Don't sweat the small stuff: skin mechanisms of sodium homeostasis and associations with long-term blood pressure.

Despite the overwhelming evidence that the kidney is the principal regulator of chronic blood pressure though the ability to sense pressure and adjust blood volume accordingly, recent clinical and preclinical evidence suggests that skin clearance of Na+ through sweat significantly contributes to long-term blood pressure and risk of hypertension. Evidence indicates that changes in skin Na+ content negatively associate with renal function, and factors that influence the concentration of Na+ in sweat are affected by major regulators of Na+ excretion by the kidney such as angiotensin and aldosterone. In addition, known regulatory mechanisms that regulate the amount of sweat produced do not include changes in Na+ intake or blood volume. Because of these reasons, it will be hard to quantify the contribution of Na+ clearance through sweat to blood pressure regulation and hypertension. While Chen et al. demonstrate significant negative associations between sweat Na+ concentration and blood pressure, it is likely that Na+ clearance through the skin has a short-term influence on blood pressure and sweat Na+ concentration is most likely a biomarker of renal function and its key role in hypertension.

Modeling the physiological roles of the heart and kidney in heart failure with preserved ejection fraction during baroreflex activation therapy.

Heart failure (HF) is a leading cause of death and is increasing in prevalence. Unfortunately, therapies that have been efficacious in patients with HF with reduced ejection fraction (HFrEF) have not convincingly shown a reduction in cardiovascular mortality in patients with HF with preserved ejection fraction (HFpEF). It is thought that high sympathetic nerve activity (SNA) in the heart plays a role in HF progression. Clinical trials demonstrate that baroreflex activation therapy reduces left ventricular (LV) mass and blood pressure (BP) in patients with HFpEF and hypertension; however, the mechanisms are unclear. In the present study, we used HumMod, a large physiology model to simulate HFpEF and predict the time-dependent changes in systemic and cardiac hemodynamics, SNA, and cardiac stresses during baroreflex activation. The baseline HFpEF model was associated with elevations in systolic BP, diastolic dysfunction, and LV hypertrophy and stiffness similar to clinical HFpEF. Simulating 12 mo of baroreflex activation resulted in reduced systolic BP (-25 mmHg) and LV mass (-15%) similar to clinical evidence. Baroreflex activation also resulted in sustained decreases in cardiac and renal SNA (-22%) and improvement in LV ß1-adrenergic function. However, the baroreflex-induced reductions in BP and improvements in cardiac stresses, mass, and function were mostly attenuated when renal SNA was clamped at baseline levels. These simulations suggest that the suppression of renal SNA could be a primary determinant of the cardioprotective effects from baroreflex activation in HFpEF.NEW & NOTEWORTHY Treatments that are efficacious in patients with HFrEF have not shown a significant impact on cardiovascular mortality in patients with HFpEF. We believe these simulations offer novel insight into the important roles of the cardiac and renal nerves in HFpEF and the potential mechanisms of how baroreflex activation alleviates HFpEF disease progression.

Physiological Mechanisms of Hypertension and Cardiovascular Disease in End-Stage Kidney Disease.

PURPOSE OF REVIEW: In this article, we summarize recent advances in understanding hypertension and cardiovascular disease in patients with end-stage kidney disease. RECENT FINDINGS: Factors such as anemia, valvular and vascular calcification, vasoconstrictors, uremic toxins, hypoglycemia, carbamylated proteins, oxidative stress, and inflammation have all been associated with the progression of cardiovascular disease in end-stage kidney disease but the causality of these mechanisms has not been proven. The high risk of cardiovascular mortality has not improved as in the general population despite many advancements in cardiovascular care over the last two decades. Mechanisms that increase hypertension risk in these patients are centered on the control of extracellular fluid volume; however, over-correction of volume with dialysis can increase risks of intradialytic hypotension and death in these patients. This review presents both recent and classic work that increases our understanding of hypertension and cardiovascular disease in end-stage kidney disease.

