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Heart failure with preserved ejection fraction (HFpEF) is a common complex clinical syndrome for which there are currently few evidence-based therapies. As patients with HFpEF very often present with comorbidities comprising the metabolic syndrome, we hypothesized, that metabolic syndrome could lead over time to the development of diastolic dysfunction and HFpEF. Obesity-prone rats were exposed to high-fat diet and compared to obesity-resistant rats fed with standard chow. Phenotyping of metabolic syndrome, associated with echocardiographic and cardiac hemodynamic measurements, was performed after 4 and 12 months. Blood and myocardial tissue sampling were performed for pathobiological evaluation. High-fat diet in obesity-prone rats elicited metabolic syndrome, characterized by increased body and abdominal fat weights, glucose intolerance and hyperlipidemia, as well as increased left ventricular (LV) systolic pressure (after 12 months). This was associated with LV diastolic dysfunction (assessed by increased LV end-diastolic pressure) and pulmonary hypertension (assessed by increased right ventricular systolic pressure). Echocardiography revealed significant concentric LV hypertrophy, while LV ejection fraction was preserved. LV remodeling was associated with cardiomyocyte hypertrophy, as well as myocardial and perivascular fibrosis. Circulating levels of soluble ST2 (the interleukin-1 receptor-like) markedly increased in rats with HFpEF, while plasma NT-proBNP levels decreased. RNA-sequencing analysis identified clusters of genes implicated in fatty acid metabolism and calcium-dependent contraction as upregulated pathways in the myocardium of rats with HFpEF. High-fat diet during 12 months in obesity-prone rats led to the development of a relevant preclinical model of HFpEF with multiple comorbidities, suitable for investigating novel therapeutic interventions.

Introduction Metabolic syndrome has become a major public-health challenge worldwide. Major cause is junk food associated with a genetic predisposition. Objective The aim of this study was to characterize a model of metabolic syndrome induced by high-fat diet (HFD) in rats having a polygenic predisposition to develop obesity. Method Obese prone (OP) and obese resistant (OR) Sprague Dawley rats were respectively fed with a HFD and a standard diet (Std) for 16 weeks or 1year (4 groups, n = 10 per group). Feeding behaviour, caloric intake, body weight and systemic arterial pressure were weekly recorded. At the end of the protocol, abdominal obesity, glucose tolerance, lipidemia and blood pressure were compared between groups. Results Despite, their high calorie diet, OP rats showed a higher daily food consumption and calorie intake. Plasma leptin was increased in OP-HFD (5.8 ± 0.5 ng/ml versus 1 ± 0.5 ng/ml in OR-Std, P Conclusion One year of HFD in Sprague Dawley rats selected for their predisposition to obesity leads to a reliable metabolic syndrome characterized by abdominal obesity, glucose intolerance, dyslipidemia and hypertension.

Aims Chemerin has been recently identified as a vasoactive adipokine implicated in blood pressure regulation. In this context, we evaluated whether chemerin could influence pulmonary vasoreactive response. Materials and methods Vascular reactivity to chemerin and to phenylephrine, serotonin and endothelin-1 after chemerin pretreatment was evaluated in rat isolated pulmonary artery versus thoracic aorta with and without endothelium. Vasoreactivity to acetylcholine in presence of nitric oxide (NO)-synthase inhibitor (L-NAME) and to NO donor sodium nitroprusside (SNP) was evaluated in chemerin-pretreated pulmonary artery versus thoracic aorta with endothelium. Pretreatment with ODQ, a soluble guanylate cyclase inhibitor and apocynin, a ROS production inhibitor, were also tested. Arteries and lung tissue were harvested for pathobiological evaluation. Key findings Chemerin contracted endothelium-denuded pulmonary artery, while no response was observed in arteries with endothelium. Chemerin potentiated phenylephrine-, endothelin-1- and serotonin-induced vasoconstriction, which was further enhanced by endothelium removal. Chemerin decreased acetylcholine-induced vasorelaxation in arteries with endothelium, while it did not affect SNP-induced relaxation. In presence of L-NAME, there remained a vasorelaxation in chemerin-pretreated arteries. Chemerin or ODQ alone partly decreased acetylcholine-induced vasorelaxation in pulmonary artery and thoracic aorta, while combined chemerin and ODQ incubation abolished it. Treatment with apocynin partly or totally reversed chemerin effects. In both types of arteries, chemerin reduced acetylcholine-induced NO production, as well as endothelial and inducible NO-synthase expression. Significance Chemerin potentiates vascular responses to vasoconstrictors in pulmonary artery and thoracic aorta and, impairs acetylcholine-induced pulmonary artery vasodilatation, by mechanisms involving at least partly NO signaling and oxidative stress.

