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 nitric oxide (NO). We previously discovered that flow-induced NO production in resistance arteries of mice and humans critically depends on endothelial inwardly rectifying K+ (Kir2.1) channels. 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 32 subjects: normotensive [n = 19; 30.6 ± 9.8 yr old; systolic blood pressure (SBP): 115.2 ± 7 mmHg; diastolic blood pressure (DBP): 75.3 ± 5.7 mmHg] and hypertensive (n = 13; 45.3 ± 15.3 yr old; SBP: 146.1 ± 15.2 mmHg; DBP: 94.4 ± 6.9 mmHg). Consistent with previous studies, we find that FIV is impaired in hypertensive adults as demonstrated by a significant reduction in FIV when compared with the normotensive adults. Furthermore, our data suggest that the impairment of FIV in hypertensive adults is partially attributed to a reduction in Kir2.1-dependent vasodilation. Specifically, we show that blocking Kir2.1 with ML133 or functionally downregulating Kir2.1 with endothelial-specific adenoviral vector containing dominant-negative Kir2.1 (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 both SBP and DBP, indicating that the Kir2.1 contribution to FIV decreases as blood pressure increases. In addition, we show that 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 hypertension-induced suppression of Kir2.1 is an important mechanism underlying endothelial dysfunction in hypertension.NEW & NOTEWORTHY Impairment of endothelial function under high blood pressure is linked to the loss of inwardly rectifying K+ (Kir2.1) channels activity in human resistance arteries, leading to a reduction in flow-induced vasodilation and possibly leading to a vicious cycle between elevation of blood pressure, and further impairment of Kir2.1 function and flow-induced vasodilation.

Prognostic value of the duke activity Status Index Questionnaire in predicting mortality in patients with chronic heart failure: 36-month follow-up study.

BACKGROUND: The Duke Activity Status Index (DASI) questionnaire has been the focus of numerous investigations - its discriminative and prognostic capacity has been continuously explored, supporting its use in the clinical setting, specifically during rehabilitation in patients with chronic heart failure (CHF).However, studies exploring optimal DASI questionnaire threshold scores are limited. OBJECTIVE: To investigate optimal DASI questionnaire thresholds values in predicting mortality in a CHF cohort and assess mortality rates based on the DASI questionnaire using a thresholds values obtained. METHODOLOGY: This is a prospective cohort study with a 36-month follow-up in patients with CHF. All patients completed a clinical assessment, followed by DASI questionnaire, pulmonary function, and echocardiography. The Receiver Operating Characteristic (ROC) curve analysis was used to discriminate the DASI questionnaire score in determining the risk of mortality. For survival analysis, the Kaplan-Meier model was used to explore the impact of ≤/>23 points on mortality occurring during the 36-month follow-up. RESULTS: One hundred and twenty-four patients were included, the majority being elderly men. Kaplan Meier analysis revealed that ≤/> 23 was a strong predictor of CHF mortality over a 36-month follow-up. CONCLUSION: A score of ≤/>23 presents good discriminatory capacity to predict mortality risk in 36 months in patients with CHF, especially in those with reduced or mildly reduced ejection fraction. Age, ejection fraction, DASI questionnaire score and use of digoxin are risk factors that influence mortality in this population.

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.

Hemispheric lateralization, endothelial function, and arterial compliance in chronic post-stroke individuals: A cross-sectional exploratory study.

Purpose/Aim: Cardiovascular function is controlled and regulated by a functional brain-heart axis. Although the exact mechanism is not fully understood, several studies suggest a hemispheric asymmetry in the neural control of cardiovascular function. Thus, the purpose of this study was to examine whether endothelial function and arterial compliance differ between individuals with left- and right-sided strokes.Materials and Methods: This was a cross-sectional exploratory study. Thirty individuals more than 6 months after stroke participated in the study. The endothelial function was assessed by ultrasound-measured flow-mediated dilation of the nonparetic arm brachial artery (baFMD). The arterial stiffness was assessed by measuring carotid-femoral pulse wave velocity (cfPWV) and central aortic pulse wave analysis [augmentation index (AIx), augmentation index normalized to a heart rate of 75 bpm (AIx@75) and reflection magnitude (RM)] using applanation tonometry. Results: Participants with right-sided stroke had worse endothelial function than those with left-sided stroke. This difference (baFMD = 2.51%) was significant (p = 0.037), and it represented a medium effect size (r = 0.38). Likewise, they had higher arterial stiffness than those with left-sided stroke. This difference (AIx = 10%; RM = 7%) was significant (p = 0.011; p = 0.012), and it represented a medium effect size (r = 0.48; r = 0.47).Conclusions: Our findings suggest that individuals with right-sided stroke have reduced endothelial function and arterial compliance compared to those with left-sided stroke. These data may indicate that those with right-sided strokes are more susceptible to cardiovascular events.

