Identification of Prominin-2 as a new player of cardiomyocyte senescence in the aging heart.

The aging heart is characterized by a number of structural changes leading to ventricular stiffness, impaired resistance to stress and increased risk of developing heart failure (HF). Genetic or pharmacological removal of senescent cells has recently demonstrated the possibility to relieve some cardiac aging features such as hypertrophy and fibrosis. However, the contribution of the different cell types in cardiac aging remains fragmentary due to a lack of cell-specific markers. Cardiomyocytes undergo post-mitotic senescence in response to telomere damage, characterized by persistent DNA damage response and expression of the classical senescence markers p21 and p16, which are shared by many other cell types. In the present study, we used transcriptomic approaches to discover new markers specific for cardiomyocyte senescence. We identified Prominin2 (Prom2), encoding a transmembrane glycoprotein, as the most upregulated gene in cardiomyocytes of aged mice compared to young mice. We showed that Prom2 was upregulated by a p53-dependent pathway in stress-induced premature senescence. Prom2 expression correlated with cardiomyocyte hypertrophy in the hearts of aged mice and was increased in atrial samples of patients with HF with preserved ejection fraction. Consistently, Prom2 overexpression was sufficient to drive senescence, hypertrophy and resistance to cytotoxic stress while Prom2 shRNA silencing inhibited these features in doxorubicin-treated cardiac cells. In conclusion, we identified Prom2 as a new player of cardiac aging, linking cardiomyocyte hypertrophy to senescence. These results could provide a better understanding and targeting of cell-type specific senescence in age-associated cardiac diseases.

Plasma Inflammatory Biomarkers and Anorexia of Ageing among Community-Dwelling Older Adults: An Exploratory Analysis of the MAPT Study.

Anorexia of aging and biological aging might share physiological underpinnings. The aim of this secondary analysis was to investigate the associations between circulating inflammation-related markers and anorexia of aging in community-dwelling older adults. C-reactive protein (CRP), tumor necrosis factor receptor-1 (TNFR-1), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1) and growth/differentiation factor-15 (GDF-15) were measured in plasma. Anorexia of aging was defined by the response "severe/moderate decrease in food intake" to the first item of the Mini-Nutritional Assessment. We included 463 subjects (median age=74y, IQR=71-78; 63.1% women). 33 subjects (7.1%) presented with anorexia at baseline, whereas 25 out of 363 (6.9%) developed it along 1-year follow-up. We found that TNFR1 (OR=1.74, 95%CI=1.27-2.39) and GDF-15 (OR=1.38, 95%CI=1.01-1.89) were associated with a significant increase in the odds of presenting with anorexia of aging cross-sectionally. No further significant associations were found. Biological aging mechanisms might be involved in the pathogenesis of anorexia of aging.

Circulating Levels of Apelin, GDF-15 and Sarcopenia: Lack of Association in the MAPT Study.

OBJECTIVES: Apelin and GDF-15 have been proposed as biomarkers of age-related sarcopenia but evidence in human models is scarce. This study aimed to explore the associations between blood apelin and GDF-15 with sarcopenia incidence and the evolution of sarcopenia components over two years in older adults >70 years. DESIGN: Secondary longitudinal analysis of the Multidomain Alzheimer Preventive Trial. PARTICIPANTS: Older adults (>70 years) attending primary care centers in France and Monaco. SETTING: Community. MEASUREMENTS: Serum Apelin (pg/mL) and plasma GDF-15 (pg/mL) were measured. Outcomes included sarcopenia defined by the European Working Group on Sarcopenia in Older People (EWGSOP) and its determinants (appendicular lean mass [ALM] evaluated through a Dual-energy X-ray Absorptiometry (DXA) scan, handgrip strength (HGS) and the 4-meter gait speed) measured over 2 years. Linear mixed models and logistic regression were used to explore the longitudinal associations. RESULTS: We included 168 subjects from MAPT (median age=76y, IQR=73-79; 78% women). Serum apelin was not significantly associated with sarcopenia incidence (OR=1.001;95%CI=1.000,1.001;p-value>0.05 in full-adjusted models) nor with ALM (ß=-5.8E-05;95%CI=-1.0E-04,2.12E-04;p>0.05), HGS (ß=-1.1E-04;95%CI=-5.0E-04,2.8E-04;p>0.05), and GS (ß=-5.1E-06;95%CI=-1.0E-05,2.0E-05;p>0.05) in fully adjusted models. Similarly, plasma GDF-15 was not associated with both the incidence of sarcopenia (OR=1.001,95%CI=1.000,1.002,p>0.05) and the evolution of its determinants ([ALM, ß=2.1E-05;95%CI=-2.6E-04,3.03E-04;p>0.05], HGS [ß=-5.9E-04;95%CI=-1.26E-03,8.1E-05; p>0.05] nor GS [ß=-2.6E-06;95%CI=-3.0E-05, 2.3E-05;p>0.05]) in fully adjusted models. CONCLUSIONS: Blood apelin and GDF-15 were not associated with sarcopenia incidence or with the evolution of sarcopenia components over a 2-year follow-up in community-dwelling older adults. Well-powered longitudinal studies are needed to confirm or refute our findings.

