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1.
Biochem Biophys Res Commun ; 593: 5-12, 2022 02 19.
Artículo en Inglés | MEDLINE | ID: mdl-35051783

RESUMEN

Skeletal muscle atrophy caused by various conditions including aging, nerve damage, and steroid administration, is a serious health problem worldwide. We recently reported that neuron-derived neurotrophic factor (NDNF) functions as a muscle-derived secreted factor, also known as myokine, which exerts protective actions on endothelial cell and cardiomyocyte function. Here, we investigated whether NDNF regulates skeletal muscle atrophy induced by steroid administration and sciatic denervation. NDNF-knockout (KO) mice and age-matched wild-type (WT) mice were subjected to continuous dexamethasone (DEX) treatment or sciatic denervation. NDNF-KO mice exhibited decreased gastrocnemius muscle weight and reduced cross sectional area of myocyte fiber after DEX treatment or sciatic denervation compared with WT mice. Administration of an adenoviral vector expressing NDNF (Ad-NDNF) or recombinant NDNF protein to gastrocnemius muscle of WT mice increased gastrocnemius muscle weight after DEX treatment. NDNF-KO mice showed increased expression of ubiquitin E3-ligases, including atrogin-1 and MuRF-1, in gastrocnemius muscle after DEX treatment, whereas Ad-NDNF reduced expression of atrogin-1 and MuRF-1 in gastrocnemius muscle of WT mice after DEX treatment. Pretreatment of cultured C2C12 myocytes with NDNF protein reversed reduced myotube diameter and increased expression of atrogin-1 and MuRF-1 after DEX stimulation. Treatment of C2C12 myocytes increased Akt phosphorylation. Pretreatment of C2C12 myotubes with the PI3-kinase/Akt inhibitor reversed NDNF-induced increase in myotube fiber diameter after DEX treatment. In conclusion, our findings indicated that NDNF prevents skeletal muscle atrophy in vivo and in vitro through reduction of ubiquitin E3-ligases expression, suggesting that NDNF could be a novel therapeutic target of muscle atrophy.


Asunto(s)
Dexametasona/toxicidad , Músculo Esquelético/efectos de los fármacos , Atrofia Muscular/prevención & control , Factores de Crecimiento Nervioso/farmacología , Neuronas/efectos de los fármacos , Sustancias Protectoras/metabolismo , Animales , Antiinflamatorios/toxicidad , Femenino , Regulación de la Expresión Génica , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Atrofia Muscular/inducido químicamente , Atrofia Muscular/metabolismo , Atrofia Muscular/patología , Neuronas/metabolismo , Neuronas/patología , Fosforilación
2.
FASEB J ; 35(12): e22048, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34807469

RESUMEN

In the heart, fatty acid is a major energy substrate to fuel contraction under aerobic conditions. Ischemia downregulates fatty acid metabolism to adapt to the limited oxygen supply, making glucose the preferred substrate. However, the mechanism underlying the myocardial metabolic shift during ischemia remains unknown. Here, we show that lipoprotein lipase (LPL) expression in cardiomyocytes, a principal enzyme that converts triglycerides to free fatty acids and glycerol, increases during myocardial infarction (MI). Cardiomyocyte-specific LPL deficiency enhanced cardiac dysfunction and apoptosis following MI. Deficiency of aquaporin 7 (AQP7), a glycerol channel in cardiomyocytes, increased the myocardial infarct size and apoptosis in response to ischemia. Ischemic conditions activated glycerol-3-phosphate dehydrogenase 2 (GPD2), which converts glycerol-3-phosphate into dihydroxyacetone phosphate to facilitate adenosine triphosphate (ATP) synthesis from glycerol. Conversely, GPD2 deficiency exacerbated cardiac dysfunction after acute MI. Moreover, cardiomyocyte-specific LPL deficiency suppressed the effectiveness of peroxisome proliferator-activated receptor alpha (PPARα) agonist treatment for MI-induced cardiac dysfunction. These results suggest that LPL/AQP7/GPD2-mediated glycerol metabolism plays an important role in preventing myocardial ischemia-related damage.


Asunto(s)
Acuaporinas/metabolismo , Cardiomiopatías/prevención & control , Glicerol/metabolismo , Glicerolfosfato Deshidrogenasa/metabolismo , Hipoxia/fisiopatología , Isquemia/prevención & control , Lipoproteína Lipasa/fisiología , Proteínas Mitocondriales/metabolismo , Animales , Acuaporinas/genética , Cardiomiopatías/etiología , Cardiomiopatías/metabolismo , Cardiomiopatías/patología , Glicerolfosfato Deshidrogenasa/genética , Isquemia/etiología , Isquemia/metabolismo , Isquemia/patología , Masculino , Ratones , Ratones Noqueados , Proteínas Mitocondriales/genética
4.
Circ Res ; 125(4): 414-430, 2019 08 02.
Artículo en Inglés | MEDLINE | ID: mdl-31221024

