Impairment of Microvascular Endothelial Kir2.1 Channels Contributes to Endothelial Dysfunction in Human Hypertension.

Hypertension is associated with decreased endothelial function through reduced contributions of NO. We previously discovered that flow-induced NO production in resistance arteries of mice and humans critically depends on endothelial inwardly-rectifying K+ channels (Kir2.1). The goal of this study was to establish whether these channels contribute to the impairment of endothelial function, measured by flow-induced vasodilation (FIV) in peripheral resistance arteries of humans with hypertension. We measured FIV in vessels isolated from subcutaneous fat biopsies from normotensive (n=19; SBP: 115±27mmHg; DBP: 75.3±5.7mmHg) and hypertensive subjects (n=13; SBP: 146.1±15.2 mmHg; DBP: 94.4±6.9mmHg). We find that FIV is impaired in hypertensive adults as demonstrated by a significant reduction in FIV when compared to the normotensive adults, which is partially attributed to a reduction in Kir2.1-dependent vasodilation. Specifically, we show that pharmacologically inhibiting Kir2.1 or functionally downregulating Kir2.1 with endothelial-specific adenoviral vector dnKir2.1 result in a significant reduction in FIV in normotensive subjects but with a smaller effect in hypertensive adults. The Kir2.1-dependent vasodilation was negatively correlated to SBP and DBP, indicating that Kir2.1 contribution to FIV decreases as blood pressure increases. Furthermore, exposing vessels from normotensive adults to acute high-pressure results in loss of Kir2.1 contribution, as high-pressure impairs vasodilation. No effect is seen when these vessels were incubated with dnKir2.1. Overexpressing wtKir2.1 in the endothelium resulted in some improvement in vasodilation in arteries from all participants, with a greater recovery in hypertensive adults. Our data suggest that high pressure-induced suppression of Kir2.1 is an important mechanism underlying endothelial dysfunction in hypertension.

The MindMoves Trial: Cross-Sectional Analyses of Baseline Vascular Risk and Cognition in Older Women with Cardiovascular Disease.

Background: Vascular diseases, including atherosclerotic cardiovascular disease (ASCVD) and stroke, increase the risk of Alzheimer's disease and cognitive impairment. Serum biomarkers, such as brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), and insulin-like growth factor 1 (IGF-1), may be indicators of cognitive health. Objective: We examined whether vascular risk was associated with levels of cognition and serum biomarkers in older women with cardiovascular disease (CVD). Methods: Baseline data from a lifestyle trial in older women (n = 253) with CVD (NCT04556305) were analyzed. Vascular risk scores were calculated for ASCVD (ASCVD risk estimator) and stroke (CHA2DS2-VASc) based on published criteria. Cognition-related serum biomarkers included BDNF, VEGF, and IGF-1. Cognition was based on a battery of neuropsychological tests that assessed episodic memory, semantic memory, working memory, and executive function. A series of separate linear regression models were used to evaluate associations of vascular risk scores with outcomes of cognition and serum biomarkers. All models were adjusted for age, education level, and racial and ethnic background. Results: In separate linear regression models, both ASCVD and CHA2DS2-VASc scores were inversely associated with semantic memory (ß= -0.22, p = 0.007 and ß= -0.15, p = 0.022, respectively), with no significant findings for the other cognitive domains. There were no significant associations between vascular risk scores and serum biomarkers. Conclusions: Future studies should prospectively examine associations between vascular risk and cognition in other populations and additionally consider other serum biomarkers that may be related to vascular risk and cognition.

Effects of Exercise Mode on Improving Cardiovascular Function and Cardiorespiratory Fitness After Bariatric Surgery: A Narrative Review.

ABSTRACT: Obesity affects 600 million people globally and increases the risk of developing cardiovascular disease, stroke, diabetes, and cancer. Bariatric surgery is an increasingly popular therapeutic intervention for morbid obesity to induce rapid weight loss and reduce obesity-related comorbidities. However, some bariatric surgery patients, after what is considered a successful surgical procedure, continue to manifest obesity-related health issues, including weight gain, reduced physical function, persistent elevations in blood pressure, and reduced cardiorespiratory fitness. Cardiorespiratory fitness is a strong predictor of mortality and several health outcomes and could be improved by an appropriate exercise prescription after bariatric surgery. This review provides a broad overview of exercise training for patients after bariatric surgery and discusses cardiorespiratory fitness and other potential physiological adaptations in response to exercise training.

