Does Early Mismatched Nutrition Predispose to Hypertension and Atherosclerosis, in Male Mice?

BACKGROUND: A link between early mismatched nutritional environment and development of components of the metabolic syndrome later in life has been shown in epidemiological and animal data. The aim of this study was to investigate whether an early mismatched nutrition produced by catch-up growth after fetal protein restriction could induce the appearance of hypertension and/or atherosclerosis in adult male mice. METHODOLOGY/PRINCIPAL FINDINGS: Wild-type C57BL6/J or LDLr-/- dams were fed a low protein (LP) or a control (C) diet during gestation. Catch-up growth was induced in LP offspring by feeding dams with a control diet and by culling the litter to 4 pups against 8 in controls. At weaning, male mice were fed either standard chow or an obesogenic diet (OB), leading to 4 experimental groups. Blood pressure (BP) and heart rate (HR) were assessed in conscious unrestrained wild-type mice by telemetry. Atherosclerosis plaque area was measured in aortic root sections of LDLr-/- mice. We found that: (1) postnatal OB diet increased significantly BP (P<0.0001) and HR (P<0.008) in 3-month old OB-C and OB-LP offspring, respectively; (2) that maternal LP diet induced a significant higher BP (P<0.009) and HR (P<0.004) and (3) an altered circadian rhythm in addition to higher plasma corticosterone concentration in 9 months-old LP offspring; (4) that, although LP offspring showed higher plasma total cholesterol than control offspring, atherosclerosis assessed in aortic roots of 6-mo old mice featured increased plaque area due to OB feeding but not due to early mismatched nutrition. CONCLUSIONS/SIGNIFICANCE: These results indicate a long-term effect of early mismatched nutrition on the appearance of hypertension independently of obesity, while no effect on atherosclerosis was noticed at this age

Le risque de vivre

Myocardial constitutive No production depends on the activity of both endothelial and neuronal NOS (eNOS and nNOS, respectively). Stimulation of myocardial β(3)-adrenergic receptor (β(3)-AR) produces a negative inotropic effect that is dependent on eNOS. We evaluated whether nNOS also plays a role in β(3)-AR signaling and found that the β(3)-AR-mediated reduction in cell shortening and [Ca(2+)](i) transient amplitude was abolished both in eNOS(−/−) and nNOS(−/−) left ventricular (LV) myocytes and in wild type LV myocytes after nNOS inhibition with S-methyl-l-thiocitrulline. LV superoxide (O(2)(˙̄)) production was increased in nNOS(−/−) mice and reduced by l-N(ω)-nitroarginine methyl ester (l-NAME), indicating uncoupling of eNOS activity. eNOS S-glutathionylation and Ser-1177 phosphorylation were significantly increased in nNOS(−/−) myocytes, whereas myocardial tetrahydrobiopterin, eNOS Thr-495 phosphorylation, and arginase activity did not differ between genotypes. Although inhibitors of xanthine oxidoreductase (XOR) or NOX2 NADPH oxidase caused a similar reduction in myocardial O(2)(˙̄), only XOR inhibition reduced eNOS S-glutathionylation and Ser-1177 phosphorylation and restored both eNOS coupled activity and the negative inotropic and [Ca(2+)](i) transient response to β(3)-AR stimulation in nNOS(−/−) mice. In summary, our data show that increased O(2)(˙̄) production by XOR selectively uncouples eNOS activity and abolishes the negative inotropic effect of β(3)-AR stimulation in nNOS(−/−) myocytes. These findings provide unequivocal evidence of a functional interaction between the myocardial constitutive NOS isoforms and indicate that aspects of the myocardial phenotype of nNOS(−/−) mice result from disruption of eNOS signaling

Specificity in S-Nitrosylation: a short-range mechanism for NO signaling?