Healthy Aging Biomarkers: The INSPIRE's Contribution.

The find solutions for optimizing healthy aging and increase health span is one of the main challenges for our society. A novel healthcare model based on integration and a shift on research and care towards the maintenance of optimal functional levels are now seen as priorities by the WHO. To address this issue, an integrative global strategy mixing longitudinal and experimental cohorts with an innovative transverse understanding of physiological functioning is missing. While the current approach to the biology of aging is mainly focused on parenchymal cells, we propose that age-related loss of function is largely determined by three elements which constitute the general ground supporting the different specific parenchyma: i.e. the stroma, the immune system and metabolism. Such strategy that is implemented in INSPIRE projects can strongly help to find a composite biomarker capable of predicting changes in capacity across the life course with thresholds signalling frailty and care dependence.

The INSPIRE Research Initiative: A Program for GeroScience and Healthy Aging Research Going from Animal Models to Humans and the Healthcare System.

Aging is the most important risk factor for the onset of several chronic diseases and functional decline. Understanding the interplays between biological aging and the biology of diseases and functional loss as well as integrating a function-centered approach to the care pathway of older adults are crucial steps towards the elaboration of preventive strategies (both pharmacological and non-pharmacological) against the onset and severity of burdensome chronic conditions during aging. In order to tackle these two crucial challenges, ie, how both the manipulation of biological aging and the implementation of a function-centered care pathway (the Integrated Care for Older People (ICOPE) model of the World Health Organization) may contribute to the trajectories of healthy aging, a new initiative on Gerosciences was built: the INSPIRE research program. The present article describes the scientific background on which the foundations of the INSPIRE program have been constructed and provides the general lines of this initiative that involves researchers from basic and translational science, clinical gerontology, geriatrics and primary care, and public health.

Towards a Large-Scale Assessment of the Relationship between Biological and Chronological Aging: The INSPIRE Mouse Cohort.

Aging is the major risk factor for the development of chronic diseases. After decades of research focused on extending lifespan, current efforts seek primarily to promote healthy aging. Recent advances suggest that biological processes linked to aging are more reliable than chronological age to account for an individual's functional status, i.e. frail or robust. It is becoming increasingly apparent that biological aging may be detectable as a progressive loss of resilience much earlier than the appearance of clinical signs of frailty. In this context, the INSPIRE program was built to identify the mechanisms of accelerated aging and the early biological signs predicting frailty and pathological aging. To address this issue, we designed a cohort of outbred Swiss mice (1576 male and female mice) in which we will continuously monitor spontaneous and voluntary physical activity from 6 to 24 months of age under either normal or high fat/high sucrose diet. At different age points (6, 12, 18, 24 months), multiorgan functional phenotyping will be carried out to identify early signs of organ dysfunction and generate a large biological fluids/feces/organs biobank (100,000 samples). A comprehensive correlation between functional and biological phenotypes will be assessed to determine: 1) the early signs of biological aging and their relationship with chronological age; 2) the role of dietary and exercise interventions on accelerating or decelerating the rate of biological aging; and 3) novel targets for the promotion of healthy aging. All the functional and omics data, as well as the biobank generated in the framework of the INSPIRE cohort will be available to the aging scientific community. The present article describes the scientific background and the strategies employed for the design of the INSPIRE Mouse cohort.