Heart failure with preserved ejection fraction (HFpEF) is a common and complex syndrome with high mortality and morbidity rates for which there are currently no evidence-based therapies. As patients with HFpEF very often harbor comorbidities of metabolic syndrome, we hypothesized, that metabolic syndrome in aging animals could be a major mechanism underlying the development of diastolic dysfunction and HFpEF. Therfeore, obesity-prone (OP) and -resistant (OR) rats were respectively fed with a high-fat diet (HFD) or a standard rat chow (Std) for 4 months or for 12 months (n = 10 rats in each group; 4 groups). At the end of the protocol, abdominal obesity, complete phenotyping of metabolic syndrome, associated to echocardiographic and left and right ventricular catheterization measurements, were performed. Blood was sampled before euthanasia of the animals. After 4- and 12-month HFD, OP rats presented increased total body and abdominal fat weights, altered glucose tolerance test and dyslipidemia. In OP rats, left ventricular systolic (164 ± 6 versus 120 ± 5 mmHg, P Metabolic syndrome induced by 12-month HFD in OP rats leads to the development of HFpEF. In these rats, circulating NT-proBNP levels were decreased, while circulating ST2 levels were largely increased.

Calretinin has been detected in various excitable cells but the presence and putative roles of such a calcium-binding protein has never been characterized in sperm.Epididymal spermatozoa were collected from C57Bl6 (wild-type, WT) or calretinin knockout (CR−/−) mice and Wistar rats. A specific staining for calretinin was detected by immunofluorescence in the principal piece of the flagellum, both in WT mouse and rat spermatozoa. Western blots confirmed the expression of calretinin in rat and WT spermatozoa as well as its absence in CR−/− mice.No significant difference was observed in the spontaneous acrosome reaction between WT and CR−/− sperm. The addition of the calcium-ionophore A-23187, Thapsigargin or Progesterone to WT or CR−/− incubated spermatozoa induced increases in the acrosome reaction but the stimulatory effects were identical in both genotypes. Motility measurements assessed by computer-assisted sperm analysis indicated that, under basal non-stimulatory conditions, CR-/- sperm exhibited a lower curvilinear velocity and a smaller lateral head movement amplitude, although no difference was observed for the beat cross frequency. After incubation with 25 mM NH4Cl, the curvilinear velocity, the amplitude of the lateral head movement and the hyperactivation were increased, while the beat cross frequency was decreased, in both genotypes.Evaluation of the in vivo fertility potential indicated that the CR−/− litter sizes were clearly reduced compared to the WT litter sizes.Our study describes, for the first time, the expression of calretinin in sperm. These data extend the potential implication of calcium-binding proteins in the sperm calcium-signaling cascade and bring new insights into the understanding of sperm physiology.

Introduction Pulmonary arterial hypertension (PAH) is a clinical condition associated with sustained elevations in pulmonary arterial pressure, leading to right ventricular failure. The adipokines leptin and adiponectin have shown respectively deleterious and protective effects in animal models of PAH. Chemerin is a novel adipokine implicated in blood pressure regulation and recently associated with atherosclerosis, essential hypertension and obesity-induced hypertension. Objective In this context, we aimed to determine whether the chemerin/CMKLR1 axis could influence pulmonary arterial pressure and the severity of pulmonary hypertension. Method Age-matched wild-type (WT) and CMKLR1 knockout (KO) mice were used. We localized chemerin and the chemokine-like receptor-1 (CMKLR1) in lung sections, pulmonary artery and thoracic aorta. WT and KO mice were exposed to normoxia (21% O2) or hypoxia (10% O2) for 3 weeks (N = 6 per group). Right ventricular systolic pressure (RVSP) was measured with a micro-tip catheter. Segments of pulmonary artery and thoracic aorta were incubated, immediately after sacrifice, with recombinant mouse chemerin (10–8 mol/L, 1 hour) or vehicle, then stimulated or not with acetylcholine (ACH) (10–4 mol/L, 5 min) to measure NO production in supernatants by determination of nitrites. Results RVSP was higher in KO than in WT mice in normoxia (26.6 ± 0.4 vs. 22.2 ± 1 mmHg, P = 0.001) and in hypoxia (37.8 ± 0.5 vs. 31.4 ± 1.2 mmHg, P = 0.001). Hypoxia reduced NO production in WT and KO mice. In WT, ACH-induced NO production was abolished by chemerin pre-incubation. In normoxia and hypoxia, basal NO production was lower in KO than WT mice and ACH-stimulated NO production was totally inhibited in KO mice. Conclusion These observations provide support for a role of the chemerin/CMKLR1 axis as regulator of pulmonary vascular homeostasis and as a disease-modifier in the context of pulmonary hypertension by the negative modulation of pulmonary vascular NO production.

