0292: Endothelial protein tyrosine phosphatase 1B deficiency reduces both endothelial and cardiac dysfunction of in a mouse model of aging

IntroductionAging is associated with an endothelial dysfunction, characterized by a decrease of nitric oxide (NO) production, which is a risk factor of development of cardiovascular diseases. However, the direct link between endothelial dysfunction and aggravation of cardiac function in aging is not established. We reported previously a new potent therapeutic approach of cardiovascular disease, based on inhibition of protein tyrosine phosphatase 1B (PTP1B), which both increases NO production (via restored PI3K/Akt/eNOS signaling) and reduces cardiac dysfunction in both post-ischemic heart failure and aging, however the exact role of endothelial PTP1B in this setting is unknown. To evaluate the endothelial and cardiac consequences of endothelial PTP1B deficiency (endoPTP1B-/-) in a mouse model of aging.Material and methodsEndoPTP1B-/- mice were developed by crossing LOX-P PTP1B mice with mice expressing CRE under the control of the endothelial promoter Tie2, or wild-type (WT). The evolution of cardiac function was assessed by echocardiography at different time points and the vascular function was evaluated ex vivo at 24 months.ResultsCompared to young (3 month-old), WT mice aged (24 month-old) showed a markedly impaired flow-mediated dilatation of isolated mesenteric arteries (3 months: 40±4%; 24 months: 1±1%; p<0.001), which was improved in endoPTP1B-/- mice (17±3%; p<0.001 vs. WT 24 months). This restored response in aged endoPTP1B-/- mice was abolished by a NO-synthase inhibitor, suggesting a restored NO production. In WT mice, aging decreased stroke volume (3 months: 0,070±0,002%; 24 months: 0,065±0,005%; p<0.001) and cardiac output (3 months: 37±1%; 24 months: 29±2%; p<0.001) and these parameters were improved in endoPTP1B-/- mice (24 months: 0.081±0,011% and 34±2%; respectively, p<0.05).ConclusionIn aged mice, endoPTP1B deficiency induced an improvement of endothelial function, and also tended to improved cardiac function. These results provide a direct demonstration of the beneficial effect of endothelial protection in aging

Metabolism

Background: Cardiovascular disease is the leading cause of deaths in nonalcoholic steatohepatitis (NASH) patients. Mouse models, while widely used for drug development, do not fully replicate human NASH nor integrate the associated cardiac dysfunction, i.e. heart failure with preserved ejection fraction (HFpEF). To overcome these limitations, we established a nutritional hamster model developing both NASH and HFpEF. We then evaluated the effects of the dual peroxisome proliferator activated receptor alpha/delta agonist elafibranor developed for the treatment of NASH patients. Methods: Male Golden Syrian hamsters were fed for 10 to 20 weeks with a free choice diet, which presents hamsters with a choice between control chow diet with normal drinking water or a high fat/high cholesterol diet with 10% fructose enriched drinking water. Biochemistry, histology and echocardiography analysis were performed to characterize NASH and HFpEF. Once the model was validated, elafibranor was evaluated at 15 mg/kg/day orally QD for 5 weeks. Results: Hamsters fed a free choice diet for up to 20 weeks developed NASH, including hepatocyte ballooning (as confirmed with cytokeratin-18 immunostaining), bridging fibrosis, and a severe diastolic dysfunction with restrictive profile, but preserved ejection fraction. Elafibranor resolved NASH, with significant reduction in ballooning and fibrosis scores, and improved diastolic dysfunction with significant reduction in E/A and E/E' ratios. Conclusion: Our data demonstrate that the free choice diet induced NASH hamster model replicates the human phenotype and will be useful for validating novel drug candidates for the treatment of NASH and associated HfpEF

Selective Vascular Endothelial Protection Reduces Cardiac Dysfunction in Chronic Heart Failure

International audienc

Reduced Insulin Resistance Contributes to the Beneficial Effect of Protein Tyrosine Phosphatase-1B Deletion in a Mouse Model of Sepsis