Differential responses of resistance arterioles to elevated intraluminal pressure in blacks and whites.

Black Americans have an earlier onset, higher average blood pressure, and higher rates of hypertension-related mortality and morbidity, compared to whites. The racial difference may be related to microvasculature, the major regulatory site of blood pressure. The goal of this study was to compare the response of resistance vessels to high intraluminal pressure between black and white participants. A total of 38 vessels were obtained from human fat samples [21 black, 17 white; mean age 32 ± 12 yr and body mass index (BMI) 26.9 ± 4.9; between-group P ≥ 0.05] and included in this study. Internal diameter was measured in response to the flow induced by various pressure gradients (Δ10, Δ20, Δ40, Δ60, and Δ100 cmH2O), and flow-induced dilation (FID) was calculated before and after high intraluminal pressure (150 cmH2O). Before high intraluminal pressure, FID was not different between blacks and whites (P = 0.112). After exposure to high intraluminal pressure, FID was reduced at every pressure gradient in vessels from blacks (P < 0.001), whereas FID did not change in white participants except at Δ100 cmH2O. When incubated with the hydrogen peroxide (H2O2) scavenger polyethylene glycol-catalase (PEG-catalase), the FID response in vessels from black, but not white, individuals was significantly reduced and the magnitude was higher at normal pressure relative to high pressure. Our findings suggest that the vessels from self-identified black individuals are more susceptible to microvascular dysfunction following transient periods of high intraluminal pressure compared to whites and show greater dependence on H2O2 as a main contributor to FID at normal pressures.NEW & NOTEWORTHY Microvascular function regulates blood pressure and may contribute to racial differences in the incidence and prevalence of hypertension and other cardiovascular diseases. Here, we show that using an ex vivo model of resistance arterioles isolated from human gluteal fat tissue, flow-induced dilation is not different between black and white participants. However, when exposed to transient increases in intraluminal pressure, the flow-induced dilation in resistance arterioles from black participants demonstrated greater reductions relative to their white counterparts, indicating a higher sensitivity to pressure change in the microvasculature.

Factors associated with phosphatidylethanol (PEth) sensitivity for detecting unhealthy alcohol use: An individual patient data meta-analysis.

BACKGROUND: Objective measurement of alcohol consumption is important for clinical care and research. Adjusting for self-reported alcohol use, we conducted an individual participant data (IPD) meta-analysis to examine factors associated with the sensitivity of phosphatidylethanol (PEth), an alcohol metabolite, among persons self-reporting unhealthy alcohol consumption. METHODS: We identified 21 eligible studies and obtained 4073 observations from 3085 participants with Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) positive scores (≥3 for women and ≥4 for men) and PEth measurements. We conducted 1-step IPD meta-analysis using mixed effects models with random intercepts for study site. We examined the associations between demographic (sex, race/ethnicity, and age) and biologic (body mass index-BMI, hemoglobin, HIV status, liver fibrosis, and venous versus finger-prick blood collection) variables with PEth sensitivity (PEth≥8 ng/ml), adjusting for the level of self-reported alcohol use using the AUDIT-C score. RESULTS: One third (31%) of participants were women, 32% were African, 28% African American, 28% White, and 12% other race/ethnicity. PEth sensitivity (i.e., ≥8 ng/ml) was 81.8%. After adjusting for AUDIT-C, we found no associations of sex, age, race/ethnicity, or method of blood collection with PEth sensitivity. In models that additionally included biologic variables, those with higher hemoglobin and indeterminate and advanced liver fibrosis had significantly higher odds of PEth sensitivity; those with higher BMI and those living with HIV had significantly lower odds of PEth sensitivity. African Americans and Africans had higher odds of PEth sensitivity than whites in models that included biologic variables. CONCLUSIONS: Among people reporting unhealthy alcohol use, several biological factors (hemoglobin, BMI, liver fibrosis, and HIV status) were associated with PEth sensitivity. Race/ethnicity was associated with PEth sensitivity in some models but age, sex, and method of blood collection were not. Clinicians should be aware of these factors, and researchers should consider adjusting analyses for these characteristics where possible.