Differential effects of obesity on visceral versus subcutaneous adipose arteries: role of shear-activated Kir2.1 and alterations to the glycocalyx.

Obesity imposes well-established deficits to endothelial function. We recently showed that obesity-induced endothelial dysfunction was mediated by disruption of the glycocalyx and a loss of Kir channel flow sensitivity. However, obesity-induced endothelial dysfunction is not observed in all vascular beds: visceral adipose arteries (VAAs), but not subcutaneous adipose arteries (SAAs), exhibit endothelial dysfunction. To determine whether differences in SAA versus VAA endothelial function observed in obesity are attributed to differential impairment of Kir channels and alterations to the glycocalyx, mice were fed a normal rodent diet, or a high-fat Western diet to induce obesity. Flow-induced vasodilation (FIV) was measured ex vivo. Functional downregulation of endothelial Kir2.1 was accomplished by transducing adipose arteries from mice and obese humans with adenovirus containing a dominant-negative Kir2.1 construct. Kir function was tested in freshly isolated endothelial cells seeded in a flow chamber for electrophysiological recordings under fluid shear. Atomic force microscopy was used to assess biophysical properties of the glycocalyx. Endothelial dysfunction was observed in VAAs of obese mice and humans. Downregulating Kir2.1 blunted FIV in SAAs, but had no effect on VAAs, from obese mice and humans. Obesity abolished Kir shear sensitivity in VAA endothelial cells and significantly altered the VAA glycocalyx. In contrast, Kir shear sensitivity was observed in SAA endothelial cells from obese mice and effects on SAA glycocalyx were less pronounced. We reveal distinct differences in Kir function and alterations to the glycocalyx that we propose contribute to the dichotomy in SAA versus VAA endothelial function with obesity.NEW & NOTEWORTHY We identified a role for endothelial Kir2.1 in the differences observed in VAA versus SAA endothelial function with obesity. The endothelial glycocalyx, a regulator of Kir activation by shear, is unequally perturbed in VAAs as compared with SAAs, which we propose results in a near complete loss of VAA endothelial Kir shear sensitivity and endothelial dysfunction. We propose that these differences underly the preserved endothelial function of SAA in obese mice and humans.

Oral vitamin C restores endothelial function during acute inflammation in young and older adults.

Oxidative stress has been linked to reductions in vascular function during acute inflammation in young adults; however, the effect of acute inflammation on vascular function with aging is inconclusive. The aim of this study was to determine if oral antioxidant administration eliminates vascular dysfunction during acute inflammation in young and older adults. Brachial flow-mediated dilation (FMD) and carotid-femoral pulse wave velocity (PWV) were measured in nine young (3 male, 24 ± 4 yrs, 26.2 ± 4.9 kg/m2 ) and 16 older (13 male, 64 ± 5 yrs, 25.8 ± 3.2 kg/m2 ) adults before and 2-h after oral consumption of 2 g of vitamin C. The vitamin C protocol was completed at rest and 24 h after acute inflammation was induced via the typhoid vaccine. Venous blood samples were taken to measure markers of inflammation and vitamin C. Both interleukin-6 (Δ+0.7 ± 1.8 pg/ml) and C-reactive protein (Δ+1.9 ± 3.1 mg/L) were increased at 24 h following the vaccine (p < 0.01). There was no change in FMD or PWV following vitamin C administration at rest (p > 0.05). FMD was lower in all groups during acute inflammation (Δ-1.4 ± 1.9%, p < 0.01), with no changes in PWV (Δ-0.0 ± 0.9 m/s, p > 0.05). Vitamin C restored FMD back to initial values in young and older adults during acute inflammation (Δ+1.0 ± 1.8%, p < 0.01) with no change in inflammatory markers or PWV (p > 0.05). In conclusion, oral vitamin C restored endothelial function during acute inflammation in young and older adults, with no effect on aortic stiffness. The effect of vitamin C on endothelial function did not appear to be due to reductions in inflammatory markers. The exact mechanisms should be further investigated.