The INSPIRE Bio-Resource Research Platform for Healthy Aging and Geroscience: Focus on the Human Translational Research Cohort (The INSPIRE-T Cohort).

BACKGROUND: The Geroscience field focuses on the core biological mechanisms of aging, which are involved in the onset of age-related diseases, as well as declines in intrinsic capacity (IC) (body functions) leading to dependency. A better understanding on how to measure the true age of an individual or biological aging is an essential step that may lead to the definition of putative markers capable of predicting healthy aging. OBJECTIVES: The main objective of the INStitute for Prevention healthy agIng and medicine Rejuvenative (INSPIRE) Platform initiative is to build a program for Geroscience and healthy aging research going from animal models to humans and the health care system. The specific aim of the INSPIRE human translational cohort (INSPIRE-T cohort) is to gather clinical, digital and imaging data, and perform relevant and extensive biobanking to allow basic and translational research on humans. METHODS: The INSPIRE-T cohort consists in a population study comprising 1000 individuals in Toulouse and surrounding areas (France) of different ages (20 years or over - no upper limit for age) and functional capacity levels (from robustness to frailty, and even dependency) with follow-up over 10 years. Diversified data are collected annually in research facilities or at home according to standardized procedures. Between two annual visits, IC domains are monitored every 4-month by using the ICOPE Monitor app developed in collaboration with WHO. Once IC decline is confirmed, participants will have a clinical assessment and blood sampling to investigate markers of aging at the time IC declines are detected. Biospecimens include blood, urine, saliva, and dental plaque that are collected from all subjects at baseline and then, annually. Nasopharyngeal swabs and cutaneous surface samples are collected in a large subgroup of subjects every two years. Feces, hair bulb and skin biopsy are collected optionally at the baseline visit and will be performed again during the longitudinal follow up. EXPECTED RESULTS: Recruitment started on October 2019 and is expected to last for two years. Bio-resources collected and explored in the INSPIRE-T cohort will be available for academic and industry partners aiming to identify robust (set of) markers of aging, age-related diseases and IC evolution that could be pharmacologically or non-pharmacologically targetable. The INSPIRE-T will also aim to develop an integrative approach to explore the use of innovative technologies and a new, function and person-centered health care pathway that will promote a healthy aging.

Case series of coronavirus (SARS-CoV-2) in a military recruit school: clinical, sanitary and logistical implications.

INTRODUCTION: A new coronavirus, called Severe Acute Respiratory Syndrome-CoronaVirus-2 (SARS-CoV-2), has emerged from China in late 2019 and has now caused a worldwide pandemic. The impact of COVID-19 has not been described so far in a military setting. We therefore report a case series of infected patients in a recruit school in Switzerland and the herein associated challenges. METHODS: Retrospective review of COVID-19 cases among Swiss Armed Forces recruits in the early weeks of SARS-CoV-2 pandemic in the canton of Ticino, the southernmost canton of Switzerland. Positive cases were defined with two positive PCR testing for SARS-CoV-2 from nasopharyngeal swabs. Serological testing was performed with a commercially available kit according to manufacturers' instructions. RESULTS: The first case was likely contaminated while skiing during weekend permission. He became symptomatic 4 days later, tested positive for SARS-CoV-2 and was put into isolation. He showed complete symptom resolution after 48 hours. Quarantine was ordered for all recruits with close contact in the past 2 days, a total of 55 persons out of 140 in the company. Seven out of nine recruits in one particular quarantine room became mildly symptomatic. SARS-CoV-2 PCR was positive in one of them. Seven days after initial diagnosis, the index patient and the other one from the quarantine retested positive for SARS-CoV-2, although they had been completely asymptomatic for over 96 hours. Serological testing revealed positive for both patients. All others showed negative IgM and IgG. CONCLUSIONS: Young healthy recruits often showed a mild course of COVID-19 with rapid symptom decline but were persistent SARS-CoV-2 carriers. This illustrates how asymptomatic patients may be responsible for covert viral transmission. An early and prolonged establishment of isolation and quarantine for patients and close contacts is essential to slow down the spread of SARS-CoV-2, especially in the confined space of a military environment.

