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1.
Cell Metab ; 36(1): 130-143.e5, 2024 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-38113888

RESUMO

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) exert anti-inflammatory effects relevant to the chronic complications of type 2 diabetes. Although GLP-1RAs attenuate T cell-mediated gut and systemic inflammation directly through the gut intraepithelial lymphocyte GLP-1R, how GLP-1RAs inhibit systemic inflammation in the absence of widespread immune expression of the GLP-1R remains uncertain. Here, we show that GLP-1R activation attenuates the induction of plasma tumor necrosis factor alpha (TNF-α) by multiple Toll-like receptor agonists. These actions are not mediated by hematopoietic or endothelial GLP-1Rs but require central neuronal GLP-1Rs. In a cecal slurry model of polymicrobial sepsis, GLP-1RAs similarly require neuronal GLP-1Rs to attenuate detrimental responses associated with sepsis, including sickness, hypothermia, systemic inflammation, and lung injury. Mechanistically, GLP-1R activation leads to reduced TNF-α via α1-adrenergic, δ-opioid, and κ-opioid receptor signaling. These data extend emerging concepts of brain-immune networks and posit a new gut-brain GLP-1R axis for suppression of peripheral inflammation.


Assuntos
Diabetes Mellitus Tipo 2 , Sepse , Humanos , Exenatida , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Peptídeos/farmacologia , Agonistas do Receptor Semelhante a Toll , Peçonhas/farmacologia , Fator de Necrose Tumoral alfa , Inflamação , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo
2.
J Am Heart Assoc ; 12(12): e022352, 2023 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-37318009

RESUMO

Background Identifying new therapeutic targets for preventing the myocardial ischemia-reperfusion injury would have profound implications in cardiovascular medicine. Myocardial ischemia-reperfusion injury remains a major clinical burden in patients with coronary artery disease. Methods and Results We studied several key mechanistic pathways known to mediate cardioprotection in myocardial ischemia-reperfusion in 2 independent genetic models with reduced cardiac phosphoinositide 3-kinase-α (PI3Kα) activity. P3Kα-deficient genetic models (PI3KαDN and PI3Kα-Mer-Cre-Mer) showed profound resistance to myocardial ischemia-reperfusion injury. In an ex vivo reperfusion protocol, PI3Kα-deficient hearts had an 80% recovery of function compared with ≈10% recovery in the wild-type. Using an in vivo reperfusion protocol, PI3Kα-deficient hearts showed a 40% reduction in infarct size compared with wild-type hearts. Lack of PI3Kα increased late Na+ current, generating an influx of Na+, facilitating the lowering of mitochondrial Ca2+, thereby maintaining mitochondrial membrane potential and oxidative phosphorylation. Consistent with these functional differences, mitochondrial structure in PI3Kα-deficient hearts was preserved following ischemia-reperfusion injury. Computer modeling predicted that PIP3, the product of PI3Kα action, can interact with the murine and human NaV1.5 channels binding to the hydrophobic pocket below the selectivity filter and occluding the channel. Conclusions Loss of PI3Kα protects from global ischemic-reperfusion injury linked to improved mitochondrial structure and function associated with increased late Na+ current. Our results strongly support enhancement of mitochondrial function as a therapeutic strategy to minimize ischemia-reperfusion injury.


Assuntos
Doença da Artéria Coronariana , Isquemia Miocárdica , Traumatismo por Reperfusão Miocárdica , Humanos , Camundongos , Animais , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Traumatismo por Reperfusão Miocárdica/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Isquemia Miocárdica/tratamento farmacológico , Mitocôndrias/metabolismo , Doença da Artéria Coronariana/metabolismo , Mitocôndrias Cardíacas/metabolismo
3.
Mol Metab ; 66: 101641, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36396031