Hyperhomocysteinemia and Low Folate and Vitamin B12 Are Associated with Vascular Dysfunction and Impaired Nitric Oxide Sensitivity in Morbidly Obese Patients.

There is a high prevalence of hyperhomocysteinemia that has been linked to high cardiovascular risk in obese individuals and could be attributed to poor nutritional status of folate and vitamin B12. We sought to examine the association between blood homocysteine (Hcy) folate, and vitamin B12 levels and vascular dysfunction in morbidly obese adults using novel ex vivo flow-induced dilation (FID) measurements of isolated adipose tissue arterioles. Brachial artery flow-mediated dilation (FMD) was also measured. Subcutaneous and visceral adipose tissue biopsies were obtained from morbidly obese individuals and non-obese controls. Resistance arterioles were isolated in which FID, acetylcholine-induced dilation (AChID), and nitric oxide (NO) production were measured in the absence or presence of the NO synthase inhibitor, L-NAME, Hcy, or the superoxide dismutase mimetic, TEMPOL. Our results demonstrated that plasma Hcy concentrations were significantly higher, while folate, vitamin B12, and NO were significantly lower in obese subjects compared to controls. Hcy concentrations correlated positively with BMI, fat %, and insulin levels but not with folate or vitamin B12. Brachial and arteriolar vasodilation were lower in obese subjects, positively correlated with folate and vitamin B12, and inversely correlated with Hcy. Arteriolar NO measurements and sensitivity to L-NAME were lower in obese subjects compared to controls. Finally, Hcy incubation reduced arteriolar FID and NO sensitivity, an effect that was abolished by TEMPOL. In conclusion, these data suggest that high concentrations of plasma Hcy and low concentrations of folate and vitamin B12 could be independent predictors of vascular dysfunction in morbidly obese individuals.

Impairment of Flow-Sensitive Inwardly Rectifying K+ Channels via Disruption of Glycocalyx Mediates Obesity-Induced Endothelial Dysfunction.

OBJECTIVE: To determine if endothelial dysfunction in a mouse model of diet-induced obesity and in obese humans is mediated by the suppression of endothelial Kir (inwardly rectifying K+) channels. Approach and Results: Endothelial dysfunction, observed as reduced dilations to flow, occurred after feeding mice a high-fat, Western diet for 8 weeks. The functional downregulation of endothelial Kir2.1 using dominant-negative Kir2.1 construct resulted in substantial reductions in the response to flow in mesenteric arteries of lean mice, whereas no effect was observed in arteries of obese mice. Overexpressing wild-type-Kir2.1 in endothelium of arteries from obese mice resulted in full recovery of the flow response. Exposing freshly isolated endothelial cells to fluid shear during patch-clamp electrophysiology revealed that the flow-sensitivity of Kir was virtually abolished in cells from obese mice. Atomic force microscopy revealed that the endothelial glycocalyx was stiffer and the thickness of the glycocalyx layer reduced in arteries from obese mice. We also identified that the length of the glycocalyx is critical to the flow-activation of Kir. Overexpressing Kir2.1 in endothelium of arteries from obese mice restored flow- and heparanase-sensitivity, indicating an important role for heparan sulfates in the flow-activation of Kir. Furthermore, the Kir2.1-dependent component of flow-induced vasodilation was lost in the endothelium of resistance arteries of obese humans obtained from biopsies collected during bariatric surgery. CONCLUSIONS: We conclude that obesity-induced impairment of flow-induced vasodilation is attributed to the loss of flow-sensitivity of endothelial Kir channels and propose that the latter is mediated by the biophysical alterations of the glycocalyx.

HIF1α/TET1 Pathway Mediates Hypoxia-Induced Adipocytokine Promoter Hypomethylation in Human Adipocytes.