ICFSR Task Force Perspective on Biomarkers for Sarcopenia and Frailty.

Biomarkers of frailty and sarcopenia are essential to advance the understanding of these conditions of aging and develop new diagnostic tools and effective treatments. The International Conference on Frailty and Sarcopenia Research (ICFSR) Task Force - a group of academic and industry scientists from around the world -- met in February 2019 to discuss the current state of biomarker development for frailty and sarcopenia. The D3Cr dilution method, which assesses creatinine excretion as a biochemical measure of muscle mass, was suggested as a more accurate measure of functional muscle mass than assessment by dual energy x-ray absorptiometry (DXA). Proposed biomarkers of frailty include markers of inflammation, the hypothalamic-pituitary-adrenal (HPA) axis response to stress, altered glucose insulin dynamics, endocrine dysregulation, aging, and others, acknowledging the complex multisystem etiology that contributes to frailty. Lack of clarity regarding a regulatory pathway for biomarker development has hindered progress; however, there are currently several international efforts to develop such biomarkers as tools to improve the treatment of individuals presenting these conditions.

Revisiting the Hallmarks of Aging to Identify Markers of Biological Age.

The Geroscience aims at a better understanding of the biological processes of aging, to prevent and/or delay the onset of chronic diseases and disability as well as to reduce the severity of these adverse clinical outcomes. Geroscience thus open up new perspectives of care to live a healthy aging, that is to say without dependency. To date, life expectancy in healthy aging is not increasing as fast as lifespan. The identification of biomarkers of aging is critical to predict adverse outcomes during aging, to implement interventions to reduce them, and to monitor the response to these interventions. In this narrative review, we gathered information about biomarkers of aging under the perspective of Geroscience. Based on the current literature, for each hallmark of biological aging, we proposed a putative biomarker of healthy aging, chosen for their association with mortality, age-related chronic diseases, frailty and/or functional loss. We also discussed how they could be validated as useful predictive biomarkers.

Intramyocardial transplantation of mesenchymal stromal cells for chronic myocardial ischemia and impaired left ventricular function: Results of the MESAMI 1 pilot trial.

BACKGROUND: The MESAMI 1 trial was a bicentric pilot study designed to test the feasibility and safety of intramyocardially injected autologous bone marrow-derived mesenchymal stromal cells (MSCs) for the treatment of ischemic cardiomyopathy. METHODS AND RESULTS: The study included 10 patients with chronic myocardial ischemia, left ventricular (LV) ejection fractions (EFs) of ≤35%, and reversible perfusion defects who were on stable optimal medical therapy and were not candidates for revascularization. MSCs (mean: 61.5×10(6) cells per patient) were injected into 10-16 viable sites at the border of the LV scar via a NOGA-guided catheter. Both primary endpoints, feasibility (successful harvest, expansion, and injection of autologous MSCs) and safety (absence of severe adverse events [SAEs]) were met in all 10 patients at the 1-month follow-up time point, and none of the SAEs reported during the full 2-year follow-up period were attributable to the study intervention. The results of secondary efficacy endpoint analyses identified significant improvements from baseline to Month 12 in LVEF (29.4±2.0% versus 35.7±2.5%; p=0.003), LV end-systolic volume (167.8±18.8mL versus 156.1±28.6mL; p=0.04), 6-min walk test and NYHA functional class. CONCLUSIONS: Our results suggest that autologous MSCs can be safely administered to the hearts of patients with severe, chronic, reversible myocardial ischemia and impaired cardiac function and may be associated with improvements in cardiac performance, LV remodeling, and patient functional status. A randomized, double blind, multicenter, placebo-controlled clinical trial (MESAMI 2) will evaluate the efficacy of this treatment approach in a larger patient population. CLINICAL TRIAL REGISTRATION: Unique identifier: NCT01076920.

Transition from metabolic adaptation to maladaptation of the heart in obesity: role of apelin.