RESUMEN

RATIONALE: Myofibroblasts have roles in tissue repair following damage associated with ischemia, aging, and inflammation and also promote fibrosis and tissue stiffening, causing organ dysfunction. One source of myofibroblasts is mesenchymal stromal/stem cells that exist as resident fibroblasts in multiple tissues. We previously identified meflin (mesenchymal stromal cell- and fibroblast-expressing Linx paralogue), a glycosylphosphatidylinositol-anchored membrane protein, as a specific marker of mesenchymal stromal/stem cells and a regulator of their undifferentiated state. The roles of meflin in the development of heart disease, however, have not been investigated. OBJECTIVE: We examined the expression of meflin in the heart and its involvement in cardiac repair after ischemia, fibrosis, and the development of heart failure. METHODS AND RESULTS: We found that meflin has an inhibitory role in myofibroblast differentiation of cultured mesenchymal stromal/stem cells. Meflin expression was downregulated by stimulation with TGF (transforming growth factor)-ß, substrate stiffness, hypoxia, and aging. Histological analysis revealed that meflin-positive fibroblastic cells and their lineage cells proliferated in the hearts after acute myocardial infarction and pressure-overload heart failure mouse models. Analysis of meflin knockout mice revealed that meflin is essential for the increase in the number of cells that highly express type I collagen in the heart walls after myocardial infarction induction. When subjected to pressure overload by transverse aortic constriction, meflin knockout mice developed marked cardiac interstitial fibrosis with defective compensation mechanisms. Analysis with atomic force microscopy and hemodynamic catheterization revealed that meflin knockout mice developed stiff failing hearts with diastolic dysfunction. Mechanistically, we found that meflin interacts with bone morphogenetic protein 7, an antifibrotic cytokine that counteracts the action of TGF-ß and augments its intracellular signaling. CONCLUSIONS: These data suggested that meflin is involved in cardiac tissue repair after injury and has an inhibitory role in myofibroblast differentiation of cardiac fibroblastic cells and the development of cardiac fibrosis.


Asunto(s)
Diástole , Inmunoglobulinas/metabolismo , Células Madre Mesenquimatosas/metabolismo , Infarto del Miocardio/metabolismo , Miofibroblastos/metabolismo , Regeneración , Animales , Células CHO , Células Cultivadas , Colágeno/genética , Colágeno/metabolismo , Cricetinae , Cricetulus , Células HEK293 , Humanos , Inmunoglobulinas/genética , Metaloproteinasa 7 de la Matriz/metabolismo , Ratones , Ratones Endogámicos C57BL , Infarto del Miocardio/genética , Infarto del Miocardio/fisiopatología , Miofibroblastos/fisiología , Unión Proteica
5.
J Biol Chem ; 294(31): 11665-11674, 2019 08 02.
Artículo en Inglés | MEDLINE | ID: mdl-31217281

RESUMEN

Extracellular vesicles (EVs) have emerged as key mediators of intercellular communication that have the potential to improve cardiac function when used in cell-based therapy. However, the means by which cardiomyocytes respond to EVs remains unclear. Here, we sought to clarify the role of exosomes in improving cardiac function by investigating the effect of cardiomyocyte endocytosis of exosomes from mesenchymal stem cells on acute myocardial infarction (MI). Exposing cardiomyocytes to the culture supernatant of adipose-derived regenerative cells (ADRCs) prevented cardiomyocyte cell damage under hypoxia in vitro. In vivo, the injection of ADRCs into the heart simultaneous with coronary artery ligation decreased overall cardiac infarct area and prevented cardiac rupture after acute MI. Quantitative RT-PCR-based analysis of the expression of 35 known anti-apoptotic and secreted microRNAs (miRNAs) in ADRCs revealed that ADRCs express several of these miRNAs, among which miR-214 was the most abundant. Of note, miR-214 silencing in ADRCs significantly impaired the anti-apoptotic effects of the ADRC treatment on cardiomyocytes in vitro and in vivo To examine cardiomyocyte endocytosis of exosomes, we cultured the cardiomyocytes with ADRC-derived exosomes labeled with the fluorescent dye PKH67 and found that hypoxic culture conditions increased the levels of the labeled exosomes in cardiomyocytes. Chlorpromazine, an inhibitor of clathrin-mediated endocytosis, significantly suppressed the ADRC-induced decrease of hypoxia-damaged cardiomyocytes and also decreased hypoxia-induced cardiomyocyte capture of both labeled EVs and extracellular miR-214 secreted from ADRCs. Our results indicate that clathrin-mediated endocytosis in cardiomyocytes plays a critical role in their uptake of circulating, exosome-associated miRNAs that inhibit apoptosis.


Asunto(s)
Clatrina/metabolismo , Endocitosis , MicroARNs/metabolismo , Enfermedad Aguda , Animales , Antagomirs/metabolismo , Apoptosis/efectos de los fármacos , Hipoxia de la Célula , Células Cultivadas , Clorpromazina/farmacología , Medios de Cultivo Condicionados/farmacología , Endocitosis/efectos de los fármacos , Exosomas/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , MicroARNs/antagonistas & inhibidores , MicroARNs/genética , Infarto del Miocardio/patología , Infarto del Miocardio/veterinaria , Miocitos Cardíacos/citología , Miocitos Cardíacos/metabolismo , Células Madre/citología , Células Madre/metabolismo
6.
Circulation ; 140(21): 1737-1752, 2019 11 19.
Artículo en Inglés | MEDLINE | ID: mdl-31564129

