Metabolic and cardiac adaptation to chronic pharmacologic blockade of facilitative glucose transport in murine dilated cardiomyopathy and myocardial ischemia

Abstract GLUT transgenic and knockout mice have provided valuable insight into the role of facilitative glucose transporters (GLUTs) in cardiovascular and metabolic disease, but compensatory physiological changes can hinder interpretation of these models. To determine whether adaptations occur in response to GLUT inhibition in the failing adult heart, we chronically treated TG9 mice, a transgenic model of dilated cardiomyopathy and heart failure, with the GLUT inhibitor ritonavir. Glucose tolerance was significantly improved with chronic treatment and correlated with decreased adipose tissue retinol binding protein 4 (RBP4) and resistin. A modest improvement in lifespan was associated with decreased cardiomyocyte brain natriuretic peptide (BNP) expression, a marker of heart failure severity. GLUT1 and −12 protein expression was significantly increased in left ventricular (LV) myocardium in ritonavir-treated animals. Supporting a switch from fatty acid to glucose utilization in these tissues, fatty acid transporter CD36 and fatty acid transcriptional regulator peroxisome proliferator-activated receptor α (PPARα) mRNA were also decreased in LV and soleus muscle. Chronic ritonavir also increased cardiac output and dV/dt-d in C57Bl/6 mice following ischemia-reperfusion injury. Taken together, these data demonstrate compensatory metabolic adaptation in response to chronic GLUT blockade as a means to evade deleterious changes in the failing heart

Inhibition of NOX1 mitigates blood pressure increases in elastin insufficiency

Elastin (ELN) insufficiency leads to the cardiovascular hallmarks of the contiguous gene deletion disorder, Williams-Beuren syndrome, including hypertension and vascular stiffness. Previous studies showed that Williams-Beuren syndrome deletions, which extended to include th

Myocardial Lipin 1 knockout in mice approximates cardiac effects of human LPIN1 mutations

Lipin 1 is a bifunctional protein that is a transcriptional regulator and has phosphatidic acid (PA) phosphohydrolase activity, which dephosphorylates PA to generate diacylglycerol. Human lipin 1 mutations lead to episodic rhabdomyolysis, and some affected patients exhibit cardiac abnormalities, including exercise-induced cardiac dysfunction and cardiac triglyceride accumulation. Furthermore, lipin 1 expression is deactivated in failing heart, but the effects of lipin 1 deactivation in myocardium are incompletely understood. We generated mice with cardiac-specific lipin 1 KO (cs-Lpin1-/-) to examine the intrinsic effects of lipin 1 in the myocardium. Cs-Lpin1-/- mice had normal systolic cardiac function but mild cardiac hypertrophy. Compared with littermate control mice, PA content was higher in cs-Lpin1-/- hearts, which also had an unexpected increase in diacylglycerol and triglyceride content. Cs-Lpin1-/- mice exhibited diminished cardiac cardiolipin content and impaired mitochondrial respiration rates when provided with pyruvate or succinate as metabolic substrates. After transverse aortic constriction-induced pressure overload, loss of lipin 1 did not exacerbate cardiac hypertrophy or dysfunction. However, loss of lipin 1 dampened the cardiac ionotropic response to dobutamine and exercise endurance in association with reduced protein kinase A signaling. These data suggest that loss of lipin 1 impairs cardiac functional reserve, likely due to effects on glycerolipid homeostasis, mitochondrial function, and protein kinase A signaling

SHARC II: a Caltech Submillimeter Observatory facility camera with 384 pixels

SHARC II is a background-limited 350 μm and 450 μm facility camera for the Caltech Submillimeter Observatory undergoing commissioning in 2002. The key component of SHARC II is a 12×32 array of doped silicon 'pop-up' bolometers developed at NASA/Goddard. Each 1 mm × 1 mm pixel is coated with a 400 Ω/square bismuth film and located λ/4 above a reflective backshort to achieve >75% absorption efficiency. The pixels cover the focal plane with >90% filling factor. At 350 μm, the SHARC II pixels are separated by 0.65 λ/D. In contrast to the silicon bolometers in the predecessor of SHARC II, each doped thermistor occupies nearly the full area of the pixel, which lowers the 1/f knee of the detector noise to <0.03 Hz, under load, at the bath temperature of 0.36 K. The bolometers are AC-biased and read in 'total power' mode to take advantage of the improved stability. Each bolometer is biased through a custom ~130 MΩ CrSi load resistor at 7 K and read with a commercial JFET at 120 K. The JFETs and load resistors are integrated with the detectors into a single assembly to minimize microphonic noise. Electrical connection across the 0.36 K to 4 K and 4 K to 120 K temperature interfaces is accomplished with lithographed metal wires on dielectric substrates. In the best 25% of winter nights on Mauna Kea, SHARC II is expected to have an NEFD at 350 μm of 1 Jy Hz-1/2 or better. The new camera should be at least 4 times faster at detecting known point sources and 30 times faster at mapping large areas compared to the prior instrument

TRAF2, an innate immune sensor, reciprocally regulates mitophagy and inflammation to maintain cardiac myocyte homeostasis

Mitochondria are essential for cardiac myocyte function, but damaged mitochondria trigger cardiac myocyte death. Although mitophagy, a lysosomal degradative pathway to remove damaged mitochondria, is robustly active in cardiac myocytes in the unstressed heart, its mechanisms and physiological role remain poorly defined. We discovered a critical role for TRAF2, an innate immunity effector protein with E3 ubiquitin ligase activity, in facilitating physiological cardiac myocyte mitophagy in the adult heart, to prevent inflammation and cell death, and maintain myocardial homeostasis

