Crosstalk between high-density lipoproteins and endothelial cells in health and disease: Insights into sex-dependent modulation

Atherosclerotic cardiovascular disease is the leading cause of death worldwide. Intense research in vascular biology has advanced our knowledge of molecular mechanisms of its onset and progression until complications; however, several aspects of the patho-physiology of atherosclerosis remain to be further elucidated. Endothelial cell homeostasis is fundamental to prevent atherosclerosis as the appearance of endothelial cell dysfunction is considered the first pro-atherosclerotic vascular modification. Physiologically, high density lipoproteins (HDLs) exert protective actions for vessels and in particular for ECs. Indeed, HDLs promote endothelial-dependent vasorelaxation, contribute to the regulation of vascular lipid metabolism, and have immune-modulatory, anti-inflammatory and anti-oxidative properties. Sex- and gender-dependent differences are increasingly recognized as important, although not fully elucidated, factors in cardiovascular health and disease patho-physiology. In this review, we highlight the importance of sex hormones and sex-specific gene expression in the regulation of HDL and EC cross-talk and their contribution to cardiovascular disease

Effects of acute administration of trimethylamine N-oxide on endothelial function: a translational study

Elevated circulating levels of nutrient-derived trimethylamine N-oxide (TMAO) have been associated with the onset and progression of cardiovascular disease by promoting athero-thrombosis. However, in conditions like bariatric surgery (Roux-en-Y gastric bypass, RYGB), stable increases of plasma TMAO are associated with improved endothelial function and reduced cardiovascular morbidity and mortality, thus questioning whether a mechanistic relationship between TMAO and endothelial dysfunction exists. Herein, we translationally assessed the effects of acute TMAO exposure on endothelial dysfunction, thrombosis and stroke. After RYGB, fasting circulating levels of TMAO increased in patients and obese rats, in parallel with an improved gluco-lipid profile and higher circulating bile acids. The latter enhanced FXR-dependent signalling in rat livers, which may lead to higher TMAO synthesis post RYGB. In lean rats, acute TMAO injection (7 mg kg$^{−1}$) 1.5-h before sacrifice and ex-vivo 30-min incubation of thoracic aortas with 10$^{−6}$ M TMAO did not impair vasodilation in response to acetylcholine (Ach), glucagon-like peptide 1, or insulin. Similarly, in lean WT mice (n = 5–6), TMAO injection prior to subjecting mice to ischemic stroke or arterial thrombosis did not increase its severity compared to vehicle treated mice. Endothelial nitric oxide synthase (eNOS) activity and intracellular stress-activated pathways remained unaltered in aorta of TMAO-injected rats, as assessed by Western Blot. Pre-incubation of human aortic endothelial cells with TMAO (10$^{−6}$ M) did not alter NO release in response to Ach. Our results indicate that increased plasmatic TMAO in the near-physiological range seems to be a neutral bystander to vascular function as translationally seen in patients after bariatric surgery or in healthy lean rodent models and in endothelial cells exposed acutely to TMAO

Seismotectonics of southeast France: from the Jura mountains to Corsica

The analysis of the seismicity catalog (1996 to 2019) covering the region from the Jura mountains to Corsica provides a first-order image of the distribution of earthquakes, highlighting large structures such as the Briançonnais and Piedmontais seismic arcs, the eastward deepening of the focal depths through the Western Alps, several large active faults (e.g. Belledonne, Middle Durance, Ligure). Over this period the magnitudes are moderate and the focal mechanisms of the main events display a diversity of seismic behaviors that can be explained by the complexity of the different geological domains with a more or less strong structural inheritage, by variable rheological characteristics at the scale of the crust and by the joint action of different mechanisms of deformation. The distribution of the historical events is in fairly good agreement with the instrumental seismicity, but several earthquakes of $M >6$ are highlighted since the 14th century until the beginning of the 20th

The effects of kisspeptin on β-cell function, serum metabolites and appetite in humans