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.

Cognitive and vascular function in older adults with and without CKD.

BACKGROUND: Cognitive impairment is a common complication of aging that is also associated with chronic kidney disease (CKD). Vascular dysfunction has been implicated as a potential cause of cognitive impairment in older adults, with particular deficits noted in those with CKD. AIMS: To determine the differences in cognitive function and vascular compliance in older adults with and without CKD with preclinical cognitive impairment and the relationship between these factors. METHODS: Utilizing a cross-sectional approach, 48 older adults with preclinical cognitive impairment (24 with and 24 without CKD) were evaluated for performance on a test of global cognition and executive function, and vascular compliance via tonometry and ultrasound. RESULTS: Cognitive function and some indicators of vascular function were significantly different in older adults with and without CKD. Global cognition was correlated with carotid-femoral pulse wave velocity (r = - 0.36, p = 0.02) in the entire sample. Vascular function was not correlated with executive function. DISCUSSION: Older adults with preclinical cognitive impairment and CKD had different cognitive and vascular function than those without CKD, and an indicator of vascular function may have a relationship with cognitive function in older adults. CONCLUSIONS: The findings of this study support the assessment of cognitive and vascular function in older adults with and without CKD with preclinical cognitive impairment.

Effect of an Exergaming-Based Dance Training Paradigm on Autonomic Nervous System Modulation in Healthy Older Adults: A Randomized Controlled Trial.

The purpose of this study was to determine if an exergaming-based dance training protocol can improve heart rate variability (HRV) in healthy older adults. A total of 20 healthy older adults (≥65 years old) were randomly assigned to two groups. The intervention group received an exergaming-based dance aerobic training for 6 weeks, while the control group received a 1-hr education on conventional physical exercises. Data obtained from HRV analysis pre- (Week 0) and postintervention (Week 7) consisted of high-frequency power, low- and high-frequency ratio, and root mean square of differences and percentage of adjacent RR intervals with a difference of duration greater than 50 ms values. HRV was assessed during rest and during a 6-min walk test. In addition, the YMCA submaximal cycle ergometer test was used to acquire estimated maximal O2 consumption pre- and postintervention. After the training, the intervention group showed significant improvement in HRV high-frequency power, root mean square of differences, and percentage of adjacent RR intervals with a difference of duration greater than 50 ms values in both rest and 6-min walk test conditions compared with the control group. Similarly, the intervention group showed higher maximal O2 consumption compared with the control group after the training. Our results support the effectiveness of an exergaming-based dance aerobic training on improving cardiac autonomic control in aging.

Sedentary Behavior in Older Adults With Preclinical Cognitive Impairment With and Without Chronic Kidney Disease.

Older adults with preclinical cognitive impairment can have chronic conditions and lifestyle factors that influence health. Sedentary behavior is common in older adults with and without chronic kidney disease (CKD). The objective of the current study was to determine the differences in sedentary behavior for older adults with preclinical cognitive impairment with and without CKD. Our study evaluated 48 older adults with preclinical cognitive impairment with and without CKD who underwent assessment of sedentary behavior via accelerometry. We found that older adults with preclinical cognitive impairment with and without CKD were sedentary, but there were no significant differences between groups. Fragmentation index was different (p < 0.05), with a lower fragmentation index found in those with CKD. Sedentary behavior should be assessed and evaluated as a potential target for interventions to improve health in these at-risk older adults; however, further investigation is needed. [Journal of Gerontological Nursing, 47(6), 35-42.].

The Influence of Sedentary Behavior on the Relationship Between Cognitive Function and Vascular Function in Older Adults with and without Chronic Kidney Disease.