Endothelin antagonism reduces hemoglobin A1c in patients with pulmonary hypertension.

Our lab recently reported that the blockade of endothelin-1 (ET-1) receptors attenuates insulin resistance in obese mice; therefore, we hypothesized that patients taking ET-1 receptor antagonists (ERAs) will have improved glycemic control. University of Mississippi Medical Center (2013-2020) electronic health record (EPIC) data were extracted from patients ≥18 years old with a clinical diagnosis of pulmonary hypertension (Food and Drug Administration indication for ERA use) and at least two clinical visits within 2 years. Patients prescribed ERAs (n = 11) were similar in age (61 ± 14 years vs. 60 ± 14 years), body mass index (BMI) (34 ± 8 kg/m 2 vs. 35 ± 11 kg/m2), diabetes prevalence (73% vs. 80%, p = 0.59), and follow-up time (209 ± 74 days vs. 283 ± 180 days) compared with patients not taking ERAs (n = 137). There was a small but similar decrease in BMI at follow-up in the ERA (-1.9 ± 3 kg/m2) and control patients (-1.6 ± 5 kg/m2). At follow-up, hemoglobin A1c (HbA1c) significantly decreased -12% ± 11% of baseline in patients taking ERAs, while this did not occur in the control patients (2% ± 20% increase in HbA1c). In the whole population, baseline HbA1c and ERA prescription predicted the fall in HbA1c, while there was no significant association with demographics, diabetes prevalence, and diabetic treatment. These data suggest a potential role of ET-1 in promoting insulin resistance and warrant further investigation into using these drugs for glycemic control.

Questioning the renoprotective role of L-type calcium channel blockers in chronic kidney disease using physiological modeling.

Chronic kidney disease (CKD) is characterized by the progressive functional loss of nephrons and hypertension (HTN). Some antihypertensive regimens attenuate the progression of CKD (blockers of the renin-angiotensin system). Although studies have suggested that calcium channel blocker (CCB) therapy mitigates the decline in renal function in humans with essential HTN, there are few long-term clinical studies that have determined the impact of CCBs in patients with hypertensive CKD. Dihydropyridine (DHP) or L-type CCBs preferentially vasodilate the afferent arteriole and have been associated with glomerular HTN and increases in proteinuria in animal models with low renal function. Small clinical studies in vulnerable populations with renal disease such as African Americans, children, and diabetics have also suggested that DHP CCBs exacerbate glomerular injury, which questions the renoprotective effect of this class of antihypertensive drug. We used an established integrative mathematical model of human physiology, HumMod, to test the hypothesis that DHP CCB therapy exacerbates pressure-induced glomerular injury in hypertensive CKD. Over a simulation of 3 yr, CCB therapy reduced mean blood pressure by 14-16 mmHg in HTN both with and without CKD. Both impaired tubuloglomerular feedback and low baseline renal function exacerbated glomerular pressure, glomerulosclerosis, and the decline in renal function during L-type CCB treatment. However, simulating CCB therapy that inhibited both L- and T-type calcium channels increased efferent arteriolar vasodilation and alleviated glomerular damage. These simulations support the evidence that DHP (L-type) CCBs potentiate glomerular HTN during CKD and suggest that T/L-type CCBs are valuable in proteinuric renal disease treatment.NEW & NOTEWORTHY Our physiological model replicates clinical trial results and provides unique insights into possible mechanisms that play a role in glomerular injury and hypertensive kidney disease progression during chronic CCB therapy. Specifically, these simulations predict the temporal changes in renal function with CCB treatment and demonstrate important roles for tubuloglomerular feedback and efferent arteriolar conductance in the control of chronic kidney disease progression.

Physiological Modeling and Simulation-Validation, Credibility, and Application.

