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1.
J Am Heart Assoc ; 12(4): e028480, 2023 02 21.
Artículo en Inglés | MEDLINE | ID: mdl-36752224

RESUMEN

Background Recent studies have suggested that cardiac nitrosative stress mediated by pathological overproduction of nitric oxide (NO) via inducible NO synthase (iNOS) contributes to the pathogenesis of heart failure with preserved ejection fraction (HFpEF). Other studies have suggested that endothelial NO synthase (eNOS) dysfunction and attenuated NO bioavailability contribute to HFpEF morbidity and mortality. We sought to further investigate dysregulated NO signaling and to examine the effects of a NO-based dual therapy (sodium nitrite+hydralazine) following the onset of HFpEF using a "2-hit" murine model. Methods and Results Nine-week-old male C57BL/6 N mice (n=15 per group) were treated concurrently with high-fat diet and N(ω)-nitro-L-arginine methyl ester (L-NAME) (0.5 g/L per day) via drinking water for 10 weeks. At week 5, mice were randomized into either vehicle (normal saline) or combination treatment with sodium nitrite (75 mg/L in the drinking water) and hydralazine (2.0 mg/kg IP, BID). Cardiac structure and function were monitored with echocardiography and invasive hemodynamic measurements. Cardiac mitochondrial respiration, aortic vascular function, and exercise performance were also evaluated. Circulating and myocardial nitrite were measured to determine the bioavailability of NO. Circulating markers of oxidative or nitrosative stress as well as systemic inflammation were also determined. Severe HFpEF was evident by significantly elevated E/E', LVEDP, and Tau in mice treated with L-NAME and HFD, which was associated with impaired NO bioavailability, mitochondrial respiration, aortic vascular function, and exercise capacity. Treatment with sodium nitrite and hydralazine restored NO bioavailability, reduced oxidative and nitrosative stress, preserved endothelial function and mitochondrial respiration, limited the fibrotic response, and improved exercise capacity, ultimately attenuating the severity of "two-hit" HFpEF. Conclusions Our data demonstrate that nitrite, a well-established biomarker of NO bioavailability and a physiological source of NO, is significantly reduced in the heart and circulation in the "2-hit" mouse HFpEF model. Furthermore, sodium nitrite+hydralazine combined therapy significantly attenuated the severity of HFpEF in the "2-hit" cardiometabolic HFpEF. These data suggest that supplementing NO-based therapeutics with a potent antioxidant and vasodilator agent may result in synergistic benefits for the treatment of HFpEF.


Asunto(s)
Agua Potable , Insuficiencia Cardíaca , Ratones , Masculino , Animales , Insuficiencia Cardíaca/tratamiento farmacológico , Nitrito de Sodio , Volumen Sistólico/fisiología , NG-Nitroarginina Metil Éster , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Hidralazina/farmacología , Óxido Nítrico Sintasa
2.
Antioxidants (Basel) ; 10(3)2021 Mar 19.
Artículo en Inglés | MEDLINE | ID: mdl-33808673

RESUMEN

Hydrogen sulfide (H2S) is an endogenous, gaseous signaling molecule that plays a critical role in cardiac and vascular biology. H2S regulates vascular tone and oxidant defenses and exerts cytoprotective effects in the heart and circulation. Recent studies indicate that H2S modulates various components of metabolic syndrome, including obesity and glucose metabolism. This review will discuss studies exhibiting H2S -derived cardioprotective signaling in heart failure with reduced ejection fraction (HFrEF). We will also discuss the role of H2S in metabolic syndrome and heart failure with preserved ejection fraction (HFpEF).

3.
JACC Basic Transl Sci ; 6(2): 154-170, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33665515

RESUMEN

A lack of preclinical large animal models of heart failure with preserved ejection fraction (HFpEF) that recapitulate this comorbid-laden syndrome has led to the inability to tease out mechanistic insights and to test novel therapeutic strategies. This study developed a large animal model that integrated multiple comorbid determinants of HFpEF in a miniswine breed that exhibited sensitivity to obesity, metabolic syndrome, and vascular disease with overt clinical signs of heart failure. The combination of a Western diet and 11-deoxycorticosterone acetate salt-induced hypertension in the Göttingen miniswine led to the development of a novel large animal model of HFpEF that exhibited multiorgan involvement and a full spectrum of comorbidities associated with human HFpEF.