BACKGROUND/OBJECTIVES: Impaired energy metabolism is the defining characteristic of obesity-related heart failure. The adipocyte-derived peptide apelin has a role in the regulation of cardiovascular and metabolic homeostasis and may contribute to the link between obesity, energy metabolism and cardiac function. Here we investigate the role of apelin in the transition from metabolic adaptation to maladaptation of the heart in obese state. METHODS: Adult male C57BL/6J, apelin knock-out (KO) or wild-type mice were fed a high-fat diet (HFD) for 18 weeks. To induce heart failure, mice were subjected to pressure overload after 18 weeks of HFD. Long-term effects of apelin on fatty acid (FA) oxidation, glucose metabolism, cardiac function and mitochondrial changes were evaluated in HFD-fed mice after 4 weeks of pressure overload. Cardiomyocytes from HFD-fed mice were isolated for analysis of metabolic responses. RESULTS: In HFD-fed mice, pressure overload-induced transition from hypertrophy to heart failure is associated with reduced FA utilization (P<0.05), accelerated glucose oxidation (P<0.05) and mitochondrial damage. Treatment of HFD-fed mice with apelin for 4 weeks prevented pressure overload-induced decline in FA metabolism (P<0.05) and mitochondrial defects. Furthermore, apelin treatment lowered fasting plasma glucose (P<0.01), improved glucose tolerance (P<0.05) and preserved cardiac function (P<0.05) in HFD-fed mice subjected to pressure overload. In apelin KO HFD-fed mice, spontaneous cardiac dysfunction is associated with reduced FA oxidation (P<0.001) and increased glucose oxidation (P<0.05). In isolated cardiomyocytes, apelin stimulated FA oxidation in a dose-dependent manner and this effect was prevented by small interfering RNA sirtuin 3 knockdown. CONCLUSIONS: These data suggest that obesity-related decline in cardiac function is associated with defective myocardial energy metabolism and mitochondrial abnormalities. Furthermore, our work points for therapeutic potential of apelin to prevent myocardial metabolic abnormalities in heart failure paired with obesity.

First evidence of increased plasma serotonin levels in Tako-Tsubo cardiomyopathy.

BACKGROUND: There is no data about the serotonergic activity during the acute phase of Tako-Tsubo Cardiomyopathy (TTC). The objective of our study was to investigate evidence of serotonin release from patients with TTC in comparison with patients with ST elevation myocardial infarction (STEMI) and healthy control subjects (HCS). METHODS AND RESULTS: Plasma serotonin levels in 14 consecutive patients with TTC were compared with those in 14 patients with STEMI and 14 HCS. Plasma serotonin levels at admission were markedly higher in patients with TTC and STEMI as compared to HCS (3.9 ± 4.6, P = 0.02 versus control; 5.7 ± 5.6, P = 0.001 versus control; and 1 ± 0.4 ng/mL, resp.). There was no difference in serotonin levels between patients with TTC and those with STEMI (P = 0.33). CONCLUSION: This finding suggests that serotonin could participate to the pathophysiology of TTC.

Role of serotonin 5-HT2A receptors in the development of cardiac hypertrophy in response to aortic constriction in mice.

Serotonin, in addition to its fundamental role as a neurotransmitter, plays a critical role in the cardiovascular system, where it is thought to be involved in the development of cardiac hypertrophy and failure. Indeed, we recently found that mice with deletion of monoamine oxidase A had enhanced levels of blood and cardiac 5-HT, which contributed to exacerbation of hypertrophy in a model of experimental pressure overload. 5-HT2A receptors are expressed in the heart and mediate a hypertrophic response to 5-HT in cardiac cells. However, their role in cardiac remodeling in vivo and the signaling pathways associated are not well understood. In the present study, we evaluated the effect of a selective 5-HT2A receptor antagonist, M100907, on the development of cardiac hypertrophy induced by transverse aortic constriction (TAC). Cardiac 5-HT2A receptor expression was transiently increased after TAC, and was recapitulated in cardiomyocytes, as observed with 5-HT2A in situ labeling by immunohistochemistry. Selective blockade of 5-HT2A receptors prevented the development of cardiac hypertrophy, as measured by echocardiography, cardiomyocyte area and heart weight-to-body weight ratio. Interestingly, activation of calmodulin kinase (CamKII), which is a core mechanism in cardiac hypertrophy, was reduced in cardiac samples from M100907-treated TAC mice compared to vehicle-treated mice. In addition, phosphorylation of histone deacetylase 4 (HDAC4), a downstream partner of CamKII was significantly diminished in M100907-treated TAC mice. Thus, our results show that selective blockade of 5-HT2A receptors has beneficial effect in the development of cardiac hypertrophy through inhibition of the CamKII/HDAC4 pathway.

