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1.
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
3.
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
4.
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
5.
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
6.
J Nucl Cardiol ; 25(5): 1677-1687, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-28176257

RESUMEN

BACKGROUND: The prognostic impact and pathophysiology of global left ventricular mechanical dyssynchrony (LVMD), namely mechanical dyssynchrony of whole left ventricle, as assessed by phase analysis of electrocardiographically gated (ECG-gated) myocardial perfusion SPECT has not been clearly elucidated in patients with dilated cardiomyopathy (DCM) and narrow QRS complex (<120 ms). METHODS AND RESULTS: Forty-six patients with DCM underwent ECG-gated myocardial 99mTc-sestamibi perfusion SPECT and endomyocardial biopsy. LV phase entropy was automatically calculated using a phase analysis of ECG-gated myocardial perfusion SPECT. The patients were divided into two groups according to the median phase entropy value: low-phase entropy (<0.61) (N = 23: LE group) and high-phase entropy (≥0.61) (N = 23: HE group). In the Kaplan-Meier survival analysis, the event-free survival rate was significantly lower in the HE group (log-rank P = 0.015). Moreover, high-phase entropy was an independent predictor of adverse cardiac events (hazard ratio, 5.77%; 95% confidence interval, 1.02-108.32; P = 0.047). Interestingly, the mRNA expression levels of sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) in endomyocardial biopsy specimens were significantly lower in the HE group (P = 0.015). CONCLUSION: LV phase entropy, which may reflect impairment of Ca2+ handling caused by decreased SERCA2a mRNA levels, is a novel prognostic predictor in patients with DCM and narrow QRS complex.


Asunto(s)
Tomografía Computarizada por Emisión de Fotón Único Sincronizada Cardíaca/métodos , Cardiomiopatía Dilatada/diagnóstico por imagen , Electrocardiografía , Entropía , Ventrículos Cardíacos/fisiopatología , Imagen de Perfusión Miocárdica/métodos , Calcio/metabolismo , Cardiomiopatía Dilatada/fisiopatología , Humanos , Pronóstico , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/genética
7.
Cardiovasc Diabetol ; 16(1): 63, 2017 05 11.
Artículo en Inglés | MEDLINE | ID: mdl-28490337

RESUMEN

BACKGROUND: Diabetes is associated closely with an increased risk of cardiovascular events, including diastolic dysfunction and heart failure that leads to a shortening of life expectancy. It is therefore extremely valuable to evaluate the impact of antidiabetic agents on cardiac function. However, the influence of dipeptidyl peptidase 4 inhibitors on cardiac function is controversial and a major matter of clinical concern. We therefore evaluated the effect of sitagliptin on echocardiographic parameters of diastolic function in patients with type 2 diabetes as a sub-analysis of the PROLOGUE study. METHODS: Patients in the PROLOGUE study were assigned randomly to either add-on sitagliptin treatment or conventional antidiabetic treatment. Of the 463 patients in the overall study, 115 patients (55 in the sitagliptin group and 60 in the conventional group) who had complete echocardiographic data of the ratio of peak early diastolic transmitral flow velocity (E) to peak early diastolic mitral annular velocity (e') at baseline and after 12 and 24 months were included in this study. The primary endpoint of this post hoc sub-analysis was a comparison of the changes in the ratio of E to e' (E/e') between the two groups from baseline to 24 months. RESULTS: The baseline-adjusted change in E/e' during 24 months was significantly lower in the sitagliptin group than in the conventional group (-0.18 ± 0.55 vs. 1.91 ± 0.53, p = 0.008), irrespective of a higher E/e' value at baseline in the sitagliptin group. In analysis of covariance, sitagliptin treatment was significantly associated with change in E/e' over 24 months (ß = -9.959, p = 0.001), independent of other clinical variables at baseline such as blood pressure, HbA1c, and medications for diabetes. Changes in other clinical variables including blood pressure and glycemic parameters, and echocardiographic parameters, such as cardiac structure and systolic function, were comparable between the two groups. There was also no significant difference in the serum levels of N-terminal-pro brain natriuretic peptide and high-sensitive C-reactive protein between the two groups during the study period. CONCLUSIONS: Adding sitagliptin to conventional antidiabetic regimens in patients with T2DM for 24 months attenuated the annual exacerbation in the echocardiographic parameter of diastolic dysfunction (E/e') independent of other clinical variables such as blood pressure and glycemic control. Trial registration UMIN000004490 (University Hospital Medical Information Network Clinical Trials). https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000005356 ; registered November 1, 2010.


Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Cardiomiopatías Diabéticas/tratamiento farmacológico , Dipeptidil Peptidasa 4/metabolismo , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Ecocardiografía Doppler , Fosfato de Sitagliptina/uso terapéutico , Disfunción Ventricular Izquierda/tratamiento farmacológico , Función Ventricular Izquierda/efectos de los fármacos , Adulto , Anciano , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/enzimología , Cardiomiopatías Diabéticas/diagnóstico por imagen , Cardiomiopatías Diabéticas/enzimología , Cardiomiopatías Diabéticas/etiología , Diástole , Quimioterapia Combinada , Femenino , Humanos , Japón , Masculino , Persona de Mediana Edad , Válvula Mitral/diagnóstico por imagen , Válvula Mitral/efectos de los fármacos , Válvula Mitral/fisiopatología , Valor Predictivo de las Pruebas , Estudios Prospectivos , Recuperación de la Función , Volumen Sistólico/efectos de los fármacos , Factores de Tiempo , Resultado del Tratamiento , Disfunción Ventricular Izquierda/diagnóstico por imagen , Disfunción Ventricular Izquierda/enzimología , Disfunción Ventricular Izquierda/etiología
8.
Circ J ; 81(3): 368-375, 2017 Feb 24.
Artículo en Inglés | MEDLINE | ID: mdl-28025461

RESUMEN

BACKGROUND: The force-frequency relation (FFR) is a hemodynamic index of the chronotropic relationship between left ventricular (LV) systolic function (percent change in dP/dtmax) and elevation of heart rate. FFR is a marker of myocardial contractile reserve and follows an upward slope in healthy myocardium [monophasic FFR (MoF)], a pattern that becomes biphasic (BiF) under pathological conditions. However, it remains uncertain whether the FFR determines a patient's prognosis. We investigated the promising role of the FFR as a predictor of cardiac events in the setting of hypertrophic cardiomyopathy (HCM).Methods and Results:A total of 113 consecutive patients with HCM (New York Heart Association (NYHA) class I-II) were retrospectively evaluated; 27 (23.9%) had a BiF pattern and they experienced a higher incidence of cardiac events compared with those showing an MoF pattern (median follow-up, 4.7 years; P<0.001). Furthermore, Cox proportional hazard regression analysis revealed that the LV end-diastolic volume index (hazard ratio: 1.051, P=0.014) and BiF pattern (hazard ratio: 15.260, P=0.001) were independent predictors of primary cardiac events. Interestingly, abnormal reductions in myocardial regulatory molecules related to contractility (SERCA2α) were observed exclusively in the patients exhibiting a BiF pattern. CONCLUSIONS: The FFR reflects latent myocardial abnormalities and predicts cardiac events in the setting of HCM, even during the asymptomatic stages of the disease.


Asunto(s)
Cardiomiopatía Hipertrófica/fisiopatología , Frecuencia Cardíaca , Contracción Miocárdica , Función Ventricular Izquierda , Anciano , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Estudios Retrospectivos
9.
J Mol Cell Cardiol ; 98: 37-47, 2016 09.
Artículo en Inglés | MEDLINE | ID: mdl-27374118