Aims: To investigate the effect of kisspeptin on glucose-stimulated insulin secretion and appetite in humans. Materials and methods: In 15 healthy men (age: 25.2 ± 1.1 years; BMI: 22.3 ± 0.5 kg m−2), we compared the effects of 1 nmol kg−1 h−1 kisspeptin versus vehicle administration on glucose-stimulated insulin secretion, metabolites, gut hormones, appetite and food intake. In addition, we assessed the effect of kisspeptin on glucose-stimulated insulin secretion in vitro in human pancreatic islets and a human β-cell line (EndoC-βH1 cells). Results: Kisspeptin administration to healthy men enhanced insulin secretion following an intravenous glucose load, and modulated serum metabolites. In keeping with this, kisspeptin increased glucose-stimulated insulin secretion from human islets and a human pancreatic cell line in vitro. In addition, kisspeptin administration did not alter gut hormones, appetite or food intake in healthy men. Conclusions: Collectively, these data demonstrate for the first time a beneficial role for kisspeptin in insulin secretion in humans in vivo. This has important implications for our understanding of the links between reproduction and metabolism in humans, as well as for the ongoing translational development of kisspeptin-based therapies for reproductive and potentially metabolic conditions

Seismotectonics of southeast France: from the Jura mountains to Corsica

The analysis of the seismicity catalog (1996 to 2019) covering the region from the Jura mountains to Corsica provides a first-order image of the distribution of earthquakes, highlighting large structures such as the Briançonnais and Piedmontais seismic arcs, the eastward deepening of the focal depths through the Western Alps, several large active faults (e.g. Belledonne, Middle Durance, Ligure). Over this period the magnitudes are moderate and the focal mechanisms of the main events display a diversity of seismic behaviors that can be explained by the complexity of the different geological domains with a more or less strong structural inheritage, by variable rheological characteristics at the scale of the crust and by the joint action of different mechanisms of deformation. The distribution of the historical events is in fairly good agreement with the instrumental seismicity, but several earthquakes of $M >6$ are highlighted since the 14th century until the beginning of the 20th

Rapid response to the M_w 4.9 earthquake of November 11, 2019 in Le Teil, Lower Rhône Valley, France

On November 11, 2019, a Mw 4.9 earthquake hit the region close to Montelimar (lower Rhône Valley, France), on the eastern margin of the Massif Central close to the external part of the Alps. Occuring in a moderate seismicity area, this earthquake is remarkable for its very shallow focal depth (between 1 and 3 km), its magnitude, and the moderate to large damages it produced in several villages. InSAR interferograms indicated a shallow rupture about 4 km long reaching the surface and the reactivation of the ancient NE-SW La Rouviere normal fault in reverse faulting in agreement with the present-day E-W compressional tectonics. The peculiarity of this earthquake together with a poor coverage of the epicentral region by permanent seismological and geodetic stations triggered the mobilisation of the French post-seismic unit and the broad French scientific community from various institutions, with the deployment of geophysical instruments (seismological and geodesic stations), geological field surveys, and field evaluation of the intensity of the earthquake. Within 7 days after the mainshock, 47 seismological stations were deployed in the epicentral area to improve the Le Teil aftershocks locations relative to the French permanent seismological network (RESIF), monitor the temporal and spatial evolution of microearthquakes close to the fault plane and temporal evolution of the seismic response of 3 damaged historical buildings, and to study suspected site effects and their influence in the distribution of seismic damage. This seismological dataset, completed by data owned by different institutions, was integrated in a homogeneous archive and distributed through FDSN web services by the RESIF data center. This dataset, together with observations of surface rupture evidences, geologic, geodetic and satellite data, will help to unravel the causes and rupture mechanism of this earthquake, and contribute to account in seismic hazard assessment for earthquakes along the major regional Cévenne fault system in a context of present-day compressional tectonics

Molecular Mechanisms and Therapeutic Potential of Endothelial Crosstalk Nodes in Cardiometabolic Disease