RESUMEN

BACKGROUND: Heart failure is a complex syndrome that results from structural or functional impairment of ventricular filling or blood ejection. Protein phosphorylation is a major and essential intracellular mechanism that mediates various cellular processes in cardiomyocytes in response to extracellular and intracellular signals. The RHOA-associated protein kinase (ROCK/Rho-kinase), an effector regulated by the small GTPase RHOA, causes pathological phosphorylation of proteins, resulting in cardiovascular diseases. RHOA also activates protein kinase N (PKN); however, the role of PKN in cardiovascular diseases remains unclear. METHODS: To explore the role of PKNs in heart failure, we generated tamoxifen-inducible, cardiomyocyte-specific PKN1- and PKN2-knockout mice by intercrossing the αMHC-CreERT2 line with Pkn1flox/flox and Pkn2flox/flox mice and applied a mouse model of transverse aortic constriction- and angiotensin II-induced heart failure. To identify a novel substrate of PKNs, we incubated GST-tagged myocardin-related transcription factor A (MRTFA) with recombinant GST-PKN-catalytic domain or GST-ROCK-catalytic domain in the presence of radiolabeled ATP and detected radioactive GST-MRTFA as phosphorylated MRTFA. RESULTS: We demonstrated that RHOA activates 2 members of the PKN family of proteins, PKN1 and PKN2, in cardiomyocytes of mice with cardiac dysfunction. Cardiomyocyte-specific deletion of the genes encoding Pkn1 and Pkn2 (cmc-PKN1/2 DKO) did not affect basal heart function but protected mice from pressure overload- and angiotensin II-induced cardiac dysfunction. Furthermore, we identified MRTFA as a novel substrate of PKN1 and PKN2 and found that MRTFA phosphorylation by PKN was considerably more effective than that by ROCK in vitro. We confirmed that endogenous MRTFA phosphorylation in the heart was induced by pressure overload- and angiotensin II-induced cardiac dysfunction in wild-type mice, whereas cmc-PKN1/2 DKO mice suppressed transverse aortic constriction- and angiotensin II-induced phosphorylation of MRTFA. Although RHOA-mediated actin polymerization accelerated MRTFA-induced gene transcription, PKN1 and PKN2 inhibited the interaction of MRTFA with globular actin by phosphorylating MRTFA, causing increased serum response factor-mediated expression of cardiac hypertrophy- and fibrosis-associated genes. CONCLUSIONS: Our results indicate that PKN1 and PKN2 activation causes cardiac dysfunction and is involved in the transition to heart failure, thus providing unique targets for therapeutic intervention for heart failure.


Asunto(s)
Actinas/metabolismo , Insuficiencia Cardíaca/enzimología , Miocitos Cardíacos/enzimología , Proteína Quinasa C/metabolismo , Transactivadores/metabolismo , Animales , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/patología , Insuficiencia Cardíaca/fisiopatología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Miocitos Cardíacos/patología , Fosforilación , Unión Proteica , Proteína Quinasa C/deficiencia , Proteína Quinasa C/genética , Transducción de Señal , Quinasas Asociadas a rho/metabolismo , Proteína de Unión al GTP rhoA/metabolismo
7.
Circ Res ; 123(12): 1326-1338, 2018 12 07.
Artículo en Inglés | MEDLINE | ID: mdl-30566056

RESUMEN

RATIONALE: Physical exercise provides benefits for various organ systems, and some of systemic effects of exercise are mediated through modulation of muscle-derived secreted factors, also known as myokines. Myonectin/C1q (complement component 1q)/TNF (tumor necrosis factor)-related protein 15/erythroferrone is a myokine that is upregulated in skeletal muscle and blood by exercise. OBJECTIVE: We investigated the role of myonectin in myocardial ischemic injury. METHODS AND RESULTS: Ischemia-reperfusion in myonectin-knockout mice led to enhancement of myocardial infarct size, cardiac dysfunction, apoptosis, and proinflammatory gene expression compared with wild-type mice. Conversely, transgenic overexpression of myonectin in skeletal muscle reduced myocardial damage after ischemia-reperfusion. Treadmill exercise increased circulating myonectin levels in wild-type mice, and it reduced infarct size after ischemia-reperfusion in wild-type mice, but not in myonectin-knockout mice. Treatment of cultured cardiomyocytes with myonectin protein attenuated hypoxia/reoxygenation-induced apoptosis via S1P (sphingosine-1-phosphate)-dependent activation of cAMP/Akt cascades. Similarly, myonectin suppressed inflammatory response to lipopolysaccharide in cultured macrophages through the S1P/cAMP/Akt-dependent signaling pathway. Moreover, blockade of S1P-dependent pathway reversed myonectin-mediated reduction of myocardial infarct size in mice after ischemia-reperfusion. CONCLUSIONS: These data indicate that myonectin functions as an endurance exercise-induced myokine which ameliorates acute myocardial ischemic injury by suppressing apoptosis and inflammation in the heart, suggesting that myonectin mediates some of the beneficial actions of exercise on cardiovascular health.


Asunto(s)
Citocinas/metabolismo , Proteínas Musculares/metabolismo , Daño por Reperfusión Miocárdica/metabolismo , Condicionamiento Físico Animal/métodos , Animales , Apoptosis , Células Cultivadas , AMP Cíclico/metabolismo , Citocinas/genética , Citocinas/farmacología , Lisofosfolípidos/metabolismo , Ratones , Ratones Endogámicos C57BL , Proteínas Musculares/genética , Proteínas Musculares/farmacología , Músculo Esquelético/metabolismo , Daño por Reperfusión Miocárdica/prevención & control , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Células RAW 264.7 , Esfingosina/análogos & derivados , Esfingosina/metabolismo
8.
Circ Res ; 118(11): 1786-807, 2016 May 27.
Artículo en Inglés | MEDLINE | ID: mdl-27230642

RESUMEN

Obesity is causally linked with the development of cardiovascular disorders. Accumulating evidence indicates that cardiovascular disease is the collateral damage of obesity-driven adipose tissue dysfunction that promotes a chronic inflammatory state within the organism. Adipose tissues secrete bioactive substances, referred to as adipokines, which largely function as modulators of inflammation. The microenvironment of adipose tissue will affect the adipokine secretome, having actions on remote tissues. Obesity typically leads to the upregulation of proinflammatory adipokines and the downregulation of anti-inflammatory adipokines, thereby contributing to the pathogenesis of cardiovascular diseases. In this review, we focus on the microenvironment of adipose tissue and how it influences cardiovascular disorders, including atherosclerosis and ischemic heart diseases, through the systemic actions of adipokines.