In this review, we discuss the science of model validation as it applies to physiological modeling. There is widespread disagreement and ambiguity about what constitutes model validity. In areas in which models affect real-world decision-making, including within the clinic, in regulatory science, or in the design and engineering of novel therapeutics, this question is of critical importance. Without an answer, it impairs the usefulness of models and casts a shadow over model credibility in all domains. To address this question, we examine the use of nonmathematical models in physiological research, in medical practice, and in engineering to see how models in other domains are used and accepted. We reflect on historic physiological models and how they have been presented to the scientific community. Finally, we look at various validation frameworks that have been proposed as potential solutions during the past decade.

Preeminent role of the cardiorenal axis in the antihypertensive response to an arteriovenous fistula: an in silico analysis.

Percutaneous creation of a small central arteriovenous (AV) fistula is currently being evaluated for the treatment of uncontrolled hypertension (HT). Although the mechanisms that contribute to the antihypertensive effects of the fistula are unclear, investigators have speculated that chronic blood pressure (BP) lowering may be due to 1) reduced total peripheral resistance (TPR), 2) increased secretion of atrial natriuretic peptide (ANP), and/or 3) suppression of renal sympathetic nerve activity (RSNA). We used an established integrative mathematical model of human physiology to investigate these possibilities from baseline conditions that mimic sympathetic overactivity and impaired renal function in patients with resistant HT. After a small fistula was stimulated, there were sustained increases in cardiac output, atrial pressures, and plasma ANP concentration (3-fold), without suppression of RSNA; at 8 wk, BP was reduced 14 mmHg along with a 32% fall in TPR. In contrast, when this simulation was repeated while clamping ANP at baseline BP decreased only 4 mmHg, despite a comparable fall in TPR. Furthermore, when chronic resetting of atrial mechanoreceptors was prevented during the fistula, RSNA decreased 7%, and along with the same threefold increase in ANP, BP fell 19 mmHg. This exaggerated fall in BP occurred with a similar decrease in TPR when compared with the above simulations. These findings suggest that ANP, but not TPR, is a key determinant of long-term BP lowering after the creation of an AV fistula and support a contribution of suppressed RSNA if resetting of the atrial-renal reflex is truly incomplete.NEW & NOTEWORTHY The mechanisms that contribute to the antihypertensive effects of a small arteriovenous (AV) fistula comparable to the size used by the ROX coupler currently in clinical trials are unclear and not readily testable in clinical or experimental studies. The integrative mathematical model of human physiology used in the current study provides a tool for understanding key causal relationships that account for blood pressure (BP) lowering and for testing competing hypotheses. The findings from the simulations suggest that after creation of a small AV fistula increased ANP secretion plays a critical role in mediating long-term reductions in BP. Measurement of natriuretic peptide levels in hypertensive patients implanted with the ROX coupler would provide one critical test of this hypothesis.

Early treatment with GLP-1 after severe trauma preserves renal function in obese Zucker rats.

Early posttrauma hyperglycemia (EPTH) is correlated with later adverse outcomes, including acute kidney injury (AKI). Controlling EPTH in the prehospital setting is difficult because of the variability in the ideal insulin dosage and the potential risk of hypoglycemia, especially in those with confounding medical comorbidities of obesity and insulin resistance. Glucagon-like peptide-1 (GLP-1) controls glucose levels in a glucose-dependent manner and is a current target in antidiabetic therapy. We have shown that after orthopedic trauma, obese Zucker rats exhibit EPTH and a later development of AKI (within 24 h). We hypothesized that GLP-1 treatment after trauma decreases EPTH and protects renal function in obese Zucker rats. Obese Zucker rats (~12 wk old) were fasted for 4 h before trauma. Soft tissue injury, fibula fracture, and homogenized bone component injection were then performed in both hind limbs to induce severe extremity trauma. Plasma glucose levels were measured before and 15, 30, 60, 120, 180, 240, and 300 min after trauma. GLP-1 (3 µg·kg-1·h-1, 1.5 ml/kg total) or saline was continuously infused from 30 min to 5 h after trauma. Afterwards, rats were placed in metabolic cages overnight for urine collection. The following day, plasma interleukin (IL)-6 levels, renal blood flow (RBF), glomerular filtration rate (GFR), and renal oxygen delivery (Do2) and consumption (V̇o2) were measured. EPTH was evident within 15 min after trauma but was significantly ameliorated during the 5 h of GLP-1 infusion. One day after trauma, plasma IL-6 was markedly increased in the trauma group and decreased in GLP-1-treated animals. RBF, GFR, and Do2 all significantly decreased with trauma, but renal V̇o2 was unchanged. GLP-1 treatment normalized RBF, GFR, and Do2 without affecting V̇o2. These results suggest that GLP-1 decreases EPTH and protects against a later development of AKI. Early treatment with GLP-1 (or its analogs) to rapidly, effectively, and safely control EPTH may be beneficial in the prehospital care of obese patients after trauma.