RESUMO

OBJECTIVES: Glucagon-like peptide-1 receptor (GLP-1R) agonists reduce the rates of major cardiovascular events, including myocardial infarction in people with type 2 diabetes, and decrease infarct size while preserving ventricular function in preclinical studies. Nevertheless, the precise cellular sites of GLP-1R expression that mediate the cardioprotective actions of GLP-1 in the setting of ischemic cardiac injury are uncertain. METHODS: Publicly available single cell RNA sequencing (scRNA-seq) datasets on mouse and human heart cells were analyzed for Glp1r/GLP1R expression. Fluorescent activated cell sorting was used to localize Glp1r expression in cell populations from the mouse heart. The importance of endothelial and hematopoietic cells for the cardioprotective response to liraglutide in the setting of acute myocardial infarction (MI) was determined by inactivating the Glp1r in Tie2+ cell populations. Cardiac gene expression profiles regulated by liraglutide were examined using RNA-seq to interrogate mouse atria and both infarcted and non-infarcted ventricular tissue after acute coronary artery ligation. RESULTS: In mice, cardiac Glp1r mRNA transcripts were exclusively detected in endocardial cells by scRNA-seq. In contrast, analysis of human heart by scRNA-seq localized GLP1R mRNA transcripts to populations of atrial and ventricular cardiomyocytes. Moreover, very low levels of GIPR, GCGR and GLP2R mRNA transcripts were detected in the human heart. Cell sorting and RNA analyses detected cardiac Glp1r expression in endothelial cells (ECs) within the atria and ventricle in the ischemic and non-ischemic mouse heart. Transcriptional responses to liraglutide administration were not evident in wild type mouse ventricles following acute MI, however liraglutide differentially regulated genes important for inflammation, cardiac repair, cell proliferation, and angiogenesis in the left atrium, while reducing circulating levels of IL-6 and KC/GRO within hours of acute MI. Inactivation of the Glp1r within the Tie2+ cell expression domain encompassing ECs revealed normal cardiac structure and function, glucose homeostasis and body weight in Glp1rTie2-/- mice. Nevertheless, the cardioprotective actions of liraglutide to reduce infarct size, augment ejection fraction, and improve survival after experimental myocardial infarction (MI), were attenuated in Glp1rTie2-/- mice. CONCLUSIONS: These findings identify the importance of the murine Tie2+ endothelial cell GLP-1R as a target for the cardioprotective actions of GLP-1R agonists and support the importance of the atrial and ventricular endocardial GLP-1R as key sites of GLP-1 action in the ischemic mouse heart. Hitherto unexplored species-specific differences in cardiac GLP-1R expression challenge the exclusive use of mouse models for understanding the mechanisms of GLP-1 action in the normal and ischemic human heart.


Assuntos
Fibrilação Atrial , Receptor do Peptídeo Semelhante ao Glucagon 1 , Liraglutida , Infarto do Miocárdio , Animais , Humanos , Camundongos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Células Endoteliais/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/efeitos dos fármacos , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Liraglutida/farmacologia , Infarto do Miocárdio/tratamento farmacológico , RNA Mensageiro , Modelos Animais de Doenças , Receptor TIE-2/metabolismo
4.
Mol Metab ; 65: 101586, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36055579

RESUMO

OBJECTIVE: The gut hormone glucose-dependent insulinotropic polypeptide (GIP) stimulates beta cell function and improves glycemia through its incretin actions. GIP also regulates endothelial function and suppresses adipose tissue inflammation through control of macrophage activity. Activation of the GIP receptor (GIPR) attenuates experimental atherosclerosis and inflammation in mice, however whether loss of GIPR signaling impacts the development of atherosclerosis is uncertain. METHODS: Atherosclerosis and related metabolic phenotypes were studied in Apoe-/-:Gipr-/- mice and in Gipr+/+ and Gipr-/- mice treated with an adeno-associated virus expressing PCSK9 (AAV-PCSK9). Bone marrow transplantation (BMT) studies were carried out using donor marrow from Apoe-/-:Gipr-/-and Apoe-/-:Gipr+/+mice transplanted into Apoe-/-:Gipr-/- recipient mice. Experimental endpoints included the extent of aortic atherosclerosis and inflammation, body weight, glucose tolerance, and circulating lipid levels, the proportions and subsets of circulating leukocytes, and tissue gene expression profiles informing lipid and glucose metabolism, and inflammation. RESULTS: Body weight was lower, circulating myeloid cells were reduced, and glucose tolerance was not different, however, aortic atherosclerosis was increased in Apoe-/-:Gipr-/- mice and trended higher in Gipr-/- mice with atherosclerosis induced by AAV-PCSK9. Levels of mRNA transcripts for genes contributing to inflammation were increased in the aortae of Apoe-/-:Gipr-/- mice and expression of a subset of inflammation-related hepatic genes were increased in Gipr-/- mice treated with AAV-PCSK9. BMT experiments did not reveal marked atherosclerosis, failing to implicate bone marrow derived GIPR + cells in the control of atherosclerosis or aortic inflammation. CONCLUSIONS: Loss of the Gipr in mice results in increased aortic atherosclerosis and enhanced inflammation in aorta and liver, despite reduced weight gain and preserved glucose homeostasis. These findings extend concepts of GIPR in the suppression of inflammation-related pathophysiology beyond its classical incretin role in the control of metabolism.