Background & Aim of the Thesis: Obesity increases the likelihood of developing the metabolic syndrome (MetSyn), a cluster of risk factors that increase the chance of debilitating or even fatal cardiometabolic diseases (CMDs). Today, obesity disables and kills, in large part, because of the associated cardiovascular complications. CMD pathogenesis is complex, in that it involves several pathways of inter-organ communication. While there is a multiplicity of target organs and pathways, few have panned out into successful, druggable, treatment avenues. A notable exception is the glucagon-like peptide-1 (GLP-1) receptor agonist drug class, which, building on solid preclinical research, resulted in the development of a very successful treatment targeting obesity and its associated CMDs. The key to this success was the identification of an intra-organ crosstalk signaling node, GLP-1, which has relevant activity in all pathologies of interest. Building on this great example of success this thesis aims to identify other key intra-organ crosstalk signaling nodes relevant in obesity, MetSyn and CMDs which have the potential to lead to new or improved therapies. Methods Employed: We employ three models throughout this thesis: patient clinical trials, rodent models, and in-vitro cell models. In order to identify relevant crosstalk nodes in humans, we analyze blood samples from patients that underwent a hypocaloric diet lifestyle weight loss intervention, and two different cohorts of patients that underwent bariatric surgeries. We use bariatric surgery as a model for the recovery of healthy cardiovascular function after metabolic disease, and compare it to diet patients, who despite incurring significant weight loss, do not recover cardiovascular function to the same extent as post-bariatric patients. Further, we use a rat model of Roux-en-Y gastric bypass (RYGB) and healthy animals to study the molecular mechanisms involved in cardiovascular function recovery. We also use primary human aortic endothelial cell as our main \emph{in-vitro} model to assess the specific molecular pathways targeted in the endothelium, the gatekeeper of vascular function. Results Highlights: Using a translational approach, we identify three potential crosstalk nodes that may influence CMD severity and recovery. Chapter 1 is a review we published in 2020 and provides a general introduction to a key signaling node in this thesis: high-density lipoproteins (HDLs). In Chapter 2, we look into the increase in bile acids (BAs) in the circulation and on HDLs after RYGB. We identify that the post-surgical improvement in HDL’s endothelial anti-apoptosis function correlates to the HDL content of cholic acid (CA). Through exogenous loading of diseased HDL with CA, we are able to partially restore its anti-apoptotic function, via the inhibition of endothelial caspase-3 activity. These data show a key synergism between HDL and BA in endothelial signaling and may open the door for interesting therapeutic developments. In Chapter 3, we further explore HDL’s role post-bariatric, looking at a cohort of patients that underwent both RYGB and biliopancreatic diversion (BPD). We see that HDL’s functional improvements are maintained 5-years post-surgically, as well as the improvements in glucose control. Further, we are able to show that there is an association between the detailed lipidome of HDL and these improvements, potentially providing further mechanistic explanations for the success of bariatric surgeries in treating MetSyn and CMDs. Finally, we show that RYGB and BPD alter the lipidome of HDL in very different ways, which may account for their differential effects. These data may suggest that some bariatric procedures could be optimized, allowing us to compound the positive effects of all surgeries in a single procedure. In Chapter 4, we explore the final signaling node identified herein, trimethylamine N-oxide (TMAO), a gut metabolite that is thought to be particularly detrimental to cardiovascular health. Interestingly, we observe a significant increase in circulating TMAO after RYGB in patients and rats, but not after hypocaloric diet. This is in spite of a well-documented improvement in endothelial function post-RYGB. Based on this, we explored the role of TMAO in healthy rodents and cell models, to parse the direct effects of TMAO on endothelial function. We concluded this study by demonstrating that, in healthy conditions, acute TMAO exposure/treatment is neutral towards endothelial function. All chapters are either reprints of accepted manuscripts (Chapter 1) or preprints of manuscripts that will be submitted shortly (Chapters 2, 3 & 4). In Chapter 5, I broaden my view from the three individual manuscripts and discuss the data and its implications together. Finally, in the appendix of this thesis, I present some notable collaborations that have resulted in publications, another review I have written, a poster and grant award I was given and my current CV. Conclusion: To briefly conclude, this thesis presents three stories which identified and discusses \emph{two key signaling nodes relevant in the resorption of cardiovascular disease after bariatric surgeries. HDLs and BAs have emerged as important whole-body crosstalk signaling nodes that warrant further investigation, and, potentially, may lead to new and exciting therapeutic applications. TMAO on the other hand, should be re-considered as a causal agent in cardiovascular disease and may potentially just be a neutral bystander

High Density Lipoproteins: Metabolism, Function, and Therapeutic Potential

High Density Lipoproteins (HDLs) have long been considered as “good cholesterol,” beneficial to the whole body and, in particular, to cardio-vascular health. However, HDLs are complex particles that undergoes dynamic remodeling through interactions with various enzymes and tissues throughout their life cycle, making the complete understanding of its functions and roles more complicated than initially expected. In this review, we explore the novel understanding of HDLs' behavior in health and disease as a multifaceted class of lipoprotein, with different size subclasses, molecular composition, receptor interactions, and functionality. Further, we report on emergent HDL-based therapeutics tested in small and larger scale clinical trials and their mixed successes.ISSN:2297-055