Asunto(s)
Tejido Adiposo/metabolismo , Enfermedades Cardiovasculares/metabolismo , Microambiente Celular , Obesidad/metabolismo , Adipoquinas/metabolismo , Animales , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/patología , Humanos , Obesidad/complicaciones , Obesidad/patología
9.
J Biol Chem ; 291(6): 2566-75, 2016 Feb 05.
Artículo en Inglés | MEDLINE | ID: mdl-26631720

RESUMEN

Wnt signaling has diverse actions in cardiovascular development and disease processes. Secreted frizzled-related protein 5 (Sfrp5) has been shown to function as an extracellular inhibitor of non-canonical Wnt signaling that is expressed at relatively high levels in white adipose tissue. The aim of this study was to investigate the role of Sfrp5 in the heart under ischemic stress. Sfrp5 KO and WT mice were subjected to ischemia/reperfusion (I/R). Although Sfrp5-KO mice exhibited no detectable phenotype when compared with WT control at baseline, they displayed larger infarct sizes, enhanced cardiac myocyte apoptosis, and diminished cardiac function following I/R. The ischemic lesions of Sfrp5-KO mice had greater infiltration of Wnt5a-positive macrophages and greater inflammatory cytokine and chemokine gene expression when compared with WT mice. In bone marrow-derived macrophages, Wnt5a promoted JNK activation and increased inflammatory gene expression, whereas treatment with Sfrp5 blocked these effects. These results indicate that Sfrp5 functions to antagonize inflammatory responses after I/R in the heart, possibly through a mechanism involving non-canonical Wnt5a/JNK signaling.


Asunto(s)
Proteínas de la Membrana/metabolismo , Isquemia Miocárdica/metabolismo , Miocarditis/metabolismo , Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , Transducción de Señal , Animales , Inflamación/genética , Inflamación/metabolismo , Inflamación/patología , MAP Quinasa Quinasa 4/genética , MAP Quinasa Quinasa 4/metabolismo , Macrófagos/metabolismo , Macrófagos/patología , Proteínas de la Membrana/genética , Ratones , Ratones Noqueados , Isquemia Miocárdica/genética , Isquemia Miocárdica/patología , Miocarditis/genética , Miocarditis/patología , Miocardio/patología , Miocitos Cardíacos/patología , Proteínas Wnt/genética , Proteínas Wnt/metabolismo , Proteína Wnt-5a
10.
FASEB J ; 30(3): 1065-75, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26578687

RESUMEN

Obesity is associated with an increased risk of cardiovascular disease. C1q/TNF-related protein (CTRP)-1 is a poorly characterized adipokine that is up-regulated in association with ischemic heart disease. We investigated the role of CTRP1 in myocardial ischemia injury. CTRP1-knockout mice showed increased myocardial infarct size, cardiomyocyte apoptosis, and proinflammatory gene expression after I/R compared with wild-type (WT) mice. In contrast, systemic delivery of CTRP1 attenuated myocardial damage after I/R in WT mice. Treatment of cardiomyocytes with CTRP1 led to reduction of hypoxia-reoxygenation-induced apoptosis and lipopolysaccharide-stimulated expression of proinflammatory cytokines, which was reversed by inhibition of sphingosine-1-phosphate (S1P) signaling. Treatment of cardiomyocytes with CTRP1 also resulted in the increased production of cAMP, which was blocked by suppression of S1P signaling. The antiapoptotic and anti-inflammatory actions of CTRP1 were cancelled by inhibition of adenylyl cyclase or knockdown of adiponectin receptor 1. Furthermore, blockade of S1P signaling reversed CTRP1-mediated inhibition of myocardial infarct size, apoptosis, and inflammation after I/R in vivo. These data indicate that CTRP1 protects against myocardial ischemic injury by reducing apoptosis and inflammatory response through activation of the S1P/cAMP signaling pathways in cardiomyocytes, suggesting that CTRP1 plays a crucial role in the pathogenesis of ischemic heart disease.


Asunto(s)
Adipoquinas/metabolismo , Corazón/fisiopatología , Isquemia Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/metabolismo , Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , Sustancias Protectoras/metabolismo , Animales , Apoptosis/fisiología , AMP Cíclico/metabolismo , Citocinas/metabolismo , Modelos Animales de Enfermedad , Inflamación/metabolismo , Lisofosfolípidos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Infarto del Miocardio/metabolismo , Transducción de Señal/fisiología , Esfingosina/análogos & derivados , Esfingosina/metabolismo
11.
Circ J ; 81(7): 920-928, 2017 Jun 23.
Artículo en Inglés | MEDLINE | ID: mdl-28603178

RESUMEN

Cardiovascular disease (CVD) is the greatest cause of death, accounting for nearly one-third of all deaths worldwide. The increase in obesity rates over 3 decades is widespread and threatens the public health in both developed and developing countries. Obesity, the excessive accumulation of visceral fat, causes the clustering of metabolic disorders, such as type 2 diabetes, dyslipidemia, and hypertension, culminating in the development of CVD. Adipose tissue is not only an energy storage organ, but an active endocrine tissue producing various biologically active proteins known as adipokines. Since leptin, a central regulator of food intake and energy expenditure, was demonstrated to be an adipose-specific adipokine, attention has focused on the identification and characterization of unknown adipokines to clarify the mechanisms underlying obesity-related disorders. Numerous adipokines have been identified in the past 2 decades; most adipokines are upregulated in the obese state. Adipokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1ß, and resistin are pro-inflammatory, and exacerbate various metabolic and cardiovascular diseases. However, a small number of adipokines, including adiponectin, are decreased by obesity, and generally exhibit antiinflammatory properties and protective functions against obesity-related diseases. Collectively, an imbalance in the production of pro- and antiinflammatory adipokines in the obese condition results in multiple complications. In this review, we focus on the pathophysiologic roles of adipokines with cardiovascular protective properties.