Assuntos
Aterosclerose , Pró-Proteína Convertase 9 , Animais , Camundongos , Apolipoproteínas E/genética , Aterosclerose/genética , Glicemia , Peso Corporal , Polipeptídeo Inibidor Gástrico/metabolismo , Incretinas , Inflamação/metabolismo , Receptores Acoplados a Proteínas G , Receptores dos Hormônios Gastrointestinais , RNA Mensageiro
5.
Cell Metab ; 34(10): 1514-1531.e7, 2022 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-36027914

RESUMO

Gut intraepithelial lymphocytes (IELs) are thought to calibrate glucagon-like peptide 1 (GLP-1) bioavailability, thereby regulating systemic glucose and lipid metabolism. Here, we show that the gut IEL GLP-1 receptor (GLP-1R) is not required for enteroendocrine L cell GLP-1 secretion and glucose homeostasis nor for the metabolic benefits of GLP-1R agonists (GLP-1RAs). Instead, the gut IEL GLP-1R is essential for the full effects of GLP-1RAs on gut microbiota. Moreover, independent of glucose control or weight loss, the anti-inflammatory actions of GLP-1RAs require the gut IEL GLP-1R to selectively restrain local and systemic T cell-induced, but not lipopolysaccharide-induced, inflammation. Such effects are mediated by the suppression of gut IEL effector functions linked to the dampening of proximal T cell receptor signaling in a protein-kinase-A-dependent manner. These data reposition key roles of the L cell-gut IEL GLP-1R axis, revealing mechanisms linking GLP-1R activation in gut IELs to modulation of microbiota composition and control of intestinal and systemic inflammation.


Assuntos
Microbioma Gastrointestinal , Linfócitos Intraepiteliais , Glicemia , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1 , Glucose/metabolismo , Humanos , Inflamação , Intestinos , Linfócitos Intraepiteliais/metabolismo , Receptores de Antígenos de Linfócitos T
6.
JCI Insight ; 6(22)2021 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-34673572

RESUMO

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are used to treat diabetes and obesity and reduce rates of major cardiovascular events, such as stroke and myocardial infarction. Nevertheless, the identity of GLP-1R-expressing cell types mediating the cardiovascular benefits of GLP-1RA remains incompletely characterized. Herein, we investigated the importance of murine Glp1r expression within endothelial and hematopoietic cells. Mice with targeted inactivation of Glp1r in Tie2+ cells exhibited reduced levels of Glp1r mRNA transcripts in aorta, liver, spleen, blood, and gut. Glp1r expression in bone marrow cells was very low and not further reduced in Glp1rTie2-/- mice. The GLP-1RA semaglutide reduced the development of atherosclerosis induced by viral PCSK9 expression in both Glp1rTie2+/+ and Glp1rTie2-/- mice. Hepatic Glp1r mRNA transcripts were reduced in Glp1rTie2-/- mice, and liver Glp1r expression was localized to γδ T cells. Moreover, semaglutide reduced hepatic Tnf, Abcg1, Tgfb1, Cd3g, Ccl2, and Il2 expression; triglyceride content; and collagen accumulation in high-fat, high-cholesterol diet-fed Glp1rTie2+/+ mice but not Glp1rTie2-/- mice. Collectively, these findings demonstrate that Tie2+ endothelial or hematopoietic cell GLP-1Rs are dispensable for the antiatherogenic actions of GLP-1RA, whereas Tie2-targeted GLP-1R+ cells are required for a subset of the antiinflammatory actions of semaglutide in the liver.


Assuntos
Aterosclerose/tratamento farmacológico , Células Endoteliais/metabolismo , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Células-Tronco Hematopoéticas/metabolismo , Fígado/efeitos dos fármacos , Síndrome Metabólica/tratamento farmacológico , Animais , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Peptídeos Semelhantes ao Glucagon/farmacologia , Humanos , Masculino , Camundongos
7.
Endocr Rev ; 42(2): 101-132, 2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33320179

RESUMO

Glucagon-like peptide-1 (GLP-1) is produced in gut endocrine cells and in the brain, and acts through hormonal and neural pathways to regulate islet function, satiety, and gut motility, supporting development of GLP-1 receptor (GLP-1R) agonists for the treatment of diabetes and obesity. Classic notions of GLP-1 acting as a meal-stimulated hormone from the distal gut are challenged by data supporting production of GLP-1 in the endocrine pancreas, and by the importance of brain-derived GLP-1 in the control of neural activity. Moreover, attribution of direct vs indirect actions of GLP-1 is difficult, as many tissue and cellular targets of GLP-1 action do not exhibit robust or detectable GLP-1R expression. Furthermore, reliable detection of the GLP-1R is technically challenging, highly method dependent, and subject to misinterpretation. Here we revisit the actions of GLP-1, scrutinizing key concepts supporting gut vs extra-intestinal GLP-1 synthesis and secretion. We discuss new insights refining cellular localization of GLP-1R expression and integrate recent data to refine our understanding of how and where GLP-1 acts to control inflammation, cardiovascular function, islet hormone secretion, gastric emptying, appetite, and body weight. These findings update our knowledge of cell types and mechanisms linking endogenous vs pharmacological GLP-1 action to activation of the canonical GLP-1R, and the control of metabolic activity in multiple organs.