Introduction The metabolic syndrome is a worldwide public health problem. Major cause is the junk food associated with a genetic predisposition. To better understand the mechanisms it is imperative to develop animal models closest to human problem. Objective Cardiometabolic alterations were studied in a polygenic rat model of metabolic syndrome. We therefore evaluated the respective roles of the substrain and the diet. Method Ten obese prone (OP), obese resistant (OR) and control (CTRL) Sprague–Dawley rats were fed with high fat (HF) or standard diet (SD) for 16 weeks. Feeding behaviour and criteria of the metabolic syndrome were determined. Arterial pressure was weekly recorded. Leptin and adiponectin were measured. Results CTRL and OR rats regulated their appetite to maintain a reasonable global calorie intake irrespective of the diet. OP rats showed higher food consumption and their calorie intake increased on HF. The mean abdominal fat % increase when on HF was higher in OP compared to CTRL and OR (236.1% vs. 89.97% and 65.99%). Total cholesterol and triglycerides were increased in OP-HF rats compared to the 5 other groups while OP showed a high nonHDL/HDL ratio already on SD. OP-HF rats had glucose intolerance. OP-HF rats showed an over time increase of systolic and diastolic arterial pressures and increased diastolic pressure at week 16 (117 ± 6 vs. 89 ± 6 and 93 ± 3 mmHg in OR-HF and CTRL-HF). Plasma leptin was increased in OP rats irrespective of the diet, suggesting a leptin resistance (4.8 ± 0.8 and 5.8 ± 0.5 ng/ml in OP-SD and OP-HF). In accordance with their satiety, leptin increased in CTRL and OR fed with HF (2.95 ± 0.6 and 2.98 ± 0.7 ng/ml vs. 0.65 ± 0.1 and 1 ± 0.1 ng/ml in CTRL-SD and OR-SD). The leptin/adiponectin ratio was elevated in OP regardless of the diet. Conclusion The OP substrain is characterized by high plasma leptin and a loss of satiety leading to obesity and increased nonHDL/HDL ratio. When associated with HF, OP rats develop a metabolic syndrome.

Introduction ATP-sensitive potassium channels (K ATP channels) have been identified in a variety of tissues. Nevertheless, the presence and role of such metabolism-sensitive K + channels still remain to be unraveled in the reproductive system. Methods The study evaluates the presence of K ATP channel subunits in human term placental explants by immunohistochemistry, proximity ligation assay, Western blot and RT-PCR techniques. The potential involvement of K ATP channels in human placental lactogen (hPL) and human chorionic gonadotrophin (hCG) release has been assessed radioimmunologically from human term placental explants incubated in the presence of different K ATP channel modulators. Results Immunolocalization of the K ATP channel subunits documented both the Kir6.2 and SUR2 subunits in the syncytiotrophoblast of human term placenta. Their colocalization was demonstrated by proximity ligation assay and their presence was further confirmed by immunoblotting and RT-PCR. Kir6.1 subunit was immunolocalized in blood vessels media. SUR1 was not expressed at the mRNA level. Incubation of human term placental explants in the presence of increasing concentrations of modulators of K ATP channels such as glibenclamide, tolbutamide, pinacidil or diazoxide did not affect the measured hCG and hPL secretory rates. Discussion Our study reports, for the first time, the presence of the K ATP channel subunits Kir6.2 and SUR2 in the human term syncytiotrophoblast. However, under the present experimental conditions, the activation or inhibition of these putative K ATP channels by different pharmacological agents did not affect the hPL and hCG secretory rate of human term placental explants. Conclusion The present findings suggest that the human term syncytiotrophoblast might be endowed with K ATP channels. Further studies should clarify their implication in the syncytiotrophoblast ionic homeostasis and hormone regulation.