Obesity is associated with the accumulation of dysfunctional adipose tissue that secretes several pro-inflammatory cytokines (adipocytokines). Recent studies have presented evidence that adipose tissues in obese individuals and animal models are hypoxic, which may result in upregulation and stabilization of the hypoxia inducible factor HIF1α. Epigenetic mechanisms such as DNA methylation enable the body to respond to microenvironmental changes such as hypoxia and may represent a mechanistic link between obesity-associated hypoxia and upregulated inflammatory adipocytokines. The purpose of this study was to investigate the role of hypoxia in modifying adipocytokine DNA methylation and subsequently adipocytokine expression. We suggested that this mechanism is mediated via the DNA demethylase, ten-eleven translocation-1 (TET1), transcription of which has been shown to be induced by HIF1α. To this end, we studied the effect of hypoxia (2% O2) in differentiated subcutaneous human adipocytes in the presence or absence of HIF1α stabilizer (Dimethyloxalylglycine (DMOG), 500 µM), HIF1α inhibitor (methyl 3-[[2-[4-(2-adamantyl) phenoxy] acetyl] amino]-4-hydroxybenzoate, 30 µM), or TET1-specific siRNA. Subjecting the adipocytes to hypoxia significantly induced HIF1α and TET1 protein levels. Moreover, hypoxia induced global hydroxymethylation, reduced adipocytokine DNA promoter methylation, and induced adipocytokine expression. These effects were abolished by either HIF1α inhibitor or TET1 gene silencing. The major hypoxia-responsive adipocytokines were leptin, interleukin-1 (IL6), IL1ß, tumor necrosis factor α (TNFα), and interferon γ (IFNγ). Overall, these data demonstrate an activation of the hydroxymethylation pathway mediated by TET1. This pathway contributes to promoter hypomethylation and gene upregulation of the inflammatory adipocytokines in adipocytes in response to hypoxia.

Vitamin D Improves Nitric Oxide-Dependent Vasodilation in Adipose Tissue Arterioles from Bariatric Surgery Patients.

There is a high prevalence of vitamin-D deficiency in obese individuals that could be attributed to vitamin-D sequestration in the adipose tissue. Associations between vitamin-D deficiency and unfavorable cardiometabolic outcomes were reported. However, the pathophysiological mechanisms behind these associations are yet to be established. In our previous studies, we demonstrated microvascular dysfunction in obese adults that was associated with reduced nitric oxide (NO) production. Herein, we examined the role of vitamin D in mitigating microvascular function in morbidly obese adults before and after weight loss surgery. We obtained subcutaneous (SAT) and visceral adipose tissue (VAT) biopsies from bariatric patients at the time of surgery (n = 15) and gluteal SAT samples three months post-surgery (n = 8). Flow-induced dilation (FID) and acetylcholine-induced dilation (AChID) and NO production were measured in the AT-isolated arterioles ± NO synthase inhibitor N(ω)-nitro-L-arginine methyl ester (L-NAME), hydrogen peroxide (H2O2) inhibitor, polyethylene glycol-modified catalase (PEG-CAT), or 1,25-dihydroxyvitamin D. Vitamin D improved FID, AChID, and NO production in AT-isolated arterioles at time of surgery; these effects were abolished by L-NAME but not by PEG-CAT. Vitamin-D-mediated improvements were of a higher magnitude in VAT compared to SAT arterioles. After surgery, significant improvements in FID, AChID, NO production, and NO sensitivity were observed. Vitamin-D-induced changes were of a lower magnitude compared to those from the time of surgery. In conclusion, vitamin D improved NO-dependent arteriolar vasodilation in obese adults; this effect was more significant before surgery-induced weight loss.

Outpatient Physical Therapist Attitudes Toward and Behaviors in Cardiovascular Disease Screening: A National Survey.