Cognitive impairment and vascular dysfunction are common in older adults with and without chronic kidney disease (CKD). Older adults with and without CKD are also sedentary - a behavior associated with cognitive and vascular function. The objective of this study was to explore whether sedentary behavior influenced the relationship between cognitive and vascular function in older adults with preclinical cognitive impairment with and without CKD. In our study, 48 older adults underwent assessment of cognition, vascular compliance, and sedentary behavior, and relationships were explored with regression moderation analysis. Sedentary time and breaks did not moderate the relationship between vascular and cognitive function. Although significant moderation was not found, cognition, vascular function, and sedentary behavior are important to assess when evaluating older adults with and without CKD.

Tetrahydrobiopterin Restores Microvascular Dysfunction in Young Adult Binge Drinkers.

BACKGROUND: Repeated binge drinking is associated with reduced microvascular function. However, microvascular responses to pathophysiological stimulus such as high pressure as well as potential mechanisms that underlie binge-induced microvascular dysfunction are unknown. Therefore, using an ex vivo experimental model, we examined microvascular responses following a brief period of high intraluminal pressure in isolated arterioles from young adults who have a history of repeated binge drinking. In addition, we examined whether the application of the endothelial nitric oxide synthase cofactor, tetrahydrobiopterin, would restore microvascular function in response to flow and high intraluminal pressure in young adult binge drinkers. METHODS: Isolated subcutaneous adipose arterioles were obtained from young adult binge drinkers (BD; n = 14), moderate drinkers (MODs; n = 10), and alcohol abstainers (ABs; n = 12; mean age: 23.7 ± 0.5 years; and body mass index: 23.4 ± 0.4 kg/m2 ). Arteriolar flow-induced dilation (FID, pressure gradient: ∆10 to 100 cm H2 O) was measured before and after acute high intraluminal pressure with and without tetrahydrobiopterin. RESULTS: Before high pressure, FID at Δ60 and Δ100 cm H2 O pressure gradient in BDs was 14% lower and 18% lower, respectively, than ABs (p < 0.05), while MODs and ABs had similar FID across all pressure gradients (p ≥ 0.2). After high pressure, FID in BDs was further reduced by 10% (p < 0.0005) and this impairment was ameliorated by the treatment of tetrahydrobiopterin (4 to 26% higher, p < 0.005). In contrast, FID after high pressure did not change in MODs and ABs (p ≥ 0.5). CONCLUSIONS: Microvascular dysfunction in young adult binge drinkers may be exacerbated with acute pathophysiological stimulus. These binge-induced dysfunctions may be reversed by tetrahydrobiopterin, which suggests a role of oxidative stress and/or uncoupled endothelial nitric oxide synthase in binge drinking.

Relationship between cardiovascular risk factors and binge drinking among college students in South Korea.

This study determined cardiovascular risk among Korean college students with a history of binge drinking. Variables included alcohol consumption, cardiovascular risk factors (increased blood pressure, body mass index, lipid values) and markers (high-sensitivity C-reactive protein, fibrinogen), and 10-year Framingham risk scores. Korean college student binge drinkers had higher triglyceride levels and higher ratios of triglyceride to high-density lipoprotein cholesterol than did abstainers. Average number of drinks on one occasion was correlated with higher body mass index, triglyceride level, ratio of triglyceride to high-density lipoprotein cholesterol, and 10-year Framingham risk score. The findings indicate that binge drinking may be associated with premature cardiovascular disease risk.

Results from the randomized controlled IHOPE trial suggest no effects of oral protein supplementation and exercise training on physical function in hemodialysis patients.