Asunto(s)
Adipoquinas/metabolismo , Tejido Adiposo , Complicaciones de la Diabetes , Diabetes Mellitus Tipo 2 , Dislipidemias , Hipertensión , Tejido Adiposo/metabolismo , Tejido Adiposo/patología , Complicaciones de la Diabetes/metabolismo , Complicaciones de la Diabetes/patología , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Dislipidemias/complicaciones , Dislipidemias/metabolismo , Dislipidemias/patología , Humanos , Hipertensión/etiología , Hipertensión/metabolismo , Hipertensión/patología
12.
FASEB J ; 29(1): 141-51, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25300621

RESUMEN

Obesity is highly linked with the development of vascular diseases. Omentin is a circulating adipokine that is downregulated in patients with cardiovascular diseases. In this study, we investigated the role of omentin in regulation of vascular remodeling in response to injury. Wild-type (WT) mice were treated intravenously with adenoviral vectors encoding human omentin (Ad-OMT) or control ß-gal and subjected to arterial wire injury. Ad-OMT treatment reduced the neointimal thickening and the frequencies of bromodeoxyuridine-positive proliferating cells in injured arteries. Treatment of vascular smooth muscle cells (VSMCs) with human omentin protein at a physiologic concentration led to suppression of growth and ERK phosphorylation after stimulation with various growth factors. Omentin stimulated AMPK signaling in VSMCs, and blockade of AMPK reversed omentin-mediated inhibition of VSMC growth and ERK phosphorylation. Furthermore, fat-specific human omentin transgenic (OMT-TG) mice exhibited reduced neointimal thickening and vascular cell growth following vascular injury. AMPK activation was enhanced in injured arteries in OMT-TG mice, and administration of AMPK inhibitor reversed the reduction of neointimal hyperplasia in OMT-TG mice. These data indicate that omentin attenuates neointimal formation after arterial injury and suppresses VSMC growth through AMPK-dependent mechanisms. Thus, omentin can represent a novel target molecule for the prevention of vascular disorders.


Asunto(s)
Citocinas/fisiología , Arteria Femoral/lesiones , Lectinas/fisiología , Neointima/prevención & control , Proteínas Quinasas Activadas por AMP/antagonistas & inhibidores , Proteínas Quinasas Activadas por AMP/metabolismo , Tejido Adiposo/fisiología , Animales , Movimiento Celular , Proliferación Celular , Células Cultivadas , Citocinas/genética , Modelos Animales de Enfermedad , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Arteria Femoral/patología , Arteria Femoral/fisiopatología , Proteínas Ligadas a GPI/genética , Proteínas Ligadas a GPI/fisiología , Humanos , Lectinas/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Miocitos del Músculo Liso/patología , Miocitos del Músculo Liso/fisiología , Neointima/patología , Neointima/fisiopatología , Remodelación Vascular/fisiología
13.
Circ J ; 80(10): 2073-80, 2016 Sep 23.
Artículo en Inglés | MEDLINE | ID: mdl-27581346

RESUMEN

Obesity is a major risk factor for progression of cardiovascular disease. Adipose tissue is recognized as an endocrine organ producing various secretory molecules, also known as adipocytokines, and dysregulated production of adipocytokines participates in the pathogenesis of obesity complications, including metabolic dysfunction and cardiovascular disorders. Recent evidence indicates that skeletal muscle also functions as an endocrine organ capable of secreting a number of bioactive substances, also referred to as myokines. Several myokines are involved in metabolic and cardiovascular regulation. This review will discuss the clinical and experimental studies that have investigated the protective role of several adipocytokines and myokines in cardiovascular diseases. (Circ J 2016; 80: 2073-2080).


Asunto(s)
Adipoquinas/metabolismo , Enfermedades Cardiovasculares/metabolismo , Músculo Esquelético/metabolismo , Obesidad/metabolismo , Animales , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/prevención & control , Humanos , Obesidad/complicaciones
14.
J Am Soc Nephrol ; 26(3): 636-46, 2015 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-25071081

