RESUMO
Phoenixin-14 (PNX) is a newly identified peptide co-expressed in the hypothalamus with the anorexic and cardioactive Nesfatin-1. Like Nesfatin-1, PNX is able to cross the blood-brain barrier and this suggests a role in peripheral modulation. Preliminary mass spectrography data indicate that, in addition to the hypothalamus, PNX is present in the mammalian heart. This study aimed to quantify PNX expression in the rat heart, and to evaluate whether the peptide influences the myocardial function under basal condition and in the presence of ischemia/reperfusion (I/R). By ELISA the presence of PNX was detected in both hypothalamus and heart. In plasma of normal, but not of obese rats, the peptide concentrations increased after meal. Exposure of the isolated and Langendorff perfused rat heart to exogenous PNX induces a reduction of contractility and relaxation, without effects on coronary pressure and heart rate. As revealed by immunoblotting, these effects were accompanied by an increase of Erk1/2, Akt and eNOS phosphorylation. PNX (EC50 dose), administered after ischemia, induced post-conditioning-like cardioprotection. This was revealed by a smaller infarct size and a better systolic recovery with respect to those detected on hearts exposed to I/R alone. The peptide also activates the cardioprotective RISK and SAFE cascades and inhibits apoptosis. These effects were also observed in the heart of obese rats. Our data provide a first evidence on the peripheral activity of PNX and on its direct cardiomodulatory and cardioprotective role under both normal conditions and in the presence of metabolic disorders.
Assuntos
Citoproteção , Coração/efeitos dos fármacos , Coração/fisiologia , Hormônios Hipotalâmicos/farmacologia , Hormônios Hipotalâmicos/fisiologia , Miocárdio/metabolismo , Hormônios Peptídicos/farmacologia , Hormônios Peptídicos/fisiologia , Animais , Cardiotônicos/metabolismo , Cardiotônicos/farmacologia , Citoproteção/efeitos dos fármacos , Citoproteção/genética , Hormônios Hipotalâmicos/isolamento & purificação , Hormônios Hipotalâmicos/metabolismo , Masculino , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/patologia , Hormônios Peptídicos/isolamento & purificação , Hormônios Peptídicos/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacosRESUMO
Dendritic cells (DCs) have a key role in regulating tumor immunity, tumor cell growth and drug resistance. We hypothesized that multiple myeloma (MM) cells might recruit and reprogram DCs to a tumor-permissive phenotype by changes within their microRNA (miRNA) network. By analyzing six different miRNA-profiling data sets, miR-29b was identified as the only miRNA upregulated in normal mature DCs and significantly downregulated in tumor-associated DCs. This finding was validated in primary DCs co-cultured in vitro with MM cell lines and in primary bone marrow DCs from MM patients. In DCs co-cultured with MM cells, enforced expression of miR-29b counteracted pro-inflammatory pathways, including signal transducer and activator of transcription 3 and nuclear factor-κB, and cytokine/chemokine signaling networks, which correlated with patients' adverse prognosis and development of bone disease. Moreover, miR-29b downregulated interleukin-23 in vitro and in the SCID-synth-hu in vivo model, and antagonized a Th17 inflammatory response. All together, these effects translated into strong anti-proliferative activity and reduction of genomic instability of MM cells. Our study demonstrates that MM reprograms the DCs functional phenotype by downregulating miR-29b whose reconstitution impairs DCs ability to sustain MM cell growth and survival. These results underscore miR-29b as an innovative and attractive candidate for miRNA-based immune therapy of MM.