Role of the heart in blood pressure lowering during chronic baroreflex activation: insight from an in silico analysis.

Electrical stimulation of the baroreflex chronically suppresses sympathetic activity and arterial pressure and is currently being evaluated for the treatment of resistant hypertension. The antihypertensive effects of baroreflex activation are often attributed to renal sympathoinhibition. However, baroreflex activation also decreases heart rate, and robust blood pressure lowering occurs even after renal denervation. Because controlling renal sympathetic nerve activity (RSNA) and cardiac autonomic activity cannot be achieved experimentally, we used an established mathematical model of human physiology (HumMod) to provide mechanistic insights into their relative and combined contributions to the cardiovascular responses during baroreflex activation. Three-week responses to baroreflex activation closely mimicked experimental observations in dogs including decreases in blood pressure, heart rate, and plasma norepinephrine and increases in plasma atrial natriuretic peptide (ANP), providing validation of the model. Simulations showed that baroreflex-induced alterations in cardiac sympathetic and parasympathetic activity lead to a sustained depression of cardiac function and increased secretion of ANP. Increased ANP and suppression of RSNA both enhanced renal excretory function and accounted for most of the chronic blood pressure lowering during baroreflex activation. However, when suppression of RSNA was blocked, the blood pressure response to baroreflex activation was not appreciably impaired due to inordinate fluid accumulation and further increases in atrial pressure and ANP secretion. These simulations provide a mechanistic understanding of experimental and clinical observations showing that baroreflex activation effectively lowers blood pressure in subjects with previous renal denervation. NEW & NOTEWORTHY Both experimental and clinical studies have shown that the presence of renal nerves is not an obligate requirement for sustained reductions in blood pressure during chronic electrical stimulation of the carotid baroreflex. Simulations using HumMod, a mathematical model of integrative human physiology, indicated that both increased secretion of atrial natriuretic peptide and suppressed renal sympathetic nerve activity play key roles in mediating long-term reductions in blood pressure during chronic baroreflex activation.

Mechanisms of blood pressure salt sensitivity: new insights from mathematical modeling.

Mathematical modeling is an important tool for understanding quantitative relationships among components of complex physiological systems and for testing competing hypotheses. We used HumMod, a large physiological model, to test hypotheses of blood pressure (BP) salt sensitivity. Systemic hemodynamics, renal, and neurohormonal responses to chronic changes in salt intake were examined during normal renal function, fixed low or high plasma angiotensin II (ANG II) levels, bilateral renal artery stenosis, increased renal sympathetic nerve activity (RSNA), and decreased nephron numbers. Simulations were run for 4 wk at salt intakes ranging from 30 to 1,000 mmol/day. Reducing functional kidney mass or fixing ANG II increased salt sensitivity. Salt sensitivity, associated with inability of ANG II to respond to changes in salt intake, occurred with smaller changes in renal blood flow but greater changes in glomerular filtration rate, renal sodium reabsorption, and total peripheral resistance (TPR). However, clamping TPR at normal or high levels had no major effect on salt sensitivity. There were no clear relationships between BP salt sensitivity and renal vascular resistance or extracellular fluid volume. Our robust mathematical model of cardiovascular, renal, endocrine, and sympathetic nervous system physiology supports the hypothesis that specific types of kidney dysfunction, associated with impaired regulation of ANG II or increased tubular sodium reabsorption, contribute to BP salt sensitivity. However, increased preglomerular resistance, increased RSNA, or inability to decrease TPR does not appear to influence salt sensitivity. This model provides a platform for testing competing concepts of long-term BP control during changes in salt intake.