BACKGROUND: Screening the cardiovascular system is an important and necessary component of the physical therapist examination to ensure patient safety, appropriate referral, and timely medical management of cardiovascular disease (CVD) and risk factors. The most basic screening includes a measurement of resting blood pressure (BP) and heart rate (HR). Previous work demonstrated that rates of BP and HR screening and perceptions toward screening by physical therapists are inadequate. OBJECTIVE: The purpose was to assess the current attitudes and behaviors of physical therapists in the United States regarding the screening of patients for CVD or risk factors in outpatient orthopedic practice. DESIGN: This was a cross-sectional, online survey study. METHODS: Data were collected from an anonymous adaptive online survey delivered via an email list. RESULTS: A total of 1812 surveys were included in this analysis. A majority of respondents (n = 931; 51.38%) reported that at least half of their current caseload included patients either with diagnosed CVD or at moderate or greater risk of a future occurrence. A total of 14.8% of respondents measured BP and HR on the initial examination for each new patient. The most commonly self-reported barriers to screening were lack of time (37.44%) and lack of perceived importance (35.62%). The most commonly self-reported facilitators of routine screening were perceived importance (79.48%) and clinic policy (38.43%). Clinicians who managed caseloads with the highest CVD risk were the most likely to screen. LIMITATIONS: Although the sampling population included was large and representative of the profession, only members of the American Physical Therapy Association Orthopaedic Section were included in this survey. CONCLUSIONS: Despite the high prevalence of patients either diagnosed with or at risk for CVD, few physical therapists consistently included BP and HR on the initial examination. The results of this survey suggest that efforts to improve understanding of the importance of screening and modifications of clinic policy could be effective strategies for improving rates of HR and BP screening.

Exercise Training Does Improve Cardiorespiratory Fitness in Post-Bariatric Surgery Patients.

Although exercise is recognized as an important component of the management for patients following bariatric surgery (BS), its effectiveness on cardiorespiratory fitness (CRF) is still unclear. To investigate this relationship between BS and CRF, a systematic review was conducted in the MEDLINE database. The literature search included studies involving exercise training in patients following BS. A total of 306 studies were identified, 7 met the criteria and were included in the meta-analysis. Exercise training was found to result in a moderate and significant increase in VO2max (SMD = 0.430, 95% CI 0.157; 0.704, p = 0.002) following BS. The results from this meta-analysis indicate that exercise training can significantly improve CRF. Further research is needed to determine the ideal training duration and exercise training parameters for patients following BS.

Precision Medicine in Weight Loss and Healthy Living.

Obesity affects 600 million people globally and over one third of the American population. Along with associated comorbidities, including cardiovascular disease, stroke, diabetes, and cancer; the direct and indirect costs of managing obesity are 21% of the total medical costs. These factors shed light on why developing effective and pragmatic strategies to reduce body weight in obese individuals is a major public health concern. An estimated 60-70% of obese Americans attempt to lose weight each year, with only a small minority able to achieve and maintain long term weight loss. To address this issue a precision medicine approach for weight loss has been considered, which places an emphasis on sustainability and real-world application to individualized therapy. In this article we review weight loss interventions in the context of precision medicine and discuss the role of genetic and epigenetic factors, pharmacological interventions, lifestyle interventions, and bariatric surgery on weight loss.

Endothelial Dysfunction and Inflammation Precedes Elevations in Blood Pressure Induced by a High-Fat Diet.

BACKGROUND: Obesity leads to a chronic inflammatory state, endothelial dysfunction and hypertension. OBJECTIVE: To establish the time-course of events regarding inflammatory markers, endothelial dysfunction, systolic blood pressure (SBP) in obesity in only one experimental model. METHODS: We fed male Wistar rats (eight-week age) with a standard diet (Control - CT, n = 35), or palatable high-fat diet (HFD, n = 35) for 24 weeks. Every six weeks, 7 animals from each group were randomly selected for euthanasia. SBP and serum levels of interleukin-6, tumor necrosis factor-α, C-reactive protein, adiponectin and nitric oxide were determined. Endothelial and vascular smooth muscle functions were determined in dissected aorta and lipid peroxidation was measured. Statistical significance was set at p < 0.05. RESULTS: Levels of pro-inflammatory cytokines began to increase after six weeks of a high-fat diet, while those of the anti-inflammatory cytokine adiponectin decreased. Interestingly, the endothelial function and serum nitric oxide began to decrease after six weeks in HFD group. The SBP and lipid peroxidation began to increase at 12 weeks in HFD group. In addition, we showed that total visceral fat mass was negatively correlated with endothelial function and positively correlated with SBP. CONCLUSION: Our results show the time-course of deleterious effects and their correlation with obesity.