Assuntos
Células Dendríticas/patologia , Inflamação/genética , MicroRNAs/genética , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Animais , Medula Óssea/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação para Baixo/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Camundongos , Camundongos SCID , NF-kappa B/genética , Fator de Transcrição STAT3/genética , Regulação para Cima/genéticaRESUMO
Arginine methyltransferases critically regulate cellular homeostasis by modulating the functional outcome of their substrates. The protein arginine methyltransferase 5 (PRMT5) is an enzyme involved in growth and survival pathways promoting tumorigenesis. However, little is known about the biologic function of PRMT5 and its therapeutic potential in multiple myeloma (MM). In the present study, we identified and validated PRMT5 as a new therapeutic target in MM. PRMT5 is overexpressed in patient MM cells and associated with decreased progression-free survival and overall survival. Either genetic knockdown or pharmacological inhibition of PRMT5 with the inhibitor EPZ015666 significantly inhibited growth of both cell lines and patient MM cells. Furthermore, PRMT5 inhibition abrogated NF-κB signaling. Interestingly, mass spectrometry identified a tripartite motif-containing protein 21 TRIM21 as a new PRMT5-partner, and we delineated a TRIM21-dependent mechanism of NF-κB inhibition. Importantly, oral administration of EPZ015666 significantly decreased MM growth in a humanized murine model of MM. These data both demonstrate the oncogenic role and prognostic relevance of PRMT5 in MM pathogenesis, and provide the rationale for novel therapies targeting PRMT5 to improve patient outcome.
Assuntos
Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Proteína-Arginina N-Metiltransferases/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Humanos , Isoquinolinas/farmacologia , NF-kappa B/metabolismo , Prognóstico , Pirimidinas/farmacologia , Ribonucleoproteínas/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
Deregulated microRNA (miR)/transcription factor (TF)-based networks represent a hallmark of cancer. We report here a novel c-Myc/miR-23b/Sp1 feed-forward loop with a critical role in multiple myeloma (MM) and Waldenstrom's macroglobulinemia (WM) cell growth and survival. We have found miR-23b to be downregulated in MM and WM cells especially in the presence of components of the tumor bone marrow milieu. Promoter methylation is one mechanism of miR-23b suppression in myeloma. In gain-of-function studies using miR-23b mimics-transfected or in miR-23b-stably expressing MM and WM cell lines, we observed a significant decrease in cell proliferation and survival, along with induction of caspase-3/7 activity over time, thus supporting a tumor suppressor role for miR-23b. At the molecular level, miR-23b targeted Sp1 3'UTR and significantly reduced Sp1-driven nuclear factor-κB activity. Finally, c-Myc, an important oncogenic transcription factor known to stimulate MM cell proliferation, transcriptionally repressed miR-23b. Thus MYC-dependent miR-23b repression in myeloma cells may promote activation of oncogenic Sp1-mediated signaling, representing the first feed-forward loop with critical growth and survival role in myeloma.
Assuntos
Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , MicroRNAs/genética , Mieloma Múltiplo/genética , Proteínas Proto-Oncogênicas c-myc/genética , Fator de Transcrição Sp1/genética , Animais , Sequência de Bases , Sítios de Ligação , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular/genética , Metilação de DNA , Modelos Animais de Doenças , Regulação para Baixo , Expressão Gênica , Perfilação da Expressão Gênica , Inativação Gênica , Genes Reporter , Humanos , MicroRNAs/química , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-myc/química , Proteínas Proto-Oncogênicas c-myc/metabolismo , Interferência de RNA , RNA Mensageiro/química , RNA Mensageiro/genética , Fator de Transcrição Sp1/química , Fator de Transcrição Sp1/metabolismoRESUMO
Interferon regulatory factor 4 (IRF4) is an attractive therapeutic target in multiple myeloma (MM). We here report that expression of IRF4 mRNA inversely correlates with microRNA (miR)-125b in MM patients. Moreover, we provide evidence that miR-125b is downregulated in TC2/3 molecular MM subgroups and in established cell lines. Importantly, constitutive expression of miR-125b-5p by lentiviral vectors or transfection with synthetic mimics impaired growth and survival of MM cells and overcame the protective role of bone marrow stromal cells in vitro. Apoptotic and autophagy-associated cell death were triggered in MM cells on miR-125b-5p ectopic expression. Importantly, we found that the anti-MM activity of miR-125b-5p was mediated via direct downregulation of IRF4 and its downstream effector BLIMP-1. Moreover, inhibition of IRF4 translated into downregulation of c-Myc, caspase-10 and cFlip, relevant IRF4-downstream effectors. Finally, in vivo intra-tumor or systemic delivery of formulated miR-125b-5p mimics against human MM xenografts in severe combined immunodeficient/non-obese diabetic mice induced significant anti-tumor activity and prolonged survival. Taken together, our findings provide evidence that miR-125b, differently from other hematologic malignancies, has tumor-suppressor activity in MM. Furthermore, our data provide proof-of-concept that synthetic miR-125b-5p mimics are promising anti-MM agents to be validated in early clinical trials.