Few long-term studies have assessed whether changes in both diet and exercise can improve the health and quality of life (QOL) of hemodialysis (HD) patients. Here we examined whether 12 months of intradialytic protein supplementation and endurance exercise improves physical function, risk of cardiovascular disease (CVD), and QOL in HD patients in a randomized controlled trial (RCT). A total of 138 HD patients (average age 58 years) were assigned for 12 months to control, intradialytic protein, or protein plus exercise groups. The protein and protein plus exercise groups consumed an oral protein supplement (30 grams of whey) three days/week during dialysis. The protein plus exercise group cycled for 30-45 minutes during dialysis treatment. The primary outcome was change in physical function at 12 months, assessed by a shuttle walk test. Secondary outcomes included arterial stiffness, blood pressure, body composition, muscle strength, markers of nutritional status, and QOL. Assessments were conducted at baseline, 6 and 12 months. In total, 101 patients completed the intervention. There were no significant differences between groups in shuttle walk test performance from baseline to 12 months. There were trends for improvements in some secondary measures of physical function and strength in the protein and protein plus exercise groups at six or 12 months, but these did not reach statistical significance. Thus, our trial did not demonstrate significant improvements in markers of physical function, risk of CVD or QOL after one year of intradialytic oral OPS and aerobic exercise training. More comprehensive lifestyle management may be needed to uncover robust improvements in the health and QOL of HD patients.

Role of matrix metalloproteinases and histone deacetylase in oxidative stress-induced degradation of the endothelial glycocalyx.

The glycocalyx is crucial for normal endothelial function. It also tethers extracellular superoxide dismutase (SOD3), which protects the endothelium against oxidative damage. Proteolytic enzymes [matrix metalloproteinases (MMPs)] are capable of disrupting endothelial cell surface proteins, such as syndecans, resulting in derangements of the endothelial glycocalyx. We sought to test the role of MMPs in oxidative stress-mediated disruption of the endothelial glycocalyx and examine the effect of pharmacological inhibition of MMPs on mitigating this detrimental effect. We also examined the role of histone deacetylase (HDAC) in the oxidative stress-mediated MMP induction and glycocalyx remodeling. Oxidative stress was experimentally induced in human adipose microvascular endothelial cells using H2O2 and buthionine sulfoximine in the presence and absence of potent MMP and HDAC inhibitors. H2O2 and buthionine sulfoximine resulted in a notable loss of the endothelial glycocalyx; they also increased the expression and proteolytic activity of MMP-2 and MMP-9 and subsequently increased the shedding of syndecan-1 and SOD3 from the endothelial cell surface. MMP upregulation was accompanied by a decline in mRNA and protein levels of their inhibitors, tissue inhibitors of metalloproteinase (TIMPs; TIMP-1 and TIMP-3). Furthermore, oxidative stress induced HDAC activity. Inhibition of MMPs and HDAC reversed syndecan-1 and SOD3 shedding and maintained endothelial glycocalyx integrity. HDAC inhibition increased TIMP expression and reduced MMP expression and activity in endothelial cells. Our findings shed light on MMPs and HDAC as therapeutically targetable mechanisms in oxidative stress-induced glycocalyx remodeling. NEW & NOTEWORTHY Oxidative stress, a hallmark of many diseases, damages the endothelial glycocalyx, resulting in vascular dysfunction. Studying the mechanistic link between oxidative stress and endothelial glycocalyx derangements might help discover new therapeutic targets to preserve vascular function. In this study, we investigated the involvement of matrix metalloproteinases and histone deacetylase in oxidative stress-induced endothelial glycocalyx degradation.

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.

Contemporary Appraisal of Sex Differences in Prevalence, Correlates, and Outcomes of Alcoholic Cardiomyopathy.

AIMS: The aims of this study were to: examine differences in alcoholic cardiomyopathy (ACM) prevalence, temporal trends and the distribution of socio-demographic factors and comorbidities by sex; and investigate differences in selected inpatient outcomes between women and men with ACM. METHODS: We used the 2002-2014 Nationwide Inpatient Sample databases. Overall and sex-specific rates of ACM were estimated across sociodemographic, clinical, and hospital characteristics. Joinpoint regression was used to estimate temporal trends (annual percent change [APC]) of ACM-related hospitalization by sex and race/ethnicity. Adjusted odds ratios (AOR) representing associations between sex and selected ACM outcomes were calculated using survey logistic regression. RESULTS: The rate of ACM among all inpatient men and women was 128 per 100,000 and 17 per 100,000 hospitalizations, respectively. Among women, the rate of ACM remained unchanged during the study period, while for men, there was 1.2% annual reduction from 2002-2010 (APC -1.3, 95% CI: -1.7, -0.8). Women with ACM were more likely than men with ACM to experience depression (AOR=2.24, 95% CI: 2.06-2.43) and anxiety (AOR=1.94, 95% CI: 1.75-2.15), while men with ACM were 21% and 24% more likely than women with ACM to experience 'any heart failure (HF)' and HF with reduced ejection fraction respectively. One in 1,471 hospitalizations were related to ACM with a male-to-female ratio of 8:1. CONCLUSION: Individuals with ACM are at increased likelihood of adverse outcomes. Women with ACM are at increased risk of depression and anxiety, while men are at increased risk of HF.