Endothelial Dysfunction and Inflammation Precedes Elevations in Blood Pressure Induced by a High-Fat Diet / Disfunção Endotelial e Inflamação Precedem a Elevação da Pressão Arterial Induzida por Dieta Hiperlipídica

Abstract Background: Obesity leads to a chronic inflammatory state, endothelial dysfunction and hypertension. Objective: To establish the time-course of events regarding inflammatory markers, endothelial dysfunction, systolic blood pressure (SBP) in obesity in only one experimental model. Methods: We fed male Wistar rats (eight-week age) with a standard diet (Control - CT, n = 35), or palatable high-fat diet (HFD, n = 35) for 24 weeks. Every six weeks, 7 animals from each group were randomly selected for euthanasia. SBP and serum levels of interleukin-6, tumor necrosis factor-α, C-reactive protein, adiponectin and nitric oxide were determined. Endothelial and vascular smooth muscle functions were determined in dissected aorta and lipid peroxidation was measured. Statistical significance was set at p < 0.05. Results: Levels of pro-inflammatory cytokines began to increase after six weeks of a high-fat diet, while those of the anti-inflammatory cytokine adiponectin decreased. Interestingly, the endothelial function and serum nitric oxide began to decrease after six weeks in HFD group. The SBP and lipid peroxidation began to increase at 12 weeks in HFD group. In addition, we showed that total visceral fat mass was negatively correlated with endothelial function and positively correlated with SBP. Conclusion: Our results show the time-course of deleterious effects and their correlation with obesity.

Resumo Fundamento: A obesidade leva a um estado de inflamação crônica, disfunção endotelial e hipertensão. Objetivo: Estabelecer a sequência de eventos relacionados a marcadores inflamatórios, disfunção endotelial e pressão arterial sistólica (PAS) na obesidade em um modelo experimental. Métodos: Ratos Wistar machos (8 semanas de idade) receberam dieta padrão (Controle - CT, n = 35) ou uma dieta palatável hiperlipídica (DHL, n = 35) por 24 semanas. A cada seis semanas, 7 animais de cada grupo foram aleatoriamente selecionados para eutanásia. Foram determinados a PAS, e níveis séricos de interleucina-6, fator de necrose tumoral-a, proteína C reativa, adiponectina e óxido nítrico. As funções do músculo liso endotelial e vascular foram determinadas na aorta dissecada, e medida a peroxidação lipídica. A significância estatística foi estabelecida em p < 0,05. Resultados: os níveis das citocinas pró-inflamatórias começaram a aumentar após seis semanas de dieta hiperlipídica, enquanto os níveis da citocina anti-inflamatória adiponectina diminuíram. Um resultado interessante foi a redução da função endotelial e do óxido nítrico após seis semanas no grupo DHL. Além disso, mostramos que a massa de tecido adiposo visceral total esteve negativamente correlacionada com função endotelial e positivamente correlacionada com a PAS. Conclusão: Nossos resultados demonstram a progressão temporal dos efeitos deletérios e sua correlação com a obesidade.

Akt2 (Protein Kinase B Beta) Stabilizes ATP7A, a Copper Transporter for Extracellular Superoxide Dismutase, in Vascular Smooth Muscle: Novel Mechanism to Limit Endothelial Dysfunction in Type 2 Diabetes Mellitus.