Assuntos
Fatores Reguladores de Interferon/genética , MicroRNAs/fisiologia , Mieloma Múltiplo/terapia , Animais , Apoptose , Autofagia , Linhagem Celular Tumoral , Proliferação de Células , Genes Supressores de Tumor/fisiologia , Humanos , Masculino , Camundongos , Mieloma Múltiplo/patologiaRESUMO
The clinical development of locally and advanced non-small cell lung cancer (NSCLC) suffers from a lack of biomarkers as a guide in the selection of optimal prognostic prediction. Circulating Tumour Cells (CTCs) are correlated to prognosis and show efficacy in cancer monitoring in patients. However, their enumeration alone might be inadequate; it might also be critical to understand the viability, the apoptotic state and the kinetics of these cells. Here, we report what we believe to be a new and selective approach to visually detect tumour specific CTCs. Firstly, using labelled human lung cancer cells, we detected a specific density interval in which NSCL-CTCs were concentrated. Secondly, to better characterize CTCs in respect to their heterogeneous composition and tumour reference, blood and tumour biopsy were performed on specimens taken from the same patient. The approach consisted in comparing phenotype profile of CTCs, and their progenitor Tumour Stem Cells, (TSCs). Moreover, NSCL-CTCs were cultivated in short-time human cultures to provide response to drug sensitivity. Our bimodal approach allowed to reveal two items. Firstly, that one part of a tumour, proximal to the bronchial structure, displays a predominance of CD133+. Secondly, specific NSCL-CTCs Epithelial Cell Adhesion Molecule (EpCAM)+CD29+ can be used as a negative prognostic factor as well the high expression of CTCs EpCAM+. These data were confirmed by drug-sensitivity tests, in vitro, and by the survival curves, in vivo.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Células Neoplásicas Circulantes , Idoso , Idoso de 80 Anos ou mais , Biópsia , Carcinoma Pulmonar de Células não Pequenas/terapia , Ciclo Celular , Humanos , Neoplasias Pulmonares/terapia , Linfócitos do Interstício Tumoral/patologia , Masculino , Pessoa de Meia-Idade , Medicina de PrecisãoRESUMO
Nesfatin-1 is an anorexic nucleobindin-2 (NUCB2)-derived hypothalamic peptide. It controls feeding behavior, water intake, and glucose homeostasis. If intracerebrally administered, it induces hypertension, thus suggesting a role in central cardiovascular control. However, it is not known whether it is able to directly control heart performance. We aimed to verify the hypothesis that, as in the case of other hypothalamic satiety peptides, Nesfatin-1 acts as a peripheral cardiac modulator. By western blotting and QT-PCR, we identified the presence of both Nesfatin-1 protein and NUCB2 mRNA in rat cardiac extracts. On isolated and Langendorff-perfused rat heart preparations, we found that exogenous Nesfatin-1 depresses contractility and relaxation without affecting coronary motility. These effects did not involve Nitric oxide, but recruited the particulate guanylate cyclase (pGC) known as natriuretic peptide receptor A (NPR-A), protein kinase G (PKG) and extracellular signal-regulated kinases1/2 (ERK1/2). Co-immunoprecipitation and bioinformatic analyses supported an interaction between Nesfatin-1 and NPR-A. Lastly, we preliminarily observed, through post-conditioning experiments, that Nesfatin-1 protects against ischemia/reperfusion (I/R) injury by reducing infarct size, lactate dehydrogenase release, and postischemic contracture. This protection involves multiple prosurvival kinases such as PKCε, ERK1/2, signal transducer and activator of transcription 3, and mitochondrial K(ATP) channels. It also ameliorates contractility recovery. Our data indicate that: (1) the heart expresses Nesfatin-1, (2) Nesfatin-1 directly affects myocardial performance, possibly involving pGC-linked NPR-A, the pGC/PKG pathway, and ERK1/2, (3) the peptide protects the heart against I/R injury. Results pave the way to include Nesfatin-1 in the neuroendocrine modulators of the cardiac function, also encouraging the clarification of its clinical potential in the presence of nutrition-dependent physio-pathologic cardiovascular diseases.
Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Proteínas de Ligação a DNA/metabolismo , Miocárdio/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Traumatismo por Reperfusão/metabolismo , Sequência de Aminoácidos , Animais , Proteínas de Ligação ao Cálcio/química , Proteínas de Ligação ao Cálcio/genética , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/genética , Canais KATP/metabolismo , L-Lactato Desidrogenase/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/genética , Óxido Nítrico/metabolismo , Nucleobindinas , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Receptores do Fator Natriurético Atrial/metabolismo , Traumatismo por Reperfusão/patologia , Transdução de SinaisRESUMO
MicroRNAs (miRNAs) with tumor-suppressor potential might have therapeutic applications in multiple myeloma (MM) through the modulation of still undiscovered molecular pathways. Here, we investigated the effects of enforced expression of miR-29b on the apoptotic occurrence in MM and highlighted its role in the context of a new transcriptional loop that is finely tuned by the proteasome inhibitor bortezomib. In details, in vitro growth inhibition and apoptosis of MM cells was induced by either transient expression of synthetic miR-29b or its stable lentivirus-enforced expression. We identified Sp1, a transcription factor endowed with oncogenic activity, as a negative regulator of miR-29b expression in MM cells. Since Sp1 expression and functions are regulated via the 26S proteasome, we investigated the effects of bortezomib on miR-29b-Sp1 loop, showing that miR-29b levels were indeed upregulated by the drug. At the same time, the bortezomib/miR-29b combination produced significant pro-apoptotic effects. We also demonstrated that the PI3K/AKT pathway plays a major role in the regulation of miR-29b-Sp1 loop and induction of apoptosis in MM cells. Finally, MM xenografts constitutively expressing miR-29b showed significant reduction of their tumorigenic potential. Our findings indicate that miR-29b is involved in a regulatory loop amenable of pharmacologic intervention and modulates the anti-MM activity of bortezomib in MM cells.
Assuntos
Apoptose/efeitos dos fármacos , Ácidos Borônicos/farmacologia , Retroalimentação Fisiológica , MicroRNAs/metabolismo , Mieloma Múltiplo/metabolismo , Pirazinas/farmacologia , Animais , Bortezomib , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos SCID , MicroRNAs/genética , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Mieloma Múltiplo/fisiopatologia , Fator de Transcrição Sp1/genética , Fator de Transcrição Sp1/metabolismo , Células Tumorais CultivadasRESUMO
MicroRNAs (miRNAs) recently emerged with a key role in multiple myeloma (MM) pathophysiology and are considered important regulators of MM cell growth and survival. Since miRNAs can act either as oncogenes or tumour suppressors, the potential of targeting the miRNA network arises as a novel therapeutic approach for human cancer. Potential strategies based on miRNA therapeutics basically rely on miRNA inhibition or miRNA replacement approaches and take benefit respectively from the use of antagomirs or synthetic miRNAs as well as from lipid-based nanoparticles which allow an efficient miRNA-delivery. The availability of experimental in vivo platforms which recapitulate the growth of MM cells within the specific human bone marrow microenvironment in immunocompromised mice (SCID-hu and SCID-synth-hu) provides powerful systems for development of miRNA-based therapeutics in MM. Preliminary findings on the anti-MM activity of synthetic miRNAs in such experimental models offer a proof-of-principle that miRNA therapeutics is a promising opportunity for this still incurable disease representing the rationale for a new venue of investigation in this specific field.