Hyperglycemia-Mediated Oxidative Stress Increases Pulmonary Vascular Permeability.

OBJECTIVE: Hyperglycemia in diabetes mellitus is associated with endothelial dysfunction as evidenced by increased oxidative stress and vascular permeability. Whether impaired glucose control in metabolic syndrome impacts pulmonary vascular permeability is unknown. We hypothesized that in metabolic syndrome, hyperglycemia increases lung vascular permeability through superoxide. METHODS: Lung capillary Kf and vascular superoxide were measured in the isolated lungs of LZ and OZ rats. OZ were subjected to 4 weeks of metformin treatment (300 mg/kg/day orally) to improve insulin sensitivity. In a separate experiment, lung vascular permeability and vascular superoxide were measured in LZ exposed to acute hyperglycemia (30 mM). RESULTS: As compared to LZ, OZ had impaired glucose and insulin tolerance and elevated vascular superoxide which was associated with an elevated lung Kf. Chronic metformin treatment in OZ improved glucose control and insulin sensitivity which was associated with decreased vascular oxidative stress and lung Kf. Acute hyperglycemia in isolated lungs from LZ increased lung Kf, which was blocked with the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, apocynin (3 mM). Apocynin also decreased baseline Kf in OZ. CONCLUSIONS: These data suggest that hyperglycemia in metabolic syndrome exacerbates lung vascular permeability through increases in vascular superoxide, possibly through NADPH oxidase.

Oxidative stress contributes to orthopedic trauma-induced acute kidney injury in obese rats.

After trauma, obese patients have an increased risk of developing acute kidney injury (AKI). We have demonstrated that obese Zucker (OZ) rats, but not lean Zucker (LZ) rats, develop AKI 24 h after orthopedic trauma. ROS have been implicated in the pathophysiology of AKI in models of critical illness. However, the contribution of ROS to trauma-induced AKI in the setting of obesity has not been determined. We hypothesized that AKI in OZ rats after trauma is mediated by increased oxidative stress. Male LZ and OZ rats were divided into control and trauma groups, with a subset receiving treatment after trauma with the antioxidant apocynin (50 mg/kg ip, 2 mM in drinking water). The day after trauma, glomerular filtration rate, plasma creatinine, urine kidney injury molecule-1, and albumin excretion as well as renal oxidant and antioxidant activity were measured. After trauma, compared with LZ rats, OZ rats exhibited a significant decrease in glomerular filtration rate along with significant increases in plasma creatinine and urine kidney injury molecule-1 and albumin excretion. Additionally, oxidative stress was significantly increased in OZ rats, as evidenced by increased renal NADPH oxidase activity and urine lipid peroxidation products (thiobarbituric acid-reactive substances), and OZ rats also had suppressed renal superoxide dismutase activity. Apocynin treatment significantly decreased oxidative stress and AKI in OZ rats but had minimal effects in LZ rats. These results suggest that ROS play an important role in AKI in OZ rats after traumatic injury and that ROS may be a potential future therapeutic target in the obese after trauma.

Inhibition of NADPH oxidase prevents acute lung injury in obese rats following severe trauma.