4.
J Am Heart Assoc ; 9(19): e017544, 2020 10 20.
Artículo en Inglés | MEDLINE | ID: mdl-32990120

RESUMEN

Background Hydrogen sulfide (H2S) is an important endogenous physiological signaling molecule and exerts protective properties in the cardiovascular system. Cystathionine γ-lyase (CSE), 1 of 3 H2S producing enzyme, is predominantly localized in the vascular endothelium. However, the regulation of CSE in vascular endothelium remains incompletely understood. Methods and Results We generated inducible endothelial cell-specific CSE overexpressed transgenic mice (EC-CSE Tg) and endothelial cell-specific CSE knockout mice (EC-CSE KO), and investigated vascular function in isolated thoracic aorta, treadmill exercise capacity, and myocardial injury following ischemia-reperfusion in these mice. Overexpression of CSE in endothelial cells resulted in increased circulating and myocardial H2S and NO, augmented endothelial-dependent vasorelaxation response in thoracic aorta, improved exercise capacity, and reduced myocardial-reperfusion injury. In contrast, genetic deletion of CSE in endothelial cells led to decreased circulating H2S and cardiac NO production, impaired endothelial dependent vasorelaxation response and reduced exercise capacity. However, myocardial-reperfusion injury was not affected by genetic deletion of endothelial cell CSE. Conclusions CSE-derived H2S production in endothelial cells is critical in maintaining endothelial function, exercise capacity, and protecting against myocardial ischemia/reperfusion injury. Our data suggest that the endothelial NO synthase-NO pathway is likely involved in the beneficial effects of overexpression of CSE in the endothelium.


Asunto(s)
Cistationina gamma-Liasa/metabolismo , Células Endoteliales/metabolismo , Tolerancia al Ejercicio/fisiología , Sulfuro de Hidrógeno/metabolismo , Daño por Reperfusión Miocárdica/metabolismo , Óxido Nítrico/metabolismo , Animales , Aorta Torácica/metabolismo , Aorta Torácica/fisiopatología , Ratones , Ratones Transgénicos , Miocardio/metabolismo , Miocardio/patología , Óxido Nítrico Sintasa/metabolismo , Transducción de Señal
5.
J Am Heart Assoc ; 9(10): e016223, 2020 05 18.
Artículo en Inglés | MEDLINE | ID: mdl-32390485

RESUMEN

Background Patients at increased risk for coronary artery disease and adverse prognosis during heart failure exhibit increased levels of circulating trimethylamine N-oxide (TMAO), a metabolite formed in the metabolism of dietary phosphatidylcholine. We investigated the efficacy of dietary withdrawal of TMAO as well as use of a gut microbe-targeted inhibitor of TMAO production, on cardiac function and structure during heart failure. Methods and Results Male C57BLK/6J mice were fed either control diet, a diet containing TMAO (0.12% wt/wt), a diet containing choline (1% wt/wt), or a diet containing choline (1% wt/wt) plus a microbial choline trimethylamine lyase inhibitor, iodomethylcholine (0.06% wt/wt), starting 3 weeks before transverse aortic constriction. At 6 weeks after transverse aortic constriction, a subset of animals in the TMAO group were switched to a control diet for the remainder of the study. Left ventricular structure and function were monitored at 3-week intervals. Withdrawal of TMAO from the diet attenuated adverse ventricular remodeling and improved cardiac function compared with the TMAO group. Similarly, inhibiting gut microbial conversion of choline to TMAO with a choline trimethylamine lyase inhibitor, iodomethylcholine, improved remodeling and cardiac function compared with the choline-fed group. Conclusions These experimental findings are clinically relevant, and they demonstrate that TMAO levels are modifiable following long-term exposure periods with either dietary withdrawal of TMAO or gut microbial blockade of TMAO generation. Furthermore, these therapeutic strategies to reduce circulating TMAO levels mitigate the negative effects of dietary choline and TMAO in heart failure.


Asunto(s)
Bacterias/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Microbioma Gastrointestinal/efectos de los fármacos , Insuficiencia Cardíaca/tratamiento farmacológico , Intestinos/microbiología , Metilaminas/metabolismo , Función Ventricular Izquierda/efectos de los fármacos , Remodelación Ventricular/efectos de los fármacos , Animales , Bacterias/enzimología , Proteínas Bacterianas/antagonistas & inhibidores , Proteínas Bacterianas/metabolismo , Colina/metabolismo , Modelos Animales de Enfermedad , Regulación hacia Abajo , Fibrosis , Insuficiencia Cardíaca/microbiología , Insuficiencia Cardíaca/patología , Insuficiencia Cardíaca/fisiopatología , Liasas/antagonistas & inhibidores , Liasas/metabolismo , Masculino , Ratones Endogámicos C57BL , Miocardio/patología
6.
J Vasc Surg ; 69(6): 1924-1935, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30777693