MicroRNA-21 Contributes to Reduced Microvascular Function in Binge Drinking Young Adults.

BACKGROUND: Binge drinking is associated with increased risk for cardiovascular (CV) disease. MicroRNA-21 (miR21) is up-regulated in the setting of excessive alcohol consumption and CV disease. Therefore, the goal of this study was to examine the vasodilatory responses to flow and acetylcholine (ACh) in the absence and presence of an anti-miR21 inhibitor in the microcirculation of young adult repeated binge drinkers (BDs). METHODS: Gluteal subcutaneous adipose tissue biopsies were obtained from young adults (18 to 30 years, n = 35 vessels from BDs and n = 28 vessels from abstainers). Resistance arteries (RAs) were isolated, incubated with anti-miR21 or a negative control (NC) to miR21 (12 hours; 50 nM), and lumen diameters measured with video microscopy. miR21 of adipose tissues was determined by quantitative polymerase chain reaction. RESULTS: Flow-induced dilation and ACh-induced dilation (AChID) were reduced in BDs as compared to abstainers. The miR21 inhibitor but not the NC abrogated these effects in BDs, but did not affect vasodilation in abstainers. Nitric oxide synthase inhibition with L-NAME reduced vasodilation in abstainers but not in BDs. In BDs, vasodilation was reduced by L-NAME in the presence of anti-miR21 but not the NC. Scavenging the reactive oxygen species, hydrogen peroxide with polyethylene glycol catalase reduced dilation in BDs but did not affect the restored dilation by the miR21 inhibitor. Maximum dilation to papaverine (endothelium independent) was similar between groups and unaffected by pharmacological inhibition. Finally, vascular endogenous miR21 was increased in BDs compared to abstainers. CONCLUSIONS: Endogenous miR21 is increased in RAs of young BDs, leading to reduced flow and AChID in the microcirculation.

Microvascular Vasodilator Plasticity After Acute Exercise.

Endothelium-dependent vasodilation is reduced after acute exercise or after high intraluminal pressure in isolated arterioles from sedentary adults but not in arterioles from regular exercisers. The preserved vasodilation in arterioles from exercisers is hydrogen peroxide (H2O2) dependent, whereas resting dilation is nitric oxide (NO) dependent. We hypothesize chronic exercise elicits adaptations allowing for maintained vasodilation when NO bioavailability is reduced.

Effects of inspiratory muscle training in professional women football players: a randomized sham-controlled trial.

This study was conducted to determine the effects of inspiratory muscle training (IMT) on respiratory and peripheral muscles oxygenation during a maximal exercise tolerance test and on repeated-sprint ability (RSA) performance in professional women football players. Eighteen athletes were randomly assigned to one of the following groups: SHAM (n = 8) or IMT (n = 10). After a maximal incremental exercise test, all participants performed (on a different day) a time-to-exhaustion (Tlim) test. Peripheral and respiratory muscles oxygenation by near-infrared spectroscopy, breath-by-breath ventilatory and metabolic variables, and blood lactate concentration were measured. The RSA test was performed on a grass field. After a 6 week intervention, all athletes were reevaluated. Both groups showed increases in inspiratory muscles strength, exercise tolerance and RSA performance, however only the IMT group presented lower deoxyhemoglobin and total hemoglobin blood concentrations on intercostal muscles concomitantly to an increased oxyhemoglobin and total hemoglobin blood concentrations on vastus lateralis muscle during Tlim. In conclusion, these results may indicate the potential role of IMT to attenuate inspiratory muscles metaboreflex and consequently improve oxygen and blood supply to limb muscles during high-intensity exercise, with a potential impact on inspiratory muscle strength, exercise tolerance and sprints performance in professional women football players.