RESUMEN

Heart disease contributes to the progression of CKD. Heart tissue produces a number of secreted proteins, also known as cardiokines, which participate in intercellular and intertissue communication. We recently reported that follistatin-like 1 (Fstl1) functions as a cardiokine with cardioprotective properties. Here, we investigated the role of cardiac Fstl1 in renal injury after subtotal nephrectomy. Cardiac-specific Fstl1-deficient (cFstl1-KO) mice and wild-type mice were subjected to subtotal (5/6) nephrectomy. cFstl1-KO mice showed exacerbation of urinary albumin excretion, glomerular hypertrophy, and tubulointerstitial fibrosis after subtotal renal ablation compared with wild-type mice. cFstl1-KO mice also exhibited increased mRNA levels of proinflammatory cytokines, including TNF-α and IL-6, NADPH oxidase components, and fibrotic mediators, in the remnant kidney. Conversely, systemic administration of adenoviral vectors expressing Fstl1 (Ad-Fstl1) to wild-type mice with subtotal nephrectomy led to amelioration of albuminuria, glomerular hypertrophy, and tubulointerstitial fibrosis, accompanied by reduced expression of proinflammatory mediators, NADPH oxidase components, and fibrotic markers in the remnant kidney. In cultured human mesangial cells, treatment with recombinant FSTL1 attenuated TNF-α-stimulated expression of proinflammatory cytokines. Treatment of mesangial cells with FSTL1 augmented the phosphorylation of AMP-activated protein kinase (AMPK), and inhibition of AMPK activation abrogated the anti-inflammatory effects of FSTL1. These data suggest that Fstl1 functions in cardiorenal communication and that the lack of Fstl1 production by myocytes promotes glomerular and tubulointerstitial damage in the kidney.


Asunto(s)
Proteínas Relacionadas con la Folistatina/fisiología , Insuficiencia Renal Crónica/etiología , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Modelos Animales de Enfermedad , Células Mesangiales/fisiología , Ratones Noqueados , Miocitos Cardíacos/metabolismo , Nefrectomía , Factor de Necrosis Tumoral alfa
15.
J Mol Cell Cardiol ; 79: 195-202, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25479337

RESUMEN

Cardiac hypertrophy occurs in many obesity-related conditions. Omentin is an adipose-derived plasma protein that is downregulated under obese conditions. Here, we investigated whether omentin modulates cardiac hypertrophic responses in vivo and in vitro. Systemic administration of an adenoviral vector expressing human omentin (Ad-OMT) to wild-type (WT) mice led to the attenuation of cardiac hypertrophy, fibrosis and ERK phosphorylation induced by transverse aortic constriction (TAC) or angiotensin II infusion. In cultured cardiomyocytes, stimulation with phenylephrine (PE) led to an increase in myocyte size, which was prevented by pretreatment with human omentin protein. Pretreatment of cardiomyocytes with omentin protein also reduced ERK phosphorylation in response to PE stimulation. Ad-OMT enhanced phosphorylation of AMP-activated protein kinase (AMPK) in the heart of WT mice after TAC operation. Blockade of AMPK activation by transduction with dominant-negative mutant forms of AMPK reversed the inhibitory effect of omentin on myocyte hypertrophy and ERK phosphorylation following PE stimulation. Moreover, fat-specific transgenic mice expressing human omentin showed reduced cardiac hypertrophy and ERK phosphorylation following TAC surgery compared to littermate controls. These data suggest that omentin functions to attenuate the pathological process of myocardial hypertrophy via the activation of AMPK in the heart, suggesting that omentin may represent a target molecule for the treatment of cardiac hypertrophy.


Asunto(s)
Cardiomegalia/tratamiento farmacológico , Citocinas/uso terapéutico , Lectinas/uso terapéutico , Proteínas Quinasas Activadas por AMP/metabolismo , Adiposidad/efectos de los fármacos , Animales , Aorta/efectos de los fármacos , Aorta/metabolismo , Aorta/patología , Cardiomegalia/patología , Constricción Patológica , Citocinas/administración & dosificación , Citocinas/farmacología , Proteínas Ligadas a GPI/administración & dosificación , Proteínas Ligadas a GPI/farmacología , Proteínas Ligadas a GPI/uso terapéutico , Humanos , Lectinas/administración & dosificación , Lectinas/farmacología , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Fenilefrina/farmacología , Ratas , Transducción de Señal/efectos de los fármacos
16.
J Biol Chem ; 289(39): 27235-27245, 2014 Sep 26.
Artículo en Inglés | MEDLINE | ID: mdl-25100725

RESUMEN

Dipeptidyl peptidase-4 inhibitors are known to lower glucose levels and are also beneficial in the management of cardiovascular disease. Here, we investigated whether a dipeptidyl peptidase-4 inhibitor, vildagliptin, modulates endothelial cell network formation and revascularization processes in vitro and in vivo. Treatment with vildagliptin enhanced blood flow recovery and capillary density in the ischemic limbs of wild-type mice, with accompanying increases in phosphorylation of Akt and endothelial nitric-oxide synthase (eNOS). In contrast to wild-type mice, treatment with vildagliptin did not improve blood flow in ischemic muscles of eNOS-deficient mice. Treatment with vildagliptin increased the levels of glucagon-like peptide-1 (GLP-1) and adiponectin, which have protective effects on the vasculature. Both vildagliptin and GLP-1 increased the differentiation of cultured human umbilical vein endothelial cells (HUVECs) into vascular-like structures, although vildagliptin was less effective than GLP-1. GLP-1 and vildagliptin also stimulated the phosphorylation of Akt and eNOS in HUVECs. Pretreatment with a PI3 kinase or NOS inhibitor blocked the stimulatory effects of both vildagliptin and GLP-1 on HUVEC differentiation. Furthermore, treatment with vildagliptin only partially increased the limb flow of ischemic muscle in adiponectin-deficient mice in vivo. GLP-1, but not vildagliptin, significantly increased adiponectin expression in differentiated 3T3-L1 adipocytes in vitro. These data indicate that vildagliptin promotes endothelial cell function via eNOS signaling, an effect that may be mediated by both GLP-1-dependent and GLP-1-independent mechanisms. The beneficial activity of GLP-1 for revascularization may also be partially mediated by its ability to increase adiponectin production.