Assuntos
MicroRNAs/genética , MicroRNAs/uso terapêutico , Mieloma Múltiplo/genética , Mieloma Múltiplo/terapia , Animais , Medula Óssea/metabolismo , Medula Óssea/patologia , Humanos , Terapia de Alvo Molecular/métodos , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologiaRESUMO
Mouse models of multiple myeloma (MM) are basic tools for translational research and play a fundamental role in the development of new therapeutics against plasma cell malignancies. All available models, including transplantable murine tumors in syngenic mice, xenografts of established human cell lines in immunocompromised mice and transgenic models that mirror specific steps of MM pathogenesis, have demonstrated some weaknesses in predicting clinical results, particularly for new drugs targeting the human bone marrow microenvironment (huBMM). The recent interest to models recapitulating the in vivo growth of primary MM cells in a human (SCID-hu) or humanized (SCID-synth-hu) host recipient has provided powerful platforms for the investigation of new compounds targeting MM and/or its huBMM. Here, we review and discuss strengths and weaknesses of the key in vivo models that are currently utilized in the MM preclinical investigation.
Assuntos
Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Modelos Animais de Doenças , Mieloma Múltiplo/tratamento farmacológico , Animais , Avaliação Pré-Clínica de Medicamentos , Humanos , CamundongosRESUMO
BACKGROUND AND AIMS: The anorexigenic glucagon-like peptide (GLP)-2 is produced by intestinal L cells and released in response to food intake. It affects intestinal function involving G-protein-coupled receptors. To verify whether GLP-2 acts as a cardiac modulator in mammals, we analysed, in the rat heart, the expression of GLP-2 receptors and the myocardial and coronary responses to GLP-2. METHODS AND RESULTS: GLP-2 receptors were detected on ventricular extracts by quantitative real-time polymerase chain reaction (Q-RT-PCR) and Western blotting. Cardiac GLP-2 effects were analysed on Langendorff perfused hearts. Intracellular GLP-2 signalling was investigated on Langendorff perfused hearts and by Western blotting and enzyme-linked immunosorbent assay (ELISA) on ventricular extracts. By immunoblotting and Q-RT-PCR, we revealed the expression of ventricular GLP-2 receptors. Perfusion analyses showed that GLP-2 induces positive inotropism at low concentration (10-12 mol l(-1)), and negative inotropism and lusitropism from 10 to 10 mol l(-1). It dose-dependently constricts coronaries. The negative effects of GLP-2 were independent from GLP-1 receptors, being unaffected by exendin-3 (9-39) amide. GLP-2-dependent negative action involves Gi/o proteins, associates with a reduction of intracellular cyclic adenosine monophosphate (cAMP), an increase in extracellular signal regulated kinases 1 and 2 (ERK1/2) and a decrease in phospholamban phosphorylation, but is independent from endothelial nitric oxide synthase (eNOS) and protein kinase G (PKG). Finally, GLP-2 competitively antagonised ß-adrenergic stimulation. CONCLUSIONS: For the first time, to our knowledge, we found that: (1) the rat heart expresses functional GLP-2 receptors; (2) GLP-2 acts on both myocardium and coronaries, negatively modulating both basal and ß-adrenergic stimulated cardiac performance; and (3) GLP-2 effects are mediated by G-proteins and involve ERK1/2.