OBJECTIVE: Copper transporter ATP7A (copper-transporting/ATPase) is required for full activation of SOD3 (extracellular superoxide dismutase), which is secreted from vascular smooth muscle cells (VSMCs) and anchors to endothelial cell surface to preserve endothelial function by scavenging extracellular superoxide. We reported that ATP7A protein expression and SOD3 activity are decreased in insulin-deficient type 1 diabetes mellitus vessels, thereby, inducing superoxide-mediated endothelial dysfunction, which are rescued by insulin treatment. However, it is unknown regarding the mechanism by which insulin increases ATP7A expression in VSMCs and whether ATP7A downregulation is observed in T2DM (type2 diabetes mellitus) mice and human in which insulin-Akt (protein kinase B) pathway is selectively impaired. APPROACH AND RESULTS: Here we show that ATP7A protein is markedly downregulated in vessels isolated from T2DM patients, as well as those from high-fat diet-induced or db/db T2DM mice. Akt2 (protein kinase B beta) activated by insulin promotes ATP7A stabilization via preventing ubiquitination/degradation as well as translocation to plasma membrane in VSMCs, which contributes to activation of SOD3 that protects against T2DM-induced endothelial dysfunction. Downregulation of ATP7A in T2DM vessels is restored by constitutive active Akt or PTP1B-/- (protein-tyrosine phosphatase 1B-deficient) T2DM mice, which enhance insulin-Akt signaling. Immunoprecipitation, in vitro kinase assay, and mass spectrometry analysis reveal that insulin stimulates Akt2 binding to ATP7A to induce phosphorylation at Ser1424/1463/1466. Furthermore, SOD3 activity is reduced in Akt2-/- vessels or VSMCs, which is rescued by ATP7A overexpression. CONCLUSION: Akt2 plays a critical role in ATP7A protein stabilization and translocation to plasma membrane in VSMCs, which contributes to full activation of vascular SOD3 that protects against endothelial dysfunction in T2DM.

Improvements in cardiometabolic risk markers, aerobic fitness, and functional performance following a physical therapy weight loss program.

OBJECTIVE: The objectives of this study were to determine the efficacy of a current physical therapy and weight loss program model on exercise performance, physical function, and cardiometabolic risk factors in obese patients. DESIGN: Retrospective pre-post design. SUBJECTS: A total of 192 patients who previously underwent testing of anthropometric measurements, cardiovascular biomarkers, and lower extremity function scale (LEFS) were included. RESULTS: There was a significant reduction in body weight [5.91 ± 3.47 (95% CI, 5.4 to 6.4) kg; p < 0.001; n = 187] and waist circumference [7.1 ± 5 (95% CI, 6.3 to 7.9) cm; p < 0.001; n = 187]. Submaximal exercise capacity (VO2ex) increased by [5.29 ± 4.74 (95% CI, 4.38 to 6.19) ml/kg/min; p < 0.001; n = 107], and lower extremity functional scale (LEFS) improved by [9 ± 11 (95% CI, 7 to 12) scale points; p < 0.001; n = 75]. Both systolic (pre SBP: 125.7 ± 15 vs. post SBP: 118.4 ± 12 mmHg; p < 0.001; n = 150) and diastolic (pre DBP: 78.5 ± 10 vs. post DBP: 74 ± 8.5 mmHg; p < 0.001; n = 150) blood pressures as well as fasting blood glucose (pre FBG: 112.8 ± 37 vs. post FBG: 99 ± 18 mg/dL; p < 0.001; n = 132) were significantly reduced. CONCLUSIONS: This study indicates the importance and significance of weight loss in improving physical function and cardiometabolic risk profiles across a cohort of outpatient physical therapy patients. Our study also suggests that weight loss can be achieved in a comprehensive exercise intensive physical therapy program for obese patients.

Nox2 contributes to hyperinsulinemia-induced redox imbalance and impaired vascular function.