Significance: Nitric oxide (NO) classical and less classical signaling mechanisms (through interaction with soluble guanylate cyclase and cytochrome c oxidase, respectively) operate through direct binding of NO to protein metal centers, and rely on diffusibility of the NO molecule. S-Nitrosylation, a covalent post-translational modification of protein cysteines, has emerged as a paradigm of nonclassical NO signaling. Recent Advances: Several nonenzymatic mechanisms for S-nitrosylation formation and destruction have been described. Enzymatic mechanisms for transnitrosylation and denitrosylation have been also studied as regulators of the modification of specific subsets of proteins. The advancement of modification-specific proteomic methodologies has allowed progress in the study of diverse S-nitrosoproteomes, raising clues and questions about the parameters for determining the protein specificity of the modification. Critical Issues: We propose that S-nitrosylation is mainly a short-range mechanism of NO signaling, exerted in a relatively limited range of action around the NO sources, and tightly related to the very controlled regulation of subcellular localization of nitric oxide synthases. We review the nonenzymatic and enzymatic mechanisms that support this concept, as well as physiological examples of mammalian systems that illustrate well the precise compartmentalization of S-nitrosylation. Future Directions: Individual and proteomic studies of protein S-nitrosylation-based signaling should take into account the subcellular localization in order to gain further insight into the functional role of this modification in (patho)physiological settings. Antioxid. Redox Signal. 19, 1220-1235.Spanish Government [CSD2007-00020, CP07/00143, PS09/00101, SAF2009-7520, PI10/02136]; Spanish-Portuguese Integrated Action Grant [PRI-AIBPT-2011-1015/E-10/12]; Foundation for Science and Technology (FCT, Portugal) [PTDC/SAU-NEU/102612/2008, PTDC/SAU-NMC/112183/2009, PEst-OE/EQB/LA0023/2011]; COST action [BM1005]info:eu-repo/semantics/publishedVersio

Prediction of the mechanical response of canine humerus to three-point bending using subject-specific finite element modelling

Subject-specific finite element models could improve decision making in canine long-bone fracture repair. However, it preliminary requires that finite element models predicting the mechanical response of canine long bone are proposed and validated. We present here a combined experimental–numerical approach to test the ability of subject-specific finite element models to predict the bending response of seven pairs of canine humeri directly from medical images. Our results show that bending stiffness and yield load are predicted with a mean absolute error of 10.1% (±5.2%) for the 14 samples. This study constitutes a basis for the forthcoming optimization of canine long-bone fracture repair

Prenatal hypoxia induces increased cardiac contractility on a background of decreased capillary density.

Background: Chronic hypoxia in utero (CHU) is one of the most common insults to fetal development and may be associated with poor cardiac recovery from ischaemia-reperfusion injury,yet the effects on normal cardiac mechanical performance are poorly understood. Methods: Pregnant female wistar rats were exposed to hypoxia (12% oxygen, balance nitrogen)for days 10–20 of pregnancy. Pups were born into normal room air and weaned normally. At 10 weeks of age, hearts were excised under anaesthesia and underwent retrograde 'Langendorff' perfusion. Mechanical performance was measured at constant filling pressure (100 cm H2O) with intraventricular balloon. Left ventricular free wall was dissected away and capillary density estimated following alkaline phosphatase staining. Expression of SERCA2a and Nitric Oxide Synthases (NOS) proteins were estimated by immunoblotting. Results: CHU significantly increased body mass (P < 0.001) compared with age-matched control rats but was without effect on relative cardiac mass. For incremental increases in left ventricular balloon volume, diastolic pressure was preserved. However, systolic pressure was significantly greater following CHU for balloon volume = 50 μl (P < 0.01) and up to 200 μl (P < 0.05). For higher balloon volumes systolic pressure was not significantly different from control. Developed pressures were correspondingly increased relative to controls for balloon volumes up to 250 μl (P < 0.05).Left ventricular free wall capillary density was significantly decreased in both epicardium (18%; P <0.05) and endocardium (11%; P < 0.05) despite preserved coronary flow. Western blot analysis revealed no change to the expression of SERCA2a or nNOS but immuno-detectable eNOS protein was significantly decreased (P < 0.001) in cardiac tissue following chronic hypoxia in utero. Conclusion: These data offer potential mechanisms for poor recovery following ischaemia, including decreased coronary flow reserve and impaired angiogenesis with subsequent detrimental effects of post-natal cardiac performance