Intraparenchymal injection of bone marrow mesenchymal stem cells reduces kidney fibrosis after ischemia-reperfusion in cyclosporine-immunosuppressed rats.

Ischemia-reperfusion and immunosuppressive therapy are a major cause of progressive renal failure after kidney transplantation. Recent studies have shown that administration of bone marrow mesenchymal stem cells (MSCs) improves kidney functional recovery in the acute phase of post ischemia-reperfusion injury. In the present study, we used an original model of renal ischemia-reperfusion in immunosuppressed rats (NIRC) to investigate the effects of bone marrow MSCs on progression of chronic renal failure and the mechanisms potentially involved. Left renal ischemia-reperfusion (IR) was induced in unilateral nephrectomized Lewis rats. After IR, rats were treated daily with cyclosporine (10 mg/kg SC) for 28 days. MSCs were injected into the kidney at day 7 after IR. At day 28 after IR, kidneys were removed for histomorphological, biochemical, and gene expression analysis. The effect of conditioned media from MSCs on epithelial-mesenchymal transition was studied in vitro on HK2 cells. Our results show that, as compared to untreated NIRC rats, rats treated by intrarenal injection of MSCs 7 days after IR displayed improvement in renal function, reduction of interstitial fibrosis, and decrease in chronic tubule injury. These effects were associated with a decrease in interstitial α-SMA accumulation and MMP2 activity, markers of fibroblast/fibroblast-like cell activation, and renal remodeling, respectively. Finally, experiments in vitro showed that MSC-conditioned medium prevented epithelial-mesenchymal transition induced by TGF-ß in HK2 cells. In conclusion, our results show that, in immunosuppressed animals, a single intrarenal administration of MSCs reduced renal fibrosis and promoted the recovery of renal function.

Step-index optical waveguide produced by multi-step ion implantation in LiNbO3.

The refractive indexes, material attenuation and damage fractions of a multi-step ion implanted Lithium Niobate (LiNbO3) waveguide were analyzed as functions of the annealing temperatures. An almost flat damage depth profile was designed to reduce the uncertainties related to the indexes profile shape, thus providing a better test-case for the characterizations. The measurements performed on the fabricated optical waveguides confirmed the predicted step-index profiles showing that the light is confined inside the damaged layer. The low measured attenuation (less than 0.8 dB/cm @ 632.8 nm) makes the obtained waveguide attractive for device fabrication.

Evaluation of alginate microspheres for mesenchymal stem cell engraftment on solid organ.

Mesenchymal stem cells (MSCs) may be used as a cell source for cell therapy of solid organs due to their differentiation potential and paracrine effect. Nevertheless, optimization of MSC-based therapy needs to develop alternative strategies to improve cell administration and efficiency. One option is the use of alginate microencapsulation, which presents an excellent biocompatibility and an in vivo stability. As MSCs are hypoimmunogenic, it was conceivable to produce microparticles with [alginate-poly-L-lysine-alginate (APA) microcapsules] or without (alginate microspheres) a surrounding protective membrane. Therefore, the aim of this study was to determine the most suitable microparticles to encapsulate MSCs for engraftment on solid organ. First, we compared the two types of microparticles with 4 × 10(6) MSCs/ml of alginate. Results showed that each microparticle has distinct morphology and mechanical resistance but both remained stable over time. However, as MSCs exhibited a better viability in microspheres than in microcapsules, the study was pursued with microspheres. We demonstrated that viable MSCs were still able to produce the paracrine factor bFGF and did not present any chondrogenic or osteogenic differentiation, processes sometimes reported with the use of polymers. We then proved that microspheres could be implanted under the renal capsule without degradation with time or inducing impairment of renal function. In conclusion, these microspheres behave as an implantable scaffold whose biological and functional properties could be adapted to fit with clinical applications.