Insulin resistance promotes vascular endothelial dysfunction and subsequent development of cardiovascular disease. Previously we found that skeletal muscle arteriolar flow-induced dilation (FID) was reduced following a hyperinsulinemic clamp in healthy adults. Therefore, we hypothesized that hyperinsulinemia, a hallmark of insulin resistance, contributes to microvascular endothelial cell dysfunction via inducing oxidative stress that is mediated by NADPH oxidase (Nox) system. We examined the effect of insulin, at levels that are comparable with human hyperinsulinemia on 1) FID of isolated arterioles from human skeletal muscle tissue in the presence and absence of Nox inhibitors and 2) human adipose microvascular endothelial cell (HAMECs) expression of nitric oxide (NO), endothelial NO synthase (eNOS), and Nox-mediated oxidative stress. In six lean healthy participants (mean age 25.5±1.6 y, BMI 21.8±0.9), reactive oxygen species (ROS) were increased while NO and arteriolar FID were reduced following 60min of ex vivo insulin incubation. These changes were reversed after co-incubation with the Nox isoform 2 (Nox2) inhibitor, VAS2870. In HAMECs, insulin-induced time-dependent increases in Nox2 expression and P47phox phosphorylation were echoed by elevations of superoxide production. In contrast, phosphorylation of eNOS and expression of superoxide dismutase (SOD2 and SOD3) isoforms showed a biphasic response with an increased expression at earlier time points followed by a steep reduction phase. Insulin induced eNOS uncoupling that was synchronized with a drop of NO and a surge of ROS production. These effects were reversed by Tempol (SOD mimetic), Tetrahydrobiopterin (BH4; eNOS cofactor), and VAS2870. Finally, insulin induced nitrotyrosine formation which was reversed by inhibiting NO or superoxide generation. In conclusions, hyperinsulinemia may reduce FID via inducing Nox2-mediated superoxide production in microvascular endothelial cells which reduce the availability of NO and enhances peroxynitrite formation. Therefore, the Nox2 pathway should be considered as a target for the prevention of oxidative stress-associated endothelial dysfunction during hyperinsulinemia.

Exploring Vascular Function Biomarkers: Implications for Rehabilitation.

The endothelium plays an important role in maintaining vascular homeostasis and regulating blood vessel function. Endothelial function is considered an independent predictor for risk of future cardiovascular events in cardiovascular and non-cardiovascular patients, as well as a predictor for postoperative complications in cardiovascular surgery patients. Brachial artery flow-mediated dilation by high-resolution ultrasound is widely used to evaluate endothelium-dependent vasodilation, which is mainly mediated by nitric oxide release. Physical exercise exerts beneficial effects on endothelial function and can be used in both primary and secondary prevention of cardiac and peripheral artery diseases, even in the postoperative period of cardiovascular surgery.

Exploring vascular function biomarkers: implications for rehabilitation

Abstract The endothelium plays an important role in maintaining vascular homeostasis and regulating blood vessel function. Endothelial function is considered an independent predictor for risk of future cardiovascular events in cardiovascular and non-cardiovascular patients, as well as a predictor for postoperative complications in cardiovascular surgery patients. Brachial artery flow-mediated dilation by high-resolution ultrasound is widely used to evaluate endothelium-dependent vasodilation, which is mainly mediated by nitric oxide release. Physical exercise exerts beneficial effects on endothelial function and can be used in both primary and secondary prevention of cardiac and peripheral artery diseases, even in the postoperative period of cardiovascular surgery.

Nonpharmacologic management of hypertension: a multidisciplinary approach.

PURPOSE OF REVIEW: Nonpharmacologic lifestyle modification interventions (LMIs), such as increasing physical activity, dietary modification, weight-loss, reducing alcohol consumption and smoking cessation, are effective strategies to lower resting blood pressures (BPs) in prehypertensive or hypertensive patients. However, the limited time shared between a physician and a patient is not adequate to instill an adoption of LMI. The purpose of this review is to therefore highlight evidence-based BP lowering, LMI strategies that can feasibly be implemented in clinical practices. RECENT FINDINGS: Interventions focusing on modifying physical activity, diet, weight-loss, drinking and smoking habits have established greater efficacy in reducing elevated BP compared with providing guideline recommendations based on national guidelines. Alone greater reductions in BP can be achieved through programmes that provide frequent contact time with exercise, nutrition and/or wellness professionals. Programmes that educate individuals to lead peer support groups can be an efficient method of ensuring compliance to LMI. SUMMARY: Evidence of a multidisciplinary approach to LMI is an effective and attractive model in managing elevated BP. This strategy is an attractive model that provides the necessary patient attention to confer lifestyle maintenance.