Genetic and environmental factors on heart rate, mean arterial pressure and carotid intima–media thickness: A longitudinal twin study

Background: Heart rate (HR), mean arterial pressure (MAP) and carotid intima–media thickness (cIMT) are moderately heritable cardiovascular traits, but the environmental effects on the longitudinal change of their heritability have never been investigated. Methods: 368 Italian and Hungarian twins (107 monozygotic, 77 dizygotic) underwent oscillometric measurement and B-mode sonography of bilateral carotid arteries in 2009/2010 and 2014. Within- -individual/cross-study wave, cross-twin/within-study wave and cross-twin/cross-study wave correlations were estimated, and bivariate Cholesky models were fitted to decompose the total variance at each wave and covariance between study waves into additive genetic, shared and unique environmental components. Results: For each trait, a moderate longitudinal stability was observed, with within-individual/crosswave correlations of 0.42 (95% CI: 0.33–0.51) for HR, 0.34 (95% CI: 0.24–0.43) for MAP, and 0.23 (95% CI: 0.12–0.33) for cIMT. Cross-twin/cross-wave correlations in monozygotic pairs were all significant and substantially higher than the corresponding dizygotic correlations. Genetic continuity was the main source of longitudinal stability, with across-time genetic correlations of 0.52 (95% CI: 0.29–0.71) for HR, 0.56 (95% CI: 0.31–0.81) for MAP, and 0.36 (95% CI: 0.07–0.64) for cIMT. Overlapping genetic factors explained respectively 57%, 77%, and 68% of the longitudinal covariance of the HR, MAP and cIMT traits. Conclusions: Genetic factors have a substantial role in the longitudinal change of HR, MAP and cIMT; however, the influence of unique environmental factors remains relevant. Further studies should better elucidate whether epigenetic mechanisms have a role in influencing the stability of the investigated traits over time

Visual shape and position sensing algorithm for a continuum robot

Continuum robots represent an actively developing and fast-growing technology in robotics. To successfully implement control and path planning of continuum robots it is important to develop an accurate three-dimensional shape and position sensing algorithm. In this paper, we propose an algorithm for the three-dimensional reconstruction of the continuum robot shape. The algorithm is performed during several steps. Initially, images from two cameras are processed by applying pre-processing and segmentation techniques. Then, the gradient descent method is applied to compare two-dimensional skeleton points of both masks. Having compared these points, it finds a skeleton of the robot in a threedimensional form. Additionally, the proposed algorithm is able to define key points using the distance from the robot base along the center line. The latter allows controlling the position of points of interest defined by a user. As a result, the developed algorithm achieved a relatively high level of accuracy and speed

Exenatide Improves Glucose Homeostasis and Prolongs Survival in a Murine Model of Dilated Cardiomyopathy

There is growing awareness of secondary insulin resistance and alterations in myocardial glucose utilization in congestive heart failure. Whether therapies that directly target these changes would be beneficial is unclear. We previously demonstrated that acute blockade of the insulin responsive facilitative glucose transporter GLUT4 precipitates acute decompensated heart failure in mice with advanced dilated cardiomyopathy. Our current objective was to determine whether pharmacologic enhancement of insulin sensitivity and myocardial glucose uptake preserves cardiac function and survival in the setting of primary heart failure.The GLP-1 agonist exenatide was administered twice daily to a murine model of dilated cardiomyopathy (TG9) starting at 56 days of life. TG9 mice develop congestive heart failure and secondary insulin resistance in a highly predictable manner with death by 12 weeks of age. Glucose homeostasis was assessed by measuring glucose tolerance at 8 and 10 weeks and tissue 2-deoxyglucose uptake at 75 days. Exenatide treatment improved glucose tolerance, myocardial GLUT4 expression and 2-deoxyglucose uptake, cardiac contractility, and survival over control vehicle-treated TG9 mice. Phosphorylation of AMP kinase and AKT was also increased in exenatide-treated animals. Total myocardial GLUT1 levels were not different between groups. Exenatide also abrogated the detrimental effect of the GLUT4 antagonist ritonavir on survival in TG9 mice.In heart failure secondary insulin resistance is maladaptive and myocardial glucose uptake is suboptimal. An incretin-based therapy, which addresses these changes, appears beneficial

Evidence for diagnosis of early chronic pancreatitis after three episodes of acute pancreatitis : a cross-sectional multicentre international study with experimental animal model

Chronic pancreatitis (CP) is an end-stage disease with no specific therapy; therefore, an early diagnosis is of crucial importance. In this study, data from 1315 and 318 patients were analysed from acute pancreatitis (AP) and CP registries, respectively. The population from the AP registry was divided into AP (n=983), recurrent AP (RAP, n=270) and CP (n=62) groups. The prevalence of CP in combination with AP, RAP2, RAP3, RAP4 and RAP5+was 0%, 1%, 16%, 50% and 47%, respectively, suggesting that three or more episodes of AP is a strong risk factor for CP. Laboratory, imaging and clinical biomarkers highlighted that patients with RAP3+do not show a significant difference between RAPs and CP. Data from CP registries showed 98% of patients had at least one AP and the average number of episodes was four. We mimicked the human RAPs in a mouse model and found that three or more episodes of AP cause early chronic-like morphological changes in the pancreas. We concluded that three or more attacks of AP with no morphological changes to the pancreas could be considered as early CP (ECP).The new diagnostic criteria for ECP allow the majority of CP patients to be diagnosed earlier. They can be used in hospitals with no additional costs in healthcare.Peer reviewe