Assuntos
Peptídeo 1 Semelhante ao Glucagon , Receptor do Peptídeo Semelhante ao Glucagon 1 , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Humanos , Obesidade
8.
Can J Diabetes ; 44(1): 68-77, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31699625

RESUMO

People with type 2 diabetes are at heightened risk for developing cardiovascular (CV) events. CV disease is the leading cause of premature death among adults with type 2 diabetes. Unfortunately, historically, some antidiabetes agents were implicated in worsening CV function, despite improving glycemic and metabolic control. Accordingly, over a decade ago, health regulatory bodies modified approval requirements for novel antidiabetes pharmacotherapies, requiring prospective evaluation of CV safety through cardiovascular outcome trials (CVOTs). To meet regulatory requirements, CVOTs were primarily designed around establishing CV safety by demonstrating noninferiority to placebo in addition to standard of care, without significant differences in blood glucose. If appropriately designed and powered, however, these CVOTs could also determine superiority, and hence CV protection. Although many of these CVOTs were initiated several years ago, the recent reporting of the results for these CVOTs has been pivotal and practice-changing. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are one such class of antidiabetes therapies, wherein multiple GLP-1RA CVOTs, but interestingly, not all, have demonstrated CV benefits. In this review, we provide a comprehensive summary of all the reported CVOTs completed with GLP-1RAs to date. Although it remains unclear why some GLP-1RAs are associated with reducing CV events, whereas others have been consistent with CV safety alone, we highlight and provide an overview of some key differences between the various GLP-1RAs and their respective CVOTs and possible implications of study design differences. We also speculate on potential mechanisms of action for glucagon-like peptide-1 receptor signalling in the CV system.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Complicações do Diabetes/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Hipoglicemiantes/uso terapêutico , Adulto , Doenças Cardiovasculares/etiologia , Ensaios Clínicos como Assunto , Complicações do Diabetes/etiologia , Humanos , Prognóstico
9.
J Mol Cell Cardiol ; 132: 98-109, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31095940

RESUMO

BACKGROUND: Phosphoinositide 3-kinase α (PI3Kα) is a proto-oncogene with high activity in the heart. BYL719 (BYL) is a PI3Kα-selective small molecule inhibitor and a prospective drug for advanced solid tumors. We investigated whether acute pharmacological inhibition of PI3Kα has pro-arrhythmic effects. METHODS & RESULTS: In isolated wild-type (WT) cardiomyocytes, pharmacological inhibition of PI3Kα (BYL719) increased contractility by 28%, Ca2+ release by 20%, and prolonged action potential (AP) repolarization by 10-15%. These effects of BYL719 were abolished by inhibition of reverse-mode Na+/Ca2+ exchanger (NCX) (KB-R7943) or by inhibition of late Na+ current (INa-L) (ranolazine). BYL719 had no effect on PI3Kα-deficient cardiomyocytes, suggesting BYL719 effects were PI3Kα-dependent and mediated via NCX and INa-L. INa-L was suppressed by activation of PI3Kα, application of exogenous intracellular PIP3, or ranolazine. Investigation of AP and Ca2+ release in whole heart preparations using epicardial optical mapping showed that inhibition of PI3Kα similarly led to prolongation of AP and enhancement of Ca2+ release. In hearts of PI3Kα-deficient mice, ß-adrenergic stimulation in the presence of high Ca2+ concentrations and 12-Hz burst pacing led to delayed afterdepolarizations and ventricular fibrillation. In vivo, administration of BYL719 prolonged QT interval [QTcF (Fridericia) increased by 15%] in WT, but not in PI3Kα-deficient mice. CONCLUSIONS: Pharmacological inhibition of PI3Kα is arrhythmogenic due to activation of INa-L leading to increased sarcoplasmic reticulum Ca2+ load and prolonged QT interval. Therefore, monitoring of cardiac electrical activity in patients receiving PI3K inhibitors may provide further insights into the arrhythmogenic potential of PI3Ka inhibition.