Lung capillary filtration coefficient (Kf) and impacts of oxidative stress have not been determined in the setting of severe trauma, especially in obese patients who exhibit increased lung injury. We hypothesized that severe trauma leads to a greater increase in lung Kf in obesity due to exacerbated production of and/or vulnerability to oxidative stress. Severe trauma was induced in lean and obese Zucker rats by muscle injury, fibula fracture, and bone component injection to both hindlimbs, with or without 24-h treatments of apocynin, a NADPH oxidase (NOX) inhibitor. Lung wet/dry weight ratios, lung vascular Kf, lung neutrophil counts, lung NOX and myeloperoxidase (MPO) activity, and plasma IL-6 levels were measured 24 h after trauma. In an additional study, lungs were isolated from nontrauma lean and obese rats to determine the acute effect of phenazime methosulfate, a superoxide donor, on pulmonary vascular Kf. After trauma, compared with lean rats, obese rats exhibited greater increases in lung capillary Kf, neutrophil accumulation, NOX and MPO activity, and plasma IL-6. The lung wet/dry weight ratio was increased in obese rats but not in lean rats. Apocynin treatment decreased lung Kf, neutrophil counts, NOX and MPO activities, wet/dry weight ratio, and plasma IL-6 in obese rats. Phenazime methosulfate treatment resulted in a greater increase in lung Kf in nontrauma obese rats compared with nontrauma lean rats. These results suggest that obese rats are susceptible to lung injury following severe trauma due to increased production of and responsiveness to pulmonary oxidative stress.

ß(2)-Adrenoreceptor blockade improves early posttrauma hyperglycemia and pulmonary injury in obese rats.

Early hyperglycemia after trauma increases morbidity and mortality. Insulin is widely used to control posttrauma glucose, but this treatment increases the risk of hypoglycemia. We tested a novel method for early posttrauma hyperglycemia control by suppressing hepatic glycogenolysis via ß2-adrenoreceptor blockade [ICI-118551 (ICI)]. We have shown that, after severe trauma, obese Zucker (OZ) rats, similar to obese patients, exhibit increased acute lung injury compared with lean Zucker (LZ) rats. We hypothesized that OZ rats exhibit a greater increase in early posttrauma glucose compared with LZ rats, with the increased posttrauma hyperglycemia suppressed by ICI treatment. Orthopedic trauma was applied to both hindlimbs in LZ and OZ rats. Fasting plasma glucose was then monitored for 6 h with or without ICI (0.2 mg·kg(-1)·h(-1) iv.) treatment. One day after trauma, plasma IL-6 levels, lung neutrophil numbers, myeloperoxidase (MPO) activity, and wet-to-dry weight ratios were measured. Trauma induced rapid hepatic glycogenolysis, as evidenced by decreased liver glycogen levels, and this was inhibited by ICI treatment. Compared with LZ rats, OZ rats exhibited higher posttrauma glucose, IL-6, lung neutrophil infiltration, and MPO activity. Lung wet-to-dry weight ratios were increased in OZ rats but not in LZ rats. ICI treatment reduced the early hyperglycemia, lung neutrophil retention, MPO activity, and wet-to-dry weight ratio in OZ rats to levels comparable with those seen in LZ rats, with no effect on blood pressure or heart rate. These results demonstrate that ß2-adrenoreceptor blockade effectively reduces the early posttrauma hyperglycemia, which is associated with decreased lung injury in OZ rats.

Oxidative stress increases pulmonary vascular permeability in diabetic rats through activation of transient receptor potential melastatin 2 channels.

OBJECTIVE: In vitro superoxide activates pulmonary endothelial TRPM2 channels and increases Kf . We hypothesized that pulmonary capillary Kf is increased in a model of type I diabetes due to elevated vascular superoxide and resultant TRPM2 channel activation. METHODS: Type I diabetes was induced in Zucker rats using STZ. Half of the STZ animals were treated with apocynin, a NOX inhibitor. After four weeks, lung Kf was measured in the isolated lung in the presence or absence of TRPM2 inhibitors (2-APB and FA). In an additional set of experiments, Kf was measured in nondiabetic Zucker rats after applying the superoxide donor (PMS). RESULTS: As compared to control rats, hyperglycemic rats exhibited increased vascular superoxide and Kf , along with decreased lung vascular TRPM2-L expression. Apocynin treatment reduced superoxide and Kf in hyperglycemic rats with no effect in control rats. TRPM2 channel inhibition decreased Kf in hyperglycemic rats with no effect in control rats. PMS increased the lung Kf in control rats, with TRPM2 inhibition attenuating this response. CONCLUSION: Diabetic rats exhibit a TRPM2-mediated increase in lung Kf , which is associated with increased TRPM2 activation and increased vascular superoxide levels.