RESUMEN

BACKGROUND: To address the impact of antidiabetic drugs on cardiovascular safety is a matter of clinical concern. Preclinical studies revealed that various protective effects of dipeptidyl peptidase-4 inhibitor (DPP4i) on cardiovascular disease; however, its impact of on hypertension remains controversial. METHODS AND RESULTS: Teneligliptin (TEN; 10mg/kg/day/p.o.) ameliorates hypertension and cardiac remodeling by normalizing a rise of angiotensin-II (AngII) that specifically observed in spontaneously hypertensive rats (SHR). TEN had no effects on vasculature and concentrations of the DPP4-related vasoactive peptides (bradykinin, neuropeptide Y, and atrial natriuretic peptide). The primary action of TEN on BP lowering was due to restoring the AngII-induced manifestation of congestive heart failure observed in SHR. Sodium-proton pump exchanger type 1 (NHE-1) is a regulator of intracellular acidity (pHi) and implicated pathophysiological role in cardiac remodeling occurred in diseased myocardium. Cardiac NHE-1 expression level was increased in SHR and this was restored in TEN-treated SHR. AngII directly augmented cardiac NHE-1 expression and its activity that contributed to hypertrophic response. TEN attenuated the AngII-induced cardiac hypertrophy with decline in pHi via suppression of NHE-1. Loss of NHE-1 activity by specific inhibitor or RNA silencing promoted intracellular acidification and consistently attenuated the AngII-mediated cardiac hypertrophy. CONCLUSION: The present study revealed the protective actions of TEN on hypertension and comorbid cardiac remodeling via AngII/NHE-1 axis and the novel pathophysiological roles of intracellular acidification via NHE-1 in cardiac hypertrophy.


Asunto(s)
Angiotensina II/metabolismo , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Hipertensión/metabolismo , Hipertensión/patología , Intercambiadores de Sodio-Hidrógeno/metabolismo , Remodelación Ventricular/efectos de los fármacos , Animales , Presión Sanguínea/efectos de los fármacos , Dipeptidil Peptidasa 4/metabolismo , Modelos Animales de Enfermedad , Ecocardiografía , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/patología , Insuficiencia Cardíaca/fisiopatología , Hipertensión/tratamiento farmacológico , Hipertensión/genética , Masculino , Miocitos Cardíacos/metabolismo , Pirazoles/farmacología , Ratas , Ratas Endogámicas SHR , Transducción de Señal/efectos de los fármacos , Tiazolidinas/farmacología , Vasodilatación/efectos de los fármacos
10.
PLoS Med ; 13(6): e1002051, 2016 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-27351380

RESUMEN

BACKGROUND: Experimental studies have suggested that dipeptidyl peptidase-4 (DPP-4) inhibitors provide cardiovascular protective effects. We performed a randomized study to evaluate the effects of sitagliptin added on to the conventional therapy compared with conventional therapy alone (diet, exercise, and/or drugs, except for incretin-related agents) on the intima-media thickness (IMT) of the carotid artery, a surrogate marker for the evaluation of atherosclerotic cardiovascular disease, in people with type 2 diabetes mellitus (T2DM). METHODS AND FINDINGS: We used a multicenter PROBE (prospective, randomized, open label, blinded endpoint) design. Individuals aged ≥30 y with T2DM (6.2% ≤ HbA1c < 9.4%) were randomly allocated to receive either sitagliptin (25 to 100 mg/d) or conventional therapy. Carotid ultrasound was performed at participating medical centers, and all parameters were measured in a core laboratory. Of the 463 enrolled participants with T2DM, 442 were included in the primary analysis (sitagliptin group, 222; conventional therapy group, 220). Estimated mean (± standard error) common carotid artery IMT at 24 mo of follow-up in the sitagliptin and conventional therapy groups was 0.827 ± 0.007 mm and 0.837 ± 0.007 mm, respectively, with a mean difference of -0.009 mm (97.2% CI -0.028 to 0.011, p = 0.309). HbA1c level at 24 mo was significantly lower with sitagliptin than with conventional therapy (6.56% ± 0.05% versus 6.72% ± 0.05%, p = 0.008; group mean difference -0.159, 95% CI -0.278 to -0.041). Episodes of serious hypoglycemia were recorded only in the conventional therapy group, and the rate of other adverse events was not different between the two groups. As it was not a placebo-controlled trial and carotid IMT was measured as a surrogate marker of atherosclerosis, there were some limitations of interpretation. CONCLUSIONS: In the PROLOGUE study, there was no evidence that treatment with sitagliptin had an additional effect on the progression of carotid IMT in participants with T2DM beyond that achieved with conventional treatment. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry UMIN000004490.


