

INTRODUCTION: Exercise training is recommended for improving health and protecting against the development of metabolic and cardiovascular pathologies. Combined resistance and aerobic exercise training (CRAE) has been shown to provide unique benefits in older adults with cardiovascular diseases. PURPOSE: We sought to determine the beneficial effects of CRAE in adolescent girls who are obese and hyperinsulinemic. METHODS: Forty adolescent girls who are obese (age 14.7 ± 1 years; BMI 30 ± 2) were randomly assigned to a "no exercise" (CON n = 20) or combined exercise group (EX n = 20). The EX group performed resistance and aerobic exercise for 12 weeks, 5 times per week. Exercise intensity was increased gradually, from 40 to 70% of heart rate reserve (HRR), every 4 weeks. The brachial-ankle pulse wave velocity (BaPWV), blood pressure (BP), heart rate (HR), blood leptin, adiponectin levels, and body composition were measured before and after the 12-week intervention. RESULTS: We observed that CRAE effectively reduced the body fat percentage, body weight, and waist circumference in the EX group (p < 0.05). After 12 weeks of training, subjects in the CRAE group maintained appropriate leptin and adiponectin levels and showed positive improvements of blood insulin, glucose, and insulin resistance parameters relative to baseline and to the CON group (p < 0.05). CONCLUSION: CRAE is a useful therapeutic method to alleviate metabolic risk factors in adolescent girls who are obese and hyperinsulinemic.

The Effects of a 12-Week Combined Exercise Training Program on Arterial Stiffness, Vasoactive Substances, Inflammatory Markers, Metabolic Profile, and Body Composition in Obese Adolescent Girls.

PURPOSE: Childhood and adolescent obesity is a major international public health crisis. It is crucial to prevent the negative effects of obesity at an early age by implementing appropriate lifestyle interventions, such as exercise training. We evaluated the effects of a combined resistance and aerobic exercise training (CET) regimen on arterial stiffness, vasoactive substances, inflammatory markers, metabolic profile, and body composition in obese adolescent girls. METHODS: A total of 30 obese adolescent girls were randomly assigned to a CET (n = 15) or a control group (n = 15). The CET group trained for 3 days per week. Plasma nitric oxide, endothelin-1, C-reactive protein, arterial stiffness, glucose, insulin, the adiponectin/leptin ratio, and body fat were measured before and after 12 weeks. RESULTS: There were significant increases (P < .05) in nitric oxide (4.0 µM) and adiponectin/leptin ratio (0.33); and decreases (P < .05) in arterial stiffness (-1.0 m/s), C-reactive protein (-0.5 mg/L), glucose (-1.2 mmol/L), insulin (-17.1 µU/mL), and body fat (-3.6%) following CET compared with control. There were no significant changes in endothelin-1 after CET or control. CONCLUSIONS: The findings of this study indicate that CET improves arterial stiffness, nitric oxide, and inflammatory and metabolic markers in obese adolescent girls. CET may have important health implications for the prevention of atherosclerosis at an early age.

Effectiveness of Tai Chi on Cardiac Autonomic Function and Symptomatology in Women With Fibromyalgia: A Randomized Controlled Trial.

The present study examined the effects of a 12-week Tai Chi (TC) training regimen on heart rate variability (HRV), symptomatology, muscle fitness and body composition in women with fibromyalgia. Participants were randomly assigned to either a TC training group (n = 18) or a control group (n = 19). HRV, symptomatology, muscle fitness and body composition were measured before and after 12 weeks. There were significant decreases (p < 0.05) in sympathovagal balance (LnLF/LnHF), sympathetic tone (LnLF, nLF), pain, and fatigue, and significant increases (p < 0.05) in parasympathetic tone (LnHF, nHF), strength and flexibility following TC compared with no changes after control. The changes in LnLF and LnLF/LnHF were correlated with changes in pain. There were no significant changes in HR, sleep quality and body composition after TC or control. TC may be an effective therapeutic intervention for improving sympathovagal balance, pain, fatigue, strength and flexibility in women with fibromyalgia.

WNT5A regulates adipose tissue angiogenesis via antiangiogenic VEGF-A165b in obese humans.

Experimental studies have suggested that Wingless-related integration site 5A (WNT5A) is a proinflammatory secreted protein that is associated with metabolic dysfunction in obesity. Impaired angiogenesis in fat depots has been implicated in the development of adipose tissue capillary rarefaction, hypoxia, inflammation, and metabolic dysfunction. We have recently demonstrated that impaired adipose tissue angiogenesis is associated with overexpression of antiangiogenic factor VEGF-A165b in human fat and the systemic circulation. In the present study, we postulated that upregulation of WNT5A is associated with angiogenic dysfunction and examined its role in regulating VEGF-A165b expression in human obesity. We biopsied subcutaneous and visceral adipose tissue from 38 obese individuals (body mass index: 44 ± 7 kg/m2, age: 37 ± 11 yr) during planned bariatric surgery and characterized depot-specific protein expression of VEGF-A165b and WNT5A using Western blot analysis. In both subcutaneous and visceral fat, VEGF-A165b expression correlated strongly with WNT5A protein (r = 0.9, P < 0.001). In subcutaneous adipose tissue where angiogenic capacity is greater than in the visceral depot, exogenous human recombinant WNT5A increased VEGF-A165b expression in both whole adipose tissue and isolated vascular endothelial cell fractions (P < 0.01 and P < 0.05, respectively). This was associated with markedly blunted angiogenic capillary sprout formation in human fat pad explants. Moreover, recombinant WNT5A increased secretion of soluble fms-like tyrosine kinase-1, a negative regulator of angiogenesis, in the sprout media (P < 0.01). Both VEGF-A165b-neutralizing antibody and secreted frizzled-related protein 5, which acts as a decoy receptor for WNT5A, significantly improved capillary sprout formation and reduced soluble fms-like tyrosine kinase-1 production (P < 0.05). We demonstrated a significant regulatory nexus between WNT5A and antiangiogenic VEGF-A165b in the adipose tissue of obese subjects that was linked to angiogenic dysfunction. Elevated WNT5A expression in obesity may function as a negative regulator of angiogenesis.NEW & NOTEWORTHY Wingless-related integration site 5a (WNT5A) negatively regulates adipose tissue angiogenesis via VEGF-A165b in human obesity.