CD8 T cells promote heart failure progression in mice with preexisting left ventricular dysfunction.

Introduction: Even under the standard medical care, patients with left ventricular (LV) failure or heart failure (HF) often progress to pulmonary hypertension and right ventricular (RV) hypertrophy. We previously showed that inflammation and regulatory T cells (Tregs) modulate HF progression in mice with preexisting LV failure. The main objective of this study is to determine the role of CD8+ T cells in modulating LV failure and the consequent pulmonary inflammation and RV hypertrophy in mice with preexisting LV failure. Methods: Mice with LV failure produced by transverse aortic constriction (TAC) were randomized to depletion of cytotoxic CD8+ T cells, Tregs, or both using specific blocking antibodies. Cardiac function, lung inflammation, fibrosis, vascular remodeling, and right ventricular remodeling were determined. Results: LV failure caused pulmonary inflammation, fibrosis, vascular remodeling, and RV hypertrophy. Depletion of CD8+ T cells significantly attenuated above changes in mice with preexisting LV failure. LV failure was associated with increased CD4+ and CD8+ T cell activation, and increased ratios of activated T cells to Tregs. Treg depletion exacerbated lung inflammation and HF progression, as well as lung CD4+ and CD8+ T cell infiltration and activation in HF mice. However, CD8+ T cells depletion rescue these mice from exacerbated lung inflammation and RV hypertrophy after Treg depletion. Discussion: Our findings demonstrate an important role of CD8+ T cells in promoting pulmonary inflammation and RV hypertrophy in mice with preexisting LV failure. Depletion of CD8+ T cells also rescued HF mice from the exacerbated HF progression by Treg depletion.

High selenium diet attenuates pressure overload-induced cardiopulmonary oxidative stress, inflammation, and heart failure.

Selenium (Se) deficiency is associated with the development of Keshan disease, a cardiomyopathy associated with massive cardiac immune cell infiltration that can lead to heart failure (HF). The purpose of this study was to determine whether high Se diet can attenuate systolic overload-induced cardiopulmonary inflammation and HF. Briefly, transverse aortic constriction (TAC)-induced cardiopulmonary oxidative stress, inflammation, left ventricular (LV) dysfunction, and pulmonary remodeling were determined in male mice fed with either high Se diet or normal Se diet. High Se diet had no detectable effect on LV structure and function in mice under control conditions, but high Se diet significantly protected mice from TAC-induced LV hypertrophy, dysfunction, increase of lung weight, and right ventricular hypertrophy. As compared with mice treated with normal Se diet, high Se diet also reduced TAC-induced LV cardiomyocyte hypertrophy, fibrosis, leukocyte infiltration, pulmonary inflammation, pulmonary fibrosis, and pulmonary micro-vessel muscularization. In addition, high Se diet significantly ameliorated TAC-induced accumulation and activation of pulmonary F4/80+ macrophages, and activation of dendritic cells. Interestingly, high Se diet also significantly attenuated TAC-induced activation of pulmonary CD4+ and CD8+ T cells. Moreover, we found that TAC caused a significant increase in cardiac and pulmonary ROS production, increases of 4-hydroxynonenal (4-HNE) and 3-nitrotyrosine (3-NT), as well as a compensatory increases of LV glutathione peroxidase 1 (GPX1) and 4 (GPX4) in mice fed with normal Se diet. Above changes were diminished in mice fed with high Se diet. Collectively, these data demonstrated that high Se diet significantly attenuated systolic pressure overload-induced cardiac oxidative stress, inflammation, HF development, and consequent pulmonary inflammation and remodeling.

Endothelial specific prolyl hydroxylase domain-containing protein 2 deficiency attenuates aging-related obesity and exercise intolerance.