Assuntos
Potenciais de Ação , Arritmias Cardíacas/etiologia , Cálcio/metabolismo , Miócitos Cardíacos/patologia , Fosfatidilinositol 3-Quinases/química , Sódio/metabolismo , Tiazóis/farmacologia , Animais , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Bloqueadores dos Canais de Sódio/farmacologia , Trocador de Sódio e Cálcio/metabolismo
10.
J Am Heart Assoc ; 8(9): e010961, 2019 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-31039672

RESUMO

Background Cancer therapies inhibiting PI 3Kα (phosphoinositide 3-kinase-α)-dependent growth factor signaling, including trastuzumab inhibition of HER 2 (Human Epidermal Growth Factor Receptor 2), can cause adverse effects on the heart. Direct inhibition of PI 3Kα is now in clinical trials, but the effects of PI 3Kα pathway inhibition on heart atrophy, remodeling, and function in the context of cancer therapy are not well understood. Method and Results Pharmacological PI 3Kα inhibition and heart-specific genetic deletion of p110α, the catalytic subunit of PI 3Kα, was characterized in conjunction with anthracycline (doxorubicin) treatment in female murine models. Biventricular changes in heart morphological characteristics and function were analyzed, with molecular characterization of signaling pathways. Both PI 3Kα inhibition and anthracycline therapy promoted heart atrophy and a combined effect of distinct right ventricular dilation, dysfunction, and cardiomyocyte remodeling in the absence of pulmonary arterial hypertension. Congruent findings of right ventricular dilation and dysfunction were seen with pharmacological and genetic suppression of PI 3Kα signaling when combined with doxorubicin treatment. Increased p38 mitogen-activated protein kinase activation was mechanistically linked to heart atrophy and correlated with right ventricular dysfunction in explanted failing human hearts. Conclusions PI 3Kα pathway inhibition promotes heart atrophy in mice. The right ventricle is specifically at risk for dilation and dysfunction in the setting of PI 3K inhibition in conjunction with chemotherapy. Inhibition of p38 mitogen-activated protein kinase is a proposed therapeutic target to minimize this mode of cardiotoxicity.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Coração/efeitos dos fármacos , Miocárdio/patologia , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Tiazóis/farmacologia , Disfunção Ventricular Direita/fisiopatologia , Remodelação Ventricular/efeitos dos fármacos , Animais , Atrofia , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Classe I de Fosfatidilinositol 3-Quinases/genética , Feminino , Coração/fisiopatologia , Camundongos , Disfunção Ventricular Direita/induzido quimicamente , Disfunção Ventricular Direita/patologia , Proteínas Quinases p38 Ativadas por Mitógeno/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
11.
Nat Commun ; 9(1): 5390, 2018 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-30568254

RESUMO

Biomechanical stress and cytoskeletal remodeling are key determinants of cellular homeostasis and tissue responses to mechanical stimuli and injury. Here we document the increased activity of gelsolin, an actin filament severing and capping protein, in failing human hearts. Deletion of gelsolin prevents biomechanical stress-induced adverse cytoskeletal remodeling and heart failure in mice. We show that phosphatidylinositol (3,4,5)-triphosphate (PIP3) lipid suppresses gelsolin actin-severing and capping activities. Accordingly, loss of PI3Kα, the key PIP3-producing enzyme in the heart, increases gelsolin-mediated actin-severing activities in the myocardium in vivo, resulting in dilated cardiomyopathy in response to pressure-overload. Mechanical stretching of adult PI3Kα-deficient cardiomyocytes disrupts the actin cytoskeleton, which is prevented by reconstituting cells with PIP3. The actin severing and capping activities of recombinant gelsolin are effectively suppressed by PIP3. Our data identify the role of gelsolin-driven cytoskeletal remodeling in heart failure in which PI3Kα/PIP3 act as negative regulators of gelsolin activity.


Assuntos
Citoesqueleto de Actina/metabolismo , Gelsolina/metabolismo , Insuficiência Cardíaca/etiologia , Mecanotransdução Celular , Miocárdio/metabolismo , Animais , Cães , Feminino , Gelsolina/genética , Humanos , Masculino , Camundongos Knockout , Pessoa de Meia-Idade , Modelos Cardiovasculares , Fosfatidilinositol 3-Quinases/metabolismo , Fosfatos de Fosfatidilinositol/metabolismo , Remodelação Ventricular
13.
Cell Metab ; 27(2): 450-460.e6, 2018 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-29275960

RESUMO

Incretin hormones exert pleiotropic metabolic actions beyond the pancreas. Although the heart expresses both incretin receptors, the cardiac biology of GIP receptor (GIPR) action remains incompletely understood. Here we show that GIPR agonism did not impair the response to cardiac ischemia. In contrast, genetic elimination of the Gipr reduced myocardial infarction (MI)-induced ventricular injury and enhanced survival associated with reduced hormone sensitive lipase (HSL) phosphorylation; it also increased myocardial triacylglycerol (TAG) stores. Conversely, direct GIPR agonism in the isolated heart reduced myocardial TAG stores and increased fatty acid oxidation. The cardioprotective phenotype in Gipr-/- mice was partially reversed by pharmacological activation or genetic overexpression of HSL. Selective Gipr inactivation in cardiomyocytes phenocopied Gipr-/- mice, resulting in improved survival and reduced adverse remodeling following experimental MI. Hence, the cardiomyocyte GIPR regulates fatty acid metabolism and the adaptive response to ischemic cardiac injury. These findings have translational relevance for developing GIPR-based therapeutics.