Assuntos
Peptídeo 2 Semelhante ao Glucagon/farmacologia , Receptores de Glucagon/genética , Receptores de Glucagon/metabolismo , Animais , Western Blotting , Cardiotônicos/farmacologia , AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de GMP Cíclico/genética , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Ensaio de Imunoadsorção Enzimática , Regulação da Expressão Gênica , Receptor do Peptídeo Semelhante ao Glucagon 1 , Receptor do Peptídeo Semelhante ao Glucagon 2 , Coração/efeitos dos fármacos , Técnicas In Vitro , Sistema de Sinalização das MAP Quinases , Masculino , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Fragmentos de Peptídeos/farmacologia , Fosforilação , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real , Transdução de SinaisRESUMO
The richly structured neuroendocrine control of the heart in health and disease requires, in addition to the autonomic nervous outflow, the essential contribute of various and often interacting humoral peptides (e.g. natriuretic peptides, Chromogranin-A-derived fragments, etc). In many cases, these molecules also influence the activity of other organ systems, including the gastrointestinal apparatus, in which they control mucosal function as well as motility and secretion. Interestingly, by acting centrally, some of these peptides also regulate satiety and appetite, thus forming an interesting link between cardiac and gastrointestinal function, and the feeding pattern. Prolonged inhibition and/or activation of these peptide pathways frequently results in severe and long-lasting dysfunctions, including cardiovascular diseases associated to alimentary disorders (e.g. obesity). Notably, their multifarious actions and mutual interactions make them excellent candidates for long-term resetting of both cardiac, gastrointestinal and nutrition homeostasis. Here we will provide only few examples taken from the quickly evolving scenario, with the purpose to provide indications concerning the complex circuits generated by multilevel signalling peptides, which contributes to orchestrate the association between cardiovascular, gastrointestinal and alimentary functions. This will highlight not only the complexity of the cardiovascular and GI regulatory networks, but also aspects of integration between feeding stimulating peptides and the other neuroendocrine systems affecting the heart and the GI tract.
Assuntos
Fenômenos Fisiológicos Cardiovasculares , Sistema Endócrino/fisiologia , Trato Gastrointestinal/fisiologia , Hipotálamo/fisiologia , Sistemas Neurossecretores/fisiologia , Animais , Sistema Cardiovascular/metabolismo , Sistema Endócrino/metabolismo , Trato Gastrointestinal/metabolismo , Grelina/metabolismo , Humanos , Hipotálamo/metabolismo , Peptídeos Natriuréticos , Neuropeptídeo Y/metabolismo , Sistemas Neurossecretores/metabolismoRESUMO
BACKGROUND AND AIMS: Moderate red wine consumption associates with lower incidence of cardiovascular diseases. Attention to the source of this cardioprotection was focused on flavonoids, the non-alcoholic component of the red wine, whose intake inversely correlates with adverse cardiovascular events. We analysed whether two red wine flavonoids, quercetin and myricetin, affect mammalian basal myocardial and coronary function. METHODS AND RESULTS: Quercetin and myricetin effects were evaluated on isolated and Langendorff perfused rat hearts under both basal conditions and α- and ß-adrenergic stimulation. The intracellular signalling involved in the effects of these flavonoids was analysed on perfused hearts and by western blotting on cardiac and HUVEC extracts. Quercetin induced biphasic inotropic and lusitropic effects, positive at lower concentrations and negative at higher concentrations. Contrarily, Myricetin elicits coronary dilation, without affecting contractility and relaxation. Simultaneous administration of the two flavonoids only induced vasodilation. Quercetin-elicited positive inotropism and lusitropism depend on ß1/ß2-adrenergic receptors and associate with increased intracellular cAMP, while the negative inotropism and lusitropism observed at higher concentrations were α-adrenergic-dependent. NOS inhibition abolished Myricetin-elicited vasodilation, also inducing Akt, ERK1/2 and eNOS phosphorylation in both ventricles and HUVEC. Myricetin-dependent vasodilation increases intracellular cGMP and is abolished by triton X-100. CONCLUSIONS: The cardiomodulation elicited on basal mechanical performance by quercetin and the selective vasodilation induced by myricetin point to these flavonoids as potent cardioactive principles, able to protect the heart in the presence of cardiovascular diseases.