Asunto(s)
Aterosclerosis/tratamiento farmacológico , Arterias Carótidas/efectos de los fármacos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Fosfato de Sitagliptina/farmacología , Fosfato de Sitagliptina/uso terapéutico , Adulto , Anciano , Aterosclerosis/etiología , Grosor Intima-Media Carotídeo , Diabetes Mellitus Tipo 2/complicaciones , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos
11.
Am J Physiol Heart Circ Physiol ; 311(6): H1360-H1366, 2016 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-27694213

RESUMEN

Anesthesia can affect respiratory, circulatory, and endocrine systems but is necessary for certain experimental procedures such as echocardiography and blood sampling in small animals. We have now investigated the effects of four types of anesthesia [pentobarbital sodium (PENT), ketamine-xylazine (K/X), and low- or high-dose isoflurane (ISO)] on hemodynamics, cardiac function, and glucose and lipid metabolism in Sprague-Dawley rats. Aortic pressure, heart rate, and echocardiographic parameters were measured at various time points up to 45 min after the induction of anesthesia, and blood was then collected for measurement of parameters of glucose and lipid metabolism. Systolic aortic pressure remained constant in the PENT group, whereas it showed a biphasic pattern in the K/X group and a gradual decline in the ISO groups. Marked bradycardia was observed in the K/X group. The serum glucose concentration was increased and the plasma insulin level was reduced in the K/X and ISO groups compared with the PENT group. The concentrations of free fatty acids and norepinephrine in plasma were increased in the K/X group. Despite the metabolic effects of K/X and ISO, our results suggest that the marked bradycardic effect of K-X renders this combination appropriate for measurement of Doppler-derived indexes of left ventricular diastolic function, whereas the relative ease with which the depth of anesthesia can be controlled with ISO makes it suitable for manipulations or data collection over long time periods. On the other hand, PENT may be best suited for experiments that focus on measurement of cardiac function by M-mode echocardiography and metabolic parameters.


Asunto(s)
Anestésicos Disociativos/farmacología , Anestésicos por Inhalación/farmacología , Glucemia/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Hemodinámica/efectos de los fármacos , Hipnóticos y Sedantes/farmacología , Metabolismo de los Lípidos/efectos de los fármacos , Aldosterona/metabolismo , Angiotensina II/efectos de los fármacos , Angiotensina II/metabolismo , Animales , Aorta/efectos de los fármacos , Glucemia/metabolismo , Colesterol/metabolismo , HDL-Colesterol/efectos de los fármacos , HDL-Colesterol/metabolismo , LDL-Colesterol/efectos de los fármacos , LDL-Colesterol/metabolismo , Dopamina/metabolismo , Ecocardiografía , Epinefrina/metabolismo , Ácidos Grasos no Esterificados/metabolismo , Glucosa/metabolismo , Insulina/metabolismo , Resistencia a la Insulina , Isoflurano/farmacología , Ketamina/farmacología , Masculino , Norepinefrina/metabolismo , Pentobarbital/farmacología , Ratas , Ratas Sprague-Dawley , Renina/efectos de los fármacos , Renina/metabolismo , Sistema Renina-Angiotensina/efectos de los fármacos , Triglicéridos/metabolismo , Xilazina/farmacología
12.
Cardiovasc Diabetol ; 15: 87, 2016 Jun 18.
Artículo en Inglés | MEDLINE | ID: mdl-27317093