Assuntos
Infarto do Miocárdio/patologia , Receptores dos Hormônios Gastrointestinais/metabolismo , Adenilil Ciclases/metabolismo , Animais , Ativação Enzimática , Polipeptídeo Inibidor Gástrico/metabolismo , Células HEK293 , Insuficiência Cardíaca/patologia , Humanos , Sistema de Sinalização das MAP Quinases , Camundongos , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/fisiopatologia , Infarto do Miocárdio/prevenção & controle , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Fosforilação , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores dos Hormônios Gastrointestinais/deficiência , Receptores dos Hormônios Gastrointestinais/genética , Transdução de Sinais , Esterol Esterase/metabolismo , Triglicerídeos/metabolismo , Remodelação Ventricular
14.
Mol Metab ; 6(11): 1339-1349, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-29107282

RESUMO

OBJECTIVES: Glucagon-like peptide-1 (GLP-1) is secreted from enteroendocrine cells and exerts a broad number of metabolic actions through activation of a single GLP-1 receptor (GLP-1R). The cardiovascular actions of GLP-1 have garnered increasing attention as GLP-1R agonists are used to treat human subjects with diabetes and obesity that may be at increased risk for development of heart disease. Here we studied mechanisms linking GLP-1R activation to control of heart rate (HR) in mice. METHODS: The actions of GLP-1R agonists were examined on the control of HR in wild type mice (WT) and in mice with cardiomyocyte-selective disruption of the GLP-1R (Glp1rCM-/-). Complimentary studies examined the effects of GLP-1R agonists in mice co-administered propranolol or atropine. The direct effects of GLP-1R agonism on HR and ventricular developed pressure were examined in isolated perfused mouse hearts ex vivo, and atrial depolarization was quantified in mouse hearts following direct application of liraglutide to perfused atrial preparations ex vivo. RESULTS: Doses of liraglutide and lixisenatide that were equipotent for acute glucose control rapidly increased HR in WT and Glp1rCM-/- mice in vivo. The actions of liraglutide to increase HR were more sustained relative to lixisenatide, and diminished in Glp1rCM-/- mice. The acute chronotropic actions of GLP-1R agonists were attenuated by propranolol but not atropine. Neither native GLP-1 nor lixisenatide increased HR or developed pressure in perfused hearts ex vivo. Moreover, liraglutide had no direct effect on sinoatrial node firing rate in mouse atrial preparations ex vivo. Despite co-localization of HCN4 and GLP-1R in primate hearts, HCN4-directed Cre expression did not attenuate levels of Glp1r mRNA transcripts, but did reduce atrial Gcgr expression in the mouse heart. CONCLUSIONS: GLP-1R agonists increase HR through multiple mechanisms, including regulation of autonomic nervous system function, and activation of the atrial GLP-1R. Surprisingly, the isolated atrial GLP-1R does not transduce a direct chronotropic effect following exposure to GLP-1R agonists in the intact heart, or isolated atrium, ex vivo. Hence, cardiac GLP-1R circuits controlling HR require neural inputs and do not function in a heart-autonomous manner.


Assuntos
Receptor do Peptídeo Semelhante ao Glucagon 1/fisiologia , Frequência Cardíaca/fisiologia , Animais , Sistema Nervoso Autônomo/fisiologia , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Frequência Cardíaca/efeitos dos fármacos , Liraglutida/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Peptídeos/farmacologia
15.
Hypertension ; 68(2): 365-77, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27217402