Expression and implication of clusterin in left ventricular remodeling after myocardial infarction

International audienceBACKGROUND: Left ventricular remodeling (LVR) after myocardial infarction is associated with an increased risk of heart failure and death. In spite of a modern therapeutic approach, LVR remains relatively frequent and difficult to predict in clinical practice. Our aim was to identify new biomarkers of LVR and understand their involvement in its development.METHODS AND RESULTS:Proteomic analysis of plasma from the REVE-2 study (Remodelage Ventriculaire)-a study dedicated to the analysis of LVR which included 246 patients after a first anterior myocardial infarction-identified increased plasma levels of CLU (clusterin) in patients with high LVR. We used a rat model of myocardial infarction to analyze CLU expression in the LV and found a significant increase that was correlated with LVR parameters. We found increased CLU expression and secretion in primary cultures of rat neonate cardiomyocytes hypertrophied by isoproterenol. Silencing of CLU in hypertrophied neonate cardiomyocytes induced a significant decrease in cell size, ANP (atrial natriuretic peptide), and BNP (B-type natriuretic peptide) expression, associated with a decreased ERK (extracellular signal-regulated kinase) 1/2 activity, suggesting a prohypertrophic role of CLU. We then confirmed a significant increase of both intracellular p-CLU (precursor form of CLU) and m-CLU (mature form of CLU) in failing human hearts. Finally, the circulating levels of CLU (secreted form) were increased in patients with chronic heart failure who died from cardiovascular cause during a 3-year follow-up (n=99) compared with survivors (n=99).CONCLUSIONS: Our results show for the first time that plasma CLU levels are associated with LVR post-myocardial infarction, have in part a cardiac origin, and are a predictor of early death in heart failure patients

Metabolic changes in hypertrophic cardiomyopathies : Scientific update from the Working Group of Myocardial Function of the European Society of Cardiology

JV is supported by the Netherlands Cardiovascular Research Initiative, an initiative with support of the Dutch Heart Foundation, CVON2014-40 DOSIS. SH has received funding from the European Union Commission’s Seventh Framework programme under grant agreement N° 305507 (HOMAGE), N° 602904 (FIBROTARGETS) and FP7-Health-2013- Innovations-1 N° 602156 (HECATOS). . We acknowledge the support from the Netherlands Cardiovascular Research Initiative, an initiative with support of the Dutch Heart Foundation, CVON2011-ARENA, CVON2016-Early HFPEF, and ShePREDICTS. This research is cofinanced as a PPP-allowance Research and Innovation by the Ministry of Economic Affairs within Top Sector Life sciences & Health. This research was co-funded by the C3 project “Vision Core Leuven” of the Leuven UniversityPeer reviewedPublisher PD

The innate immune system in chronic cardiomyopathy : a European Society of Cardiology (ESC) scientific statement from the Working Group on Myocardial Function of the ESC

Funded by Regione Campania CISI-Lab European Union Commission's Seventh Framework . Grant Number: 305507, 602904 FP7-Health-2013-Innovations-1. Grant Number: 602156 FWO Flanders, Belgium. Grant Number: FWO G080014 N European Union Horizon2020. Grant Number: UE LSHM-CT-05-018833, FNRS PDR T.0144.13 Bundesministerium für Bildung und Forschung. Grant Number: BMBF01 EO1004 Deutsche Forschungsgemeinschaft. Grant Number: SFB688 TP A10Peer reviewedPublisher PD