Dose-dependent activation of distinct hypertrophic pathways by serotonin in cardiac cells.

There is substantial evidence supporting a hypertrophic action of serotonin [5-hydroxytryptamine (5-HT)] in cardiomyocytes. However, little is known about the mechanisms involved. We previously demonstrated that 5-HT-induced hypertrophy depends, in part, on the generation of reactive oxygen species by monoamine oxidase-A (MAO-A) (see Ref. 3). Cardiomyocytes express 5-HT(2) receptors, which may also participate in hypertrophy. Here, we analyzed the respective contribution of 5-HT(2) receptors and MAO-A in H9C2 cardiomyoblast hypertrophy. 5-HT induced a dose-dependent increase in [(3)H]leucine incorporation and stimulation of two markers of cardiac hypertrophy, ANF-luc and alphaSK-actin-luc reporter genes. Experiments using 1 microM 5-HT showed that hypertrophic response occurred independently from MAO-A. Using pharmacological inhibitors (M100907 and ketanserin), we identified a novel mechanism of action involving 5-HT(2A) receptors and requiring Ca(2+)/calcineurin/nuclear factor of activated T-cell activation. The activation of this hypertrophic pathway was fully prevented by 5-HT(2A) inhibitors and was unaffected by MAO inhibition. When 10 microM 5-HT was used, an additional hypertrophic response, prevented by the MAO inhibitors pargyline and RO 41-1049, was observed. Unlike the 5-HT(2A)-receptor-mediated H9C2 cell hypertrophy, MAO-A-dependent hypertrophic response required activation of extracellular-regulated kinases. In conclusion, our results show the existence of a dose-dependent shift of activation of distinct intracellular pathways involved in 5-HT-mediated hypertrophy of cardiac cells.

New insights on receptor-dependent and monoamine oxidase-dependent effects of serotonin in the heart.

Biogenic amines like serotonin (5-HT) and catecholamines usually act through stimulation of G-protein coupled receptors (GPCRs). We now have strong evidence that they can signal through receptor-independent mechanisms. One well described pathway is the degradation of biogenic amine by monoamine oxidases (MAOs) after transport into the cells by selective transporters. The oxidation of biogenic amines generates hydrogen peroxide, H(2)O(2), that can act as a signalling intermediate in the cell. This original mechanism of action of 5-HT is relevant in the heart since it is responsible for both cardiomyocyte hypertrophy and apoptosis. Moreover, in vivo experiments indicate a physiological significance for MAO in the damage during ischemia-reperfusion in the heart. Since functional 5-HT receptors are present in the heart and have also been demonstrated to contribute to cardiomyocyte growth and apoptosis, it is of major interest to evaluate respective contribution and cross-regulations between 5-HT receptors and MAO in cardiac function.

[Cardiac cellular therapy: from cells to the first clinical uses]. / Thérapie cellulaire cardiaque: des cellules aux premières indications cliniques.

Despite the improvement in revascularisation techniques, coronary artery disease remains the principal aetiology of cardiac failure in developed countries. The therapeutic management of cardiac failure has been improved over recent years, yet cardiac failure is still associated with significant morbidity and mortality. As cardiac transplantation lacks donors, techniques that allow myocardial regeneration represent an attractive alternative. To date, several types of cells are under study and are suitable for implantation into infarcted myocardium (myoblasts, medullary stem cells...). Following good preclinical study results, the first human cell therapy trials, using the intramyocardial route, have begun, in the course of aorto-coronary bypass surgery in patients with chronic ischaemic cardiopathy and little altered left ventricular function, and then in those with ventricular dysfunction. Different modes of administration of these cell therapy products are under study and could be envisaged in clinical situations such as just after infarction in order to improve ventricular remodelling with an intracoronary injection technique. As for every new treatment, there are numerous problems to resolve, from understanding the relevant mechanisms of cellular transplantation, to the secondary effects that it could entail. Nevertheless, cardiac cellular transplantation is expanding rapidly and with the evolution of techniques it allows a glimpse of a new field of treatment for cardiac failure.