Asunto(s)
Adamantano/análogos & derivados , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Isquemia/metabolismo , Músculo Esquelético/metabolismo , Neovascularización Fisiológica , Óxido Nítrico Sintasa de Tipo III/metabolismo , Nitrilos/farmacología , Pirrolidinas/farmacología , Transducción de Señal , Células 3T3-L1 , Adamantano/farmacología , Adipocitos/metabolismo , Adiponectina/metabolismo , Animales , Diferenciación Celular , Péptido 1 Similar al Glucagón/metabolismo , Miembro Posterior/irrigación sanguínea , Miembro Posterior/metabolismo , Ratones , Ratones Noqueados , Músculo Esquelético/irrigación sanguínea , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Vildagliptina
17.
J Biol Chem ; 289(20): 14132-44, 2014 May 16.
Artículo en Inglés | MEDLINE | ID: mdl-24706764

RESUMEN

Strategies to stimulate revascularization are valuable for cardiovascular diseases. Here we identify neuron-derived neurotrophic factor (NDNF)/epidermacan as a secreted molecule that is up-regulated in endothelial cells in ischemic limbs of mice. NDNF was secreted from cultured human endothelial cells, and its secretion was stimulated by hypoxia. NDNF promoted endothelial cell network formation and survival in vitro through activation of Akt/endothelial NOS (eNOS) signaling involving integrin αvß3. Conversely, siRNA-mediated knockdown of NDNF in endothelial cells led to reduction of cellular responses and basal Akt signaling. Intramuscular overexpression of NDNF led to enhanced blood flow recovery and capillary density in ischemic limbs of mice, which was accompanied by enhanced phosphorylation of Akt and eNOS. The stimulatory actions of NDNF on perfusion recovery in ischemic muscles of mice were abolished by eNOS deficiency or NOS inhibition. Furthermore, siRNA-mediated reduction of NDNF in muscles of mice resulted in reduction of perfusion recovery and phosphorylation of Akt and eNOS in response to ischemia. Our data indicate that NDNF acts as an endogenous modulator that promotes endothelial cell function and ischemia-induced revascularization through eNOS-dependent mechanisms. Thus, NDNF can represent a therapeutic target for the manipulation of ischemic vascular disorders.


Asunto(s)
Células Endoteliales/citología , Neovascularización Fisiológica , Factores de Crecimiento Nervioso/metabolismo , Animales , Circulación Sanguínea , Vasos Sanguíneos/citología , Vasos Sanguíneos/patología , Vasos Sanguíneos/fisiología , Vasos Sanguíneos/fisiopatología , Células COS , Supervivencia Celular , Chlorocebus aethiops , Células Endoteliales/patología , Humanos , Isquemia/metabolismo , Isquemia/patología , Isquemia/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Factores de Crecimiento Nervioso/genética , Óxido Nítrico Sintasa de Tipo III/metabolismo , Fenotipo , Fosforilación , Proteínas Proto-Oncogénicas c-akt/metabolismo
18.
Biochem Biophys Res Commun ; 459(1): 124-30, 2015 Mar 27.
Artículo en Inglés | MEDLINE | ID: mdl-25712519

RESUMEN

Ischemic heart disease is one of the leading causes of death. Fibroblast growth factor 21 (FGF21) is a circulating factor with an anti-diabetic property. Skeletal muscle is an important source of FGF21 production. Here, we investigated whether skeletal muscle-derived FGF21 modulates cardiac remodeling in a murine model of myocardial infarction. Myocardial infarction was produced in C57BL/6J wild-type (WT) mice by the permanent ligation of the left anterior descending coronary artery (LAD). Adenoviral vectors expressing FGF21 (Ad-FGF21) or control ß-galactosidase were intramuscularly injected into mice at 3 days before permanent LAD ligation. Intramuscular injection of Ad-FGF21 increased plasma FGF21 levels in WT mice compared with control. Treatment of WT mice with Ad-FGF21 led to improvement of left ventricular systolic dysfunction and dilatation at 2 weeks after LAD ligation. Ad-FGF21 administration to WT mice also led to enhancement of capillary density in the infarct border zone, and reduction of myocyte apoptosis in the remote zone, which were accompanied by decreased expression of pro-inflammatory cytokines. Furthermore, treatment of WT mice with Ad-FGF21 increased plasma levels of adiponectin, which is a cardioprotective adipokine. The beneficial effects of Ad-FGF21 on cardiac dysfunction and inflammatory response after myocardial infarction were diminished in adiponectin-knockout mice. These data suggest that muscle-derived FGF21 ameliorates adverse cardiac remodeling after myocardial infarction, at least in part, through an adiponectin-dependent mechanism.


Asunto(s)
Factores de Crecimiento de Fibroblastos/administración & dosificación , Factores de Crecimiento de Fibroblastos/metabolismo , Infarto del Miocardio/fisiopatología , Infarto del Miocardio/terapia , Adiponectina/sangre , Adiponectina/genética , Animales , Apoptosis/genética , Capilares/fisiología , Vasos Coronarios/cirugía , Citocinas/metabolismo , Modelos Animales de Enfermedad , Factores de Crecimiento de Fibroblastos/sangre , Factores de Crecimiento de Fibroblastos/genética , Terapia Genética/métodos , Inyecciones Intramusculares , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Infarto del Miocardio/metabolismo , Miocitos Cardíacos/patología , Resultado del Tratamiento , Disfunción Ventricular Izquierda/genética , Disfunción Ventricular Izquierda/fisiopatología , beta-Galactosidasa/genética , beta-Galactosidasa/metabolismo
19.
J Vasc Surg ; 61(2): 489-96, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24993950