International audienceHyperglycemia is a common feature of septic patients and has been associated with poor outcome and high mortality. In contrast, insulin has been shown to decrease mortality and to prevent the incidence of multiorgan failure but is often associated with deleterious hypoglycemia. Protein Tyrosine Phosphatase 1B (PTP1B) is a negative regulator of both insulin signaling and NO production, and has been shown to be an aggravating factor in septic shock. To evaluate the potential therapeutic effect of PTP1B blockade on glucose metabolism and insulin resistance in an experimental model of sepsis, we assessed the effect of PTP1B gene deletion in a cecal ligation and puncture (CLP) model of sepsis. PTP1B gene deletion significantly limited CLP-induced insulin resistance, improved AMP-activated protein kinase signaling pathway and Glucose Transporter 4 translocation, and decreased inflammation. These effects were associated with a reduction of sepsis-induced endothelial dysfunction/impaired NO production and especially of insulin-mediated dilatation. This modulation of insulin resistance may contribute to the beneficial effect of PTP1B blockade in septic shock, especially in terms of inflammation and cardiac metabolism. KEYWORDS-Glucose, hyperglycemia, insulin resistance, PTP1B, severe sepsis, vascular dysfunction ABBREVIATIONS-Akt-kinase protein B; AMPK-adenosine monophosphate-activated protein kinase; CD45-cluster of differenciation 45; CLP-cecal ligation and puncture; DNA-desoxyribo nucleotide acid; eNOS-endothelial nitric oxide synthase; FMD-flow-mediated dilatation; GLUT-1-glucose transporter 1; GLUT-4-glucose transporter 4; GLUTs-glucose transporters; HOMA-homeostasis model assessment; ICAM-1-intercellular adhesion molecule 1; ICU-intensive care unit; IL-1b-interleukin-1b; IL-10-interleukin-10; IL-6-interleukin-6; iNOS-inducible nitric oxide synthase; IR-insulin receptors; IRS-1-insulin receptor substrate 1; IRSs-insulin receptor substrates; KH-Krebs-Henseleit

Crest maturation at the cardiomyocyte surface contributes to a new late postnatal development stage that controls the diastolic function of the adult heart

Abstract RATIONALE In addition to its typical rod-shape, the mammalian adult cardiomyocyte (CM) harbors a unique lateral membrane surface architecture with periodic crests, relying on the presence of subsarcolemmal mitochondria (SSM) the role of which is still unknown. OBJECTIVE To investigate the development and functional role of CM crests during the postnatal period. METHODS AND RESULTS Electron/confocal microscopy and western-blot of left ventricular tissues from rat hearts indicated a late CM surface crest maturation, between postnatal day 20 (P20) and P60, as shown by substantial SSM swelling and increased claudin-5 cell surface expression. The P20-P60 postnatal stage also correlates with an ultimate maturation of the T-Tubules and the intercalated disk. At the cellular level, we identified an atypical CM hypertrophy characterized by an increase in long- and short-axes without myofibril addition and with sarcomere lateral stretching, indicative of lateral stretch-based CM hypertrophy. We confirmed the P20-P60 hypertrophy at the organ level by echocardiography but also demonstrated a transcriptomic program after P20 targeting all the cardiac cell populations. At the functional level, using Doppler echocardiography, we found that the P20-P60 period is specifically dedicated to the improvement of relaxation. Mechanistically, using CM-specific knock-out mice, we identified ephrin-B1 as a determinant of CM crest maturation after P20 controlling lateral CM stretch-hypertrophy and relaxation. Interestingly, while young adult Efnb1 CMspe−/− mice essentially show a relaxation impairment with exercise intolerance, they progressively switch toward heart failure with 100% KO mice dying after 13 months. CONCLUSIONS This study highlights a new late P20-P60 postnatal developmental stage of the heart in rodents during which the CM surface crests mature through an ephrin-B1-dependant mechanism and regulate the diastolic function. Moreover, we demonstrate for the first time that the CM crest architecture is cardioprotective