RESUMO

Apelin peptides mediate beneficial effects on the cardiovascular system and are being targeted as potential new drugs. However, apelin peptides have extremely short biological half-lives, and improved understanding of apelin peptide metabolism may lead to the discovery of biologically stable analogues with therapeutic potential. We examined the ability of angiotensin-converting enzyme 2 (ACE2) to cleave and inactivate pyr-apelin 13 and apelin 17, the dominant apelin peptides. Computer-assisted modeling shows a conserved binding of pyr-apelin 13 and apelin 17 to the ACE2 catalytic site. In ACE2 knockout mice, hypotensive action of pyr-apelin 13 and apelin 17 was potentiated, with a corresponding greater elevation in plasma apelin levels. Similarly, pharmacological inhibition of ACE2 potentiated the vasodepressor action of apelin peptides. Biochemical analysis confirmed that recombinant human ACE2 can cleave pyr-apelin 13 and apelin 17 efficiently, and apelin peptides are degraded slower in ACE2-deficient plasma. The biological relevance of ACE2-mediated proteolytic processing of apelin peptides was further supported by the reduced potency of pyr-apelin 12 and apelin 16 on the activation of signaling pathways and nitric oxide production from endothelial cells. Importantly, although pyr-apelin 13 and apelin 17 rescued contractile function in a myocardial ischemia-reperfusion model, ACE2 cleavage products, pyr-apelin 12 and 16, were devoid of these cardioprotective effects. We designed and synthesized active apelin analogues that were resistant to ACE2-mediated degradation, thereby confirming that stable apelin analogues can be designed as potential drugs. We conclude that ACE2 represents a major negative regulator of apelin action in the vasculature and heart.


Assuntos
Adipocinas/metabolismo , Sistema Cardiovascular , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Traumatismo por Reperfusão Miocárdica , Peptidil Dipeptidase A/metabolismo , Vasoconstrição , Enzima de Conversão de Angiotensina 2 , Animais , Apelina , Cardiotônicos/metabolismo , Cardiotônicos/farmacologia , Sistema Cardiovascular/efeitos dos fármacos , Sistema Cardiovascular/metabolismo , Sistema Cardiovascular/fisiopatologia , Simulação por Computador , Descoberta de Drogas , Meia-Vida , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Camundongos , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Fatores de Proteção , Ligação Proteica/fisiologia , Vasoconstrição/efeitos dos fármacos , Vasoconstrição/fisiologia
17.
Diabetes ; 65(1): 85-95, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26224885

RESUMO

Obesity is increasing in prevalence and is strongly associated with metabolic and cardiovascular disorders. The renin-angiotensin system (RAS) has emerged as a key pathogenic mechanism for these disorders; angiotensin (Ang)-converting enzyme 2 (ACE2) negatively regulates RAS by metabolizing Ang II into Ang 1-7. We studied the role of ACE2 in obesity-mediated cardiac dysfunction. ACE2 null (ACE2KO) and wild-type (WT) mice were fed a high-fat diet (HFD) or a control diet and studied at 6 months of age. Loss of ACE2 resulted in decreased weight gain but increased glucose intolerance, epicardial adipose tissue (EAT) inflammation, and polarization of macrophages into a proinflammatory phenotype in response to HFD. Similarly, human EAT in patients with obesity and heart failure displayed a proinflammatory macrophage phenotype. Exacerbated EAT inflammation in ACE2KO-HFD mice was associated with decreased myocardial adiponectin, decreased phosphorylation of AMPK, increased cardiac steatosis and lipotoxicity, and myocardial insulin resistance, which worsened heart function. Ang 1-7 (24 µg/kg/h) administered to ACE2KO-HFD mice resulted in ameliorated EAT inflammation and reduced cardiac steatosis and lipotoxicity, resulting in normalization of heart failure. In conclusion, ACE2 plays a novel role in heart disease associated with obesity wherein ACE2 negatively regulates obesity-induced EAT inflammation and cardiac insulin resistance.


Assuntos
Tecido Adiposo/imunologia , Dieta Hiperlipídica , Insuficiência Cardíaca/genética , Macrófagos/imunologia , Miocárdio/metabolismo , Obesidade/genética , Peptidil Dipeptidase A/deficiência , Pericárdio/imunologia , Proteínas Quinases Ativadas por AMP/metabolismo , Adiponectina/metabolismo , Angiotensina I/farmacologia , Enzima de Conversão de Angiotensina 2 , Animais , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Western Blotting , Ensaio de Imunoadsorção Enzimática , Intolerância à Glucose/genética , Intolerância à Glucose/metabolismo , Coração/fisiopatologia , Insuficiência Cardíaca/imunologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Inflamação/genética , Inflamação/imunologia , Resistência à Insulina/genética , Camundongos , Camundongos Knockout , Obesidade/imunologia , Obesidade/fisiopatologia , Estresse Oxidativo , Fragmentos de Peptídeos/farmacologia , Peptidil Dipeptidase A/genética , Fosforilação , Reação em Cadeia da Polimerase em Tempo Real , Volume Sistólico , Fator de Necrose Tumoral alfa/imunologia , Vasodilatadores/farmacologia , Aumento de Peso/genética
18.
Sci Rep ; 5: 18132, 2015 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-26638758