Obesity and exercise intolerance greatly reduce the life quality of older people. Prolyl hydroxylase domain-containing protein 2 (PHD2) is an important enzyme in modulating hypoxia-inducible factor-alpha (HIF) protein. Using vascular endothelial cell-specific PHD2 gene knockout (PHD2 ECKO) mice, we investigated the role of endothelial PHD2 in aging-related obesity and exercise capacity. Briefly, PHD2 ECKO mice were obtained by crossing PHD2-floxed mice with VE-Cadherin (Cdh5)-Cre transgenic mice. The effect of PHD2 ECKO on obesity and exercise capacity in PHD2 ECKO mice and control PHD2f/f mice were determined in young mice (6 to 7 months) and aged mice (16-18 months). We found that aged PHD2 ECKO mice, but not young mice, exhibited a lean phenotype, characterized by lower fat mass, and its ratio to lean weight, body weight, or tibial length, while their food uptake was not reduced compared with controls. Moreover, as compared with aged control mice, aged PHD2 ECKO mice exhibited increased oxygen consumption at rest and during exercise, and the maximum rate of oxygen consumption (VO2 max) during exercise. Furthermore, as compared with corresponding control mice, both young and aged PHD2 ECKO mice demonstrated improved glucose tolerance and lower insulin resistance. Together, these data demonstrate that inhibition of vascular endothelial PHD2 signaling significantly attenuates aging-related obesity, exercise intolerance, and glucose intolerance.

Revisiting sex as a biological variable in hypertension research.

Half of adults in the United States have hypertension as defined by clinical practice guidelines. Interestingly, women are generally more likely to be aware of their hypertension and have their blood pressure controlled with treatment compared with men, yet hypertension-related mortality is greater in women. This may reflect the fact that the female sex remains underrepresented in clinical and basic science studies investigating the effectiveness of therapies and the mechanisms controlling blood pressure. This Review provides an overview of the impact of the way hypertension research has explored sex as a biological variable (SABV). Emphasis is placed on epidemiological studies, hypertension clinical trials, the genetics of hypertension, sex differences in immunology and gut microbiota in hypertension, and the effect of sex on the central control of blood pressure. The goal is to offer historical perspective on SABV in hypertension, highlight recent studies that include SABV, and identify key gaps in SABV inclusion and questions that remain in the field. Through continued awareness campaigns and engagement/education at the level of funding agencies, individual investigators, and in the editorial peer review system, investigation of SABV in the field of hypertension research will ultimately lead to improved clinical outcomes.

Impaired vascular KATP function attenuates exercise capacity in obese zucker rats.

OBJECTIVE: Obese subjects exhibit decreased exercise capacity (VO2max ). We have shown that vascular KATP channel mediates arteriolar dilation to muscle contraction. We hypothesize that exercise capacity is decreased in obesity due to impaired vascular KATP function. METHODS: The VO2max was measured in LZR and OZR by treadmill running before and following treatment with the KATP blocker glibenclamide i.p. One week later, the spinotrapezius muscle was prepared for in vivo microscopy. Arcade arteriolar diameters were measured following muscle contraction or application of the KATP opener cromakalim before and after glibenclamide application. In additional animals, LZR and OZR were treated with apocynin for five weeks. VO2max and arteriolar dilation experiments were repeated. RESULTS: The OZR exhibited decreased VO2max , functional and cromakalim-induced vasodilation as compared with LZR. Glibenclamide had no effect on VO2max and functional vasodilation in OZR, but significantly inhibited responses in LZR. Vascular superoxide levels and NADPH oxidase activity were increased in OZR, but reduced in apocynin-treated OZR. Apocynin increased the VO2max , functional and cromakalim-induced vasodilation in OZR with no effect in LZR. CONCLUSIONS: Exercise capacity is dependent on vascular KATP channel function. The reduced exercise capacity in OZR appears to be due in part to superoxide-mediated impairment in vascular KATP function.