RESUMEN

OBJECTIVE: As first-line treatment for type 2 diabetes, metformin has gained a strong position. In addition, type 2 diabetics benefit from the fact that metformin is associated with a reduction in cardiovascular events. Nevertheless, there is a dearth of information concerning the functional role of metformin in regulating angiogenesis. Our present study explores whether metformin is involved in the modulation of the revascularization processes in vivo by employing a hindlimb mice model of ischemia-induced angiogenesis. METHODS: For comparative purposes, randomly selected wild-type (WT) mice or endothelial nitric oxide synthase (eNOS) deficient mice were assigned to one of two groups. One group was orally administered a daily dose of metformin through a gastric tube whereas the other group served as a control with no metformin administered. Both groups were subjected to unilateral hindlimb ischemia. Laser Doppler analysis coupled with capillary density staining with CD31was the method employed to determine revascularization. Adenosine monophosphate-activated protein kinase (AMPK) and eNOS phosphorylation levels were assessed using Western blot analysis. RESULTS: Subsequent to hindlimb ischemic surgery, in comparison to the nontreated mice, metformin-treated WT mice showed accelerated limb perfusion, which was substantiated by laser Doppler blood-flow measurements and the presence of increased capillary density in the ischemic adductor muscle. Treatment with metformin significantly enhanced the increase in AMPK and eNOS phosphorylation levels of muscle tissues in WT mice induced by ischemia. In eNOS- deficient knockout mice, there was a significant increase in ischemic tissue AMPK phosphorylation induced by metformin; however, blood flow recovery in ischemic limb after surgery was unaffected. CONCLUSIONS: Metformin promoted revascularization in the presence of tissue ischemia through an AMPK/eNOS-related mechanism. Our study indicates that, in addition to its glucose-lowering effect, metformin fosters improved revascularization, which is responsible for its positive effect on patients with critical limb ischemia.


Asunto(s)
Inductores de la Angiogénesis/farmacología , Isquemia/tratamiento farmacológico , Metformina/farmacología , Músculo Esquelético/irrigación sanguínea , Músculo Esquelético/efectos de los fármacos , Neovascularización Fisiológica/efectos de los fármacos , Óxido Nítrico Sintasa de Tipo III/metabolismo , Adenilato Quinasa/metabolismo , Animales , Velocidad del Flujo Sanguíneo , Capilares/efectos de los fármacos , Capilares/metabolismo , Capilares/fisiopatología , Modelos Animales de Enfermedad , Activación Enzimática , Miembro Posterior , Isquemia/enzimología , Isquemia/genética , Isquemia/fisiopatología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Músculo Esquelético/enzimología , Óxido Nítrico Sintasa de Tipo III/deficiencia , Óxido Nítrico Sintasa de Tipo III/genética , Fosforilación , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismo , Recuperación de la Función , Flujo Sanguíneo Regional , Transducción de Señal/efectos de los fármacos , Factores de Tiempo
20.
Liver Int ; 35(8): 2017-26, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25488180

RESUMEN

BACKGROUND & AIMS: Obesity-related adipocytokine dysregulation is known to accelerate liver fibrosis progression. Recently, a natural Wnt5a inhibitor, secreted frizzled-related protein 5 (Sfrp5), was identified as a novel adipocytokine that has reduced expression in obese adipose tissue in both rodents and human. In addition, hepatic gene expression of Wnt5a and its receptor frizzled 2 (Fz2) is elevated during fibrosis progression. Therefore, Sfrp5 could have biological significance in liver fibrosis. METHODS: We first investigated the effects of Sfrp5 on primary cultured mouse hepatic stellate cells (HSCs) in vitro. Next, to elucidate the roles of Sfrp5 in liver fibrosis, we investigated a carbon-tetrachloride (CCl4 )-induced liver fibrosis model using Sfrp5 knockout (KO) and wild type (WT) mice in vivo. Each mouse was injected intraperitoneally with CCl4 (0.5 ml/kg) or olive oil as a single dose (acute liver injury model), or twice a week for 6 weeks (liver fibrosis model). RESULTS: In in vitro studies, Wnt5a enhanced both proliferation and migration of HSCs, and these effects could be completely blocked by Sfrp5. Moreover, siRNA knockdown of Fz2 in HSCs could block the effects of Wnt5a on both HSC proliferation and migration. In in vivo studies, there were no differences in the CCl4 -induced liver injury between KO and WT mice. Hepatic Wnt5a gene expression and plasma Wnt5a levels significantly increased after a single CCl4 injection in both mice. Sfrp5 knockout significantly enhanced CCl4 -induced liver fibrosis. CONCLUSIONS: Our findings demonstrate that Sfrp5 may ameliorate mouse liver fibrosis through inhibition of Wnt5a/Fz2 signalling.


Asunto(s)
Movimiento Celular/fisiología , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Cirrosis Hepática/patología , Proteínas Wnt/metabolismo , Proteínas Adaptadoras Transductoras de Señales , Análisis de Varianza , Animales , Tetracloruro de Carbono/farmacología , Proliferación Celular/fisiología , Células Cultivadas , Modelos Animales de Enfermedad , Células Estrelladas Hepáticas/metabolismo , Humanos , Cirrosis Hepática/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Distribución Aleatoria , Sensibilidad y Especificidad , Transducción de Señal , Estadísticas no Paramétricas , Proteína Wnt-5a
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