RESUMEN

BACKGROUND: Xanthine oxidase inhibitors are anti-hyperuricemic drugs that decrease serum uric acid levels by inhibiting its synthesis. Xanthine oxidase is also recognized as a pivotal enzyme in the production of oxidative stress. Excess oxidative stress induces endothelial dysfunction and inflammatory reactions in vascular systems, leading to atherosclerosis. Many experimental studies have suggested that xanthine oxidase inhibitors have anti-atherosclerotic effects by decreasing in vitro and in vivo oxidative stress. However, there is only limited evidence on the clinical implications of xanthine oxidase inhibitors on atherosclerotic cardiovascular disease in patients with hyperuricemia. We designed the PRIZE study to evaluate the effects of febuxostat on a surrogate marker of cardiovascular disease risk, ultrasonography-based intima-media thickness of the carotid artery in patients with hyperuricemia. METHODS: The study is a multicenter, prospective, randomized, open-label and blinded-endpoint evaluation (PROBE) design. A total of 500 patients with asymptomatic hyperuricemia (uric acid >7.0 mg/dL) and carotid intima-media thickness ≥1.1 mm will be randomized centrally to receive either febuxostat (10-60 mg/day) or non-pharmacological treatment. Randomization is carried out using the dynamic allocation method stratified according to age (<65, ≥65 year), gender, presence or absence of diabetes mellitus, serum uric acid (<8.0, ≥8.0 mg/dL), and carotid intima-media thickness (<1.3, ≥1.3 mm). In addition to administering the study drug, we will also direct lifestyle modification in all participants, including advice on control of body weight, sleep, exercise and healthy diet. Carotid intima-media thickness will be evaluated using ultrasonography performed by skilled technicians at a central laboratory. Follow-up will be continued for 24 months. The primary endpoint is percentage change in mean intima-media thickness of the common carotid artery 24 months after baseline, measured by carotid ultrasound imaging. CONCLUSIONS: PRIZE will be the first study to provide important data on the effects of febuxostat on atherosclerosis in patients with asymptomatic hyperuricemia. Trial Registration Unique trial Number, UMIN000012911 ( https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=R000015081&language=E ).


Asunto(s)
Aterosclerosis/tratamiento farmacológico , Inhibidores Enzimáticos/uso terapéutico , Febuxostat/uso terapéutico , Hiperuricemia/tratamiento farmacológico , Ácido Úrico/sangre , Xantina Oxidasa/antagonistas & inhibidores , Adulto , Anciano , Anciano de 80 o más Años , Arteria Carótida Común/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Hiperuricemia/sangre , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Factores de Riesgo , Adulto Joven
15.
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.
Circ J ; 78(3): 576-83, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24500073

RESUMEN

As the link between heart failure (HF) and diabetes mellitus (DM) becomes unignorable, so the need is further increasing for pathological comprehension: What is "diabetic cardiomyopathy (DMC)?" In response to current concern, the most updated guidelines stated by the ACCF/AHA and by the ESC/EASD take one step further, including the definition of DMC, although it is a matter yet to be completed. For more than 40 years, coronary artery disease and hypertension have been considered as the main causes of diabetes-related cardiac dysfunction. HF was originally considered as a result of reduced left ventricular ejection fraction (HF-REF); however, it has been recognized that HF symptoms are often observed in patients with preserved EF (HF-PEF). DMC includes HF with both reduced and preserved entities independent of coronary stenosis and hypertension. Cardiologists are thus facing a sort of chaos without clear guidelines for the "deadly intersection" of DM and HF. Today, the increasing interest and concern have caused DMC to be revisited and the first step in controlling the chaos around DMC is to organize and analyze all of the available evidence from preclinical and clinical studies. This review aims to illustrate the current concepts of DMC by shedding light on the new molecular mechanisms. (Circ J 2014; 78: 576-583).