RESUMO

Iron-overload cardiomyopathy is a prevalent cause of heart failure on a world-wide basis and is a major cause of mortality and morbidity in patients with secondary iron-overload and genetic hemochromatosis. We investigated the therapeutic effects of resveratrol in acquired and genetic models of iron-overload cardiomyopathy. Murine iron-overload models showed cardiac iron-overload, increased oxidative stress, altered Ca(2+) homeostasis and myocardial fibrosis resulting in heart disease. Iron-overload increased nuclear and acetylated levels of FOXO1 with corresponding inverse changes in SIRT1 levels in the heart corrected by resveratrol therapy. Resveratrol, reduced the pathological remodeling and improved cardiac function in murine models of acquired and genetic iron-overload at varying stages of iron-overload. Echocardiography and hemodynamic analysis revealed a complete normalization of iron-overload mediated diastolic and systolic dysfunction in response to resveratrol therapy. Myocardial SERCA2a levels were reduced in iron-overloaded hearts and resveratrol therapy restored SERCA2a levels and corrected altered Ca(2+) homeostasis. Iron-mediated pro-oxidant and pro-fibrotic effects in human and murine cardiomyocytes and cardiofibroblasts were suppressed by resveratrol which correlated with reduction in iron-induced myocardial oxidative stress and myocardial fibrosis. Resveratrol represents a clinically and economically feasible therapeutic intervention to reduce the global burden from iron-overload cardiomyopathy at early and chronic stages of iron-overload.


Assuntos
Cardiomiopatias/complicações , Cardiomiopatias/tratamento farmacológico , Sobrecarga de Ferro/complicações , Sobrecarga de Ferro/tratamento farmacológico , Modelos Genéticos , Estilbenos/uso terapêutico , Animais , Cardiomiopatias/fisiopatologia , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose , Proteína Forkhead Box O1 , Fatores de Transcrição Forkhead/metabolismo , Proteínas Ligadas por GPI , Terapia Genética , Proteína da Hemocromatose , Humanos , Sobrecarga de Ferro/fisiopatologia , Masculino , Proteínas de Membrana/deficiência , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miocárdio/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Oxidantes/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Resveratrol , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/metabolismo , Estilbenos/farmacologia
20.
Cardiovasc Res ; 105(3): 292-303, 2015 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-25618408

RESUMO

AIMS: Genetic mouse models have yielded conflicting conclusions about the role of PI3Kα in heart physiology: specifically, the question of whether PI3Kα has a direct role in regulating myocardial contractility. This has led to concerns that PI3K inhibitors currently in clinical trials for cancer may potentiate cardiotoxicity. Here we seek to clarify the role of PI3Kα in normal heart physiology and investigate changes in related signalling pathways. METHODS AND RESULTS: Targeted deletion of PI3Kα and PI3Kß in the heart with a tamoxifen-dependent Cre recombinase transgene caused transient heart dysfunction in all genotypes, but only PI3Kα deletion prevented functional recovery. Reduction in tamoxifen dosing allowed for maintained gene deletion without any cardiomyopathy, possibly through activation of survival signalling through the related ERK pathway. Similarly, mice with PI3Kα deletion induced by constitutively active Cre recombinase had normal heart function. Insulin-mediated activation of Akt, a marker of PI3Kα activity, was impaired with increased ERK1/2 activation in PI3Kα mutant hearts. Pharmacological inhibition of PI3Kα with BYL-719 also caused impaired insulin signalling in murine and human cardiomyocytes as well as in vivo in mice, with increased fasting blood glucose levels, but did not affect myocardial contractility as determined by echocardiography and invasive pressure-volume loop analysis. CONCLUSION: Our results show that PI3Kα does not directly regulate myocardial contractility, but is required for recovery from tamoxifen/Cre toxicity. The important role for PI3Kα in insulin signalling and recovery from tamoxifen/Cre toxicity justifies caution when using PI3Kα inhibitors in combination with other cardiovascular comorbidities and cardiotoxic compounds in cancer patients.


Assuntos
Cardiopatias/enzimologia , Insulina/metabolismo , Integrases/metabolismo , Contração Miocárdica , Miocárdio/enzimologia , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais , Tamoxifeno/farmacologia , Animais , Classe I de Fosfatidilinositol 3-Quinases , Modelos Animais de Doenças , Genótipo , Cardiopatias/genética , Cardiopatias/fisiopatologia , Integrases/genética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Contração Miocárdica/efeitos dos fármacos , Fenótipo , Fosfatidilinositol 3-Quinases/deficiência , Fosfatidilinositol 3-Quinases/genética , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo
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