Asunto(s)
Cardiomiopatías Diabéticas/metabolismo , Insuficiencia Cardíaca/metabolismo , Estenosis Coronaria/metabolismo , Estenosis Coronaria/patología , Estenosis Coronaria/fisiopatología , Estenosis Coronaria/terapia , Cardiomiopatías Diabéticas/patología , Cardiomiopatías Diabéticas/fisiopatología , Cardiomiopatías Diabéticas/terapia , Insuficiencia Cardíaca/patología , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/terapia , Humanos , Hipertensión/metabolismo , Hipertensión/patología , Hipertensión/fisiopatología , Hipertensión/terapia , Volumen Sistólico
18.
Circulation ; 126(15): 1838-51, 2012 Oct 09.
Artículo en Inglés | MEDLINE | ID: mdl-23035207

RESUMEN

BACKGROUND: The inhibition of dipeptidyl peptidase-4 (DPP4) protects the heart from acute myocardial ischemia. However, the role of DPP4 in chronic heart failure independent of coronary artery disease remains unclear. METHODS AND RESULTS: We first localized the membrane-bound form of DPP4 to the capillary endothelia of rat and human heart tissue. Diabetes mellitus promoted the activation of the membrane-bound form of DPP4, leading to reduced myocardial stromal cell-derived factor-1α concentrations and resultant angiogenic impairment in rats. The diabetic rats exhibited diastolic left ventricular dysfunction (DHF) with enhanced interstitial fibrosis caused partly by the increased ratio of matrix metalloproteinase-2 to tissue inhibitor of metalloproteinase-2 in a DPP4-dependent fashion. Both genetic and pharmacological DPP4 suppression reversed the stromal cell-derived factor-1α-dependent microvasculopathy and DHF associated with diabetes mellitus. Pressure overload induced DHF, which was reversed by DPP4 inhibition via a glucagon-like peptide-1/cAMP-dependent mechanism distinct from that for diabetic heart. In patients with DHF, the circulating DPP4 activity in peripheral veins was associated with that in coronary sinus and with E/e', an echocardiographic parameter representing DHF. Comorbid diabetes mellitus increased the circulating DPP4 activities in both peripheral veins and coronary sinus. CONCLUSIONS: DPP4 inhibition reverses DHF via membrane-bound DPP4/stromal cell-derived factor-1α-dependent local actions on angiogenesis and circulating DPP4/glucagon-like peptide-1-mediated inotropic actions. Myocardium-derived DPP4 activity in coronary sinus can be monitored by peripheral vein sampling, which partly correlates with DHF index; thus, circulating DPP4 may potentially serve as a biomarker for monitoring DHF.


Asunto(s)
Complicaciones de la Diabetes/metabolismo , Dipeptidil Peptidasa 4/metabolismo , Insuficiencia Cardíaca/metabolismo , Disfunción Ventricular Izquierda/metabolismo , Animales , Enfermedad Crónica , Complicaciones de la Diabetes/fisiopatología , Diástole , Dipeptidil Peptidasa 4/sangre , Modelos Animales de Enfermedad , Insuficiencia Cardíaca/fisiopatología , Humanos , Masculino , Neovascularización Patológica/fisiopatología , Ratas , Ratas Endogámicas , Disfunción Ventricular Izquierda/fisiopatología
19.
Am J Physiol Heart Circ Physiol ; 305(3): H295-304, 2013 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-23709595

RESUMEN

Glucagon-like peptide-1 receptor (GLP-1R) agonist exendin-4 (Ex-4) is a remedy for type 2 diabetes mellitus (T2DM). Ex-4 ameliorates cardiac dysfunction induced by myocardial infarction in preclinical and clinical settings. However, it remains unclear whether Ex-4 may modulate diabetic cardiomyopathy. We tested the impact of Ex-4 on two types of diabetic cardiomyopathy models, genetic (KK) and acquired T2DM induced by high-fat diet [diet-induced obesity (DIO)], to clarify whether Ex-4 may combat independently of etiology. Each type of mice was divided into Ex-4 (24 nmol·kg(-1)·day(-1) for 40 days; KK-ex4 and DIO-ex4) and vehicle (KK-v and DIO-v) groups. Ex-4 ameliorated systemic and cardiac insulin resistance and dyslipidemia in both T2DM models. T2DM mice exhibited systolic (DIO-v) and diastolic (DIO-v and KK-v) left ventricular dysfunctions, which were restored by Ex-4 with reduction in left ventricular hypertrophy. DIO-v and KK-v exhibited increased myocardial fibrosis and steatosis (lipid accumulation), in which were observed cardiac mitochondrial remodeling and enhanced mitochondrial oxidative damage. Ex-4 treatment reversed these cardiac remodeling and oxidative stress. Cytokine array revealed that Ex-4-sensitive inflammatory cytokines were ICAM-1 and macrophage colony-stimulating factor. Ex-4 ameliorated myocardial oxidative stress via suppression of NADPH oxidase 4 with concomitant elevation of antioxidants (SOD-1 and glutathione peroxidase). In conclusion, GLP-1R agonism reverses cardiac remodeling and dysfunction observed in T2DM via normalizing imbalance of lipid metabolism and related inflammation/oxidative stress.


Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Cardiomiopatías Diabéticas/tratamiento farmacológico , Hipoglucemiantes/farmacología , Metabolismo de los Lípidos/efectos de los fármacos , Miocardio/metabolismo , Estrés Oxidativo/efectos de los fármacos , Péptidos/farmacología , Receptores de Glucagón/agonistas , Ponzoñas/farmacología , Remodelación Ventricular/efectos de los fármacos , Animales , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/genética , Cardiomiopatías Diabéticas/sangre , Cardiomiopatías Diabéticas/diagnóstico por imagen , Cardiomiopatías Diabéticas/fisiopatología , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Dislipidemias/sangre , Dislipidemias/tratamiento farmacológico , Ecocardiografía Doppler , Exenatida , Fibrosis , Receptor del Péptido 1 Similar al Glucagón , Glutatión Peroxidasa/metabolismo , Hipertrofia Ventricular Izquierda/sangre , Hipertrofia Ventricular Izquierda/tratamiento farmacológico , Hipertrofia Ventricular Izquierda/fisiopatología , Hipoglucemiantes/administración & dosificación , Mediadores de Inflamación/metabolismo , Infusiones Subcutáneas , Resistencia a la Insulina , Molécula 1 de Adhesión Intercelular/metabolismo , Factor Estimulante de Colonias de Macrófagos/metabolismo , Masculino , Ratones , Mitocondrias Cardíacas/efectos de los fármacos , Mitocondrias Cardíacas/metabolismo , Mitocondrias Cardíacas/patología , Miocardio/patología , NADPH Oxidasa 4 , NADPH Oxidasas/metabolismo , Péptidos/administración & dosificación , Receptores de Glucagón/metabolismo , Superóxido Dismutasa/metabolismo , Superóxido Dismutasa-1 , Factores de Tiempo , Ponzoñas/administración & dosificación , Disfunción Ventricular Izquierda/sangre , Disfunción Ventricular Izquierda/tratamiento farmacológico , Disfunción Ventricular Izquierda/fisiopatología , Función Ventricular Izquierda/efectos de los fármacos
20.
iScience ; 26(5): 106591, 2023 May 19.
Artículo en Inglés | MEDLINE | ID: mdl-37250342

RESUMEN

Although chronic kidney disease (CKD) is a major health problem worldwide, its underlining mechanism is incompletely understood. We previously identified adipolin as an adipokine which provides benefits for cardiometabolic diseases. Here, we investigated the role of adipolin in the development of CKD. Adipolin-deficiency exacerbated urinary albumin excretion, tubulointerstitial fibrosis and oxidative stress of remnant kidneys in mice after subtotal nephrectomy through inflammasome activation. Adipolin positively regulated the production of ketone body, ß-hydroxybutyrate (BHB) and expression of a catalytic enzyme producing BHB, HMGCS2 in the remnant kidney. Treatment of proximal tubular cells with adipolin attenuated inflammasome activation through the PPARα/HMGCS2-dependent pathway. Furthermore, systemic administration of adipolin to wild-type mice with subtotal nephrectomy ameliorated renal injury, and these protective effects of adipolin were diminished in PPARα-deficient mice. Thus, adipolin protects against renal injury by reducing renal inflammasome activation through its ability to induce HMGCS2-dependent ketone body production via PPARα activation.

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