RESUMEN

OBJECTIVE: Previous studies have shown that hydrogen sulfide (H2S) exerts potent proangiogenic properties under in vitro conditions and in rodent models. We sought to determine whether a novel H2S prodrug promotes peripheral revascularization in a swine model of acute limb ischemia (ALI). METHODS: ALI was induced in 17 female miniswine via intravascular occlusion of the external iliac. At day 7 after ALI induction, miniswine (n = 17) were randomized to received placebo or the H2S prodrug, SG-1002 (800 mg per os twice a day), for 35 days. At day 35 SG-1002 increased circulating levels of H2S (5.0 ± 1.2 µmol/L vs 1.8 ± 0.50 µmol/L; P < .05), sulfane sulfur (10.6 ± 2.3 µmol/L vs 2.6 ± 0.8 µmol/L; P < .05), and nitrite (0.5 ± 0.05 µmol/L vs 0.3 ± 0.03 µmol/L; P < .005) compared with placebo. SG-1002 therapy increased angiographic scoring in ischemic limb vessel number (27.6 ± 1.6 vs 22.2 ± 1.8; P < .05) compared with placebo. Treatment with SG-1002 preserved existing capillaries in ischemic limbs (128.3 ± 18.7 capillaries/mm2 vs 79.0 ± 9.8 capillaries/mm2; P < .05) compared with placebo. Interestingly, treatment with SG-1002 also improved coronary vasorelaxation responses to bradykinin and substance P in miniswine with ALI. CONCLUSIONS: Our results suggest that daily administration of the H2S prodrug, SG-1002, leads to an increase in circulating H2S and nitric oxide signaling and preserves vessel number and density in ischemic limbs. Furthermore, SG-1002 therapy improved endothelial-dependent coronary artery vasorelaxation in the setting of ALI. Our data demonstrate that SG-1002 preserves the vascular architecture in ischemic limbs and exerts vascular protective effects in the coronary vasculature in a model of peripheral vascular disease.


Asunto(s)
Inductores de la Angiogénesis/farmacología , Extremidades/irrigación sanguínea , Sulfuro de Hidrógeno/farmacología , Isquemia/tratamiento farmacológico , Neovascularización Fisiológica/efectos de los fármacos , Enfermedad Arterial Periférica/tratamiento farmacológico , Profármacos/farmacología , Enfermedad Aguda , Inductores de la Angiogénesis/sangre , Inductores de la Angiogénesis/farmacocinética , Animales , Vasos Coronarios/efectos de los fármacos , Vasos Coronarios/fisiopatología , Modelos Animales de Enfermedad , Femenino , Sulfuro de Hidrógeno/sangre , Sulfuro de Hidrógeno/farmacocinética , Isquemia/sangre , Isquemia/fisiopatología , Óxido Nítrico/sangre , Nitritos/sangre , Estrés Oxidativo/efectos de los fármacos , Enfermedad Arterial Periférica/sangre , Enfermedad Arterial Periférica/fisiopatología , Profármacos/farmacocinética , Flujo Sanguíneo Regional , Transducción de Señal , Porcinos , Porcinos Enanos , Vasodilatación/efectos de los fármacos
7.
Basic Res Cardiol ; 114(2): 9, 2019 01 17.
Artículo en Inglés | MEDLINE | ID: mdl-30656501

RESUMEN

Enthusiasm for cell therapy for myocardial injury has waned due to equivocal benefits in clinical trials. In an attempt to improve efficacy, we investigated repeated cell therapy and adjunct renal denervation (RDN) as strategies for augmenting cardioprotection with cardiosphere-derived cells (CDCs). We hypothesized that combining CDC post-conditioning with repeated CDC doses or delayed RDN therapy would result in superior function and remodeling. Wistar-Kyoto (WKY) rats or spontaneously hypertensive rats (SHR) were subjected to 45 min of coronary artery ligation followed by reperfusion for 12-14 weeks. In the first study arm, SHR were treated with CDCs (0.5 × 106 i.c.) or PBS 20 min following reperfusion, or additionally treated with CDCs (1.0 × 106 i.v.) at 2, 4, and 8 weeks. In the second arm, at 4 weeks following myocardial infarction (MI), SHR received CDCs (0.5 × 106 i.c.) or CDCs + RDN. In the third arm, WKY rats were treated with i.c. CDCs administered 20 min following reperfusion and RDN or a sham at 4 weeks. Early i.c. + multiple i.v. dosing, but not single i.c. dosing, of CDCs improved long-term left ventricular (LV) function, but not remodeling. Delayed CDC + RDN therapy was not superior to single-dose delayed CDC therapy. Early CDC + delayed RDN therapy improved LV ejection fraction and remodeling compared to both CDCs alone and RDN alone. Given that both RDN and CDCs are currently in the clinic, our findings motivate further translation targeting a heart failure indication with combined approaches.


Asunto(s)
Desnervación Autonómica/métodos , Daño por Reperfusión Miocárdica , Trasplante de Células Madre/métodos , Animales , Insuficiencia Cardíaca , Riñón/inervación , Riñón/cirugía , Masculino , Infarto del Miocardio , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Remodelación Ventricular/fisiología
8.
J Am Coll Cardiol ; 72(21): 2609-2621, 2018 11 27.
Artículo en Inglés | MEDLINE | ID: mdl-30466519

RESUMEN

BACKGROUND: Previously, we have shown that radiofrequency (RF) renal denervation (RDN) reduces myocardial infarct size in a rat model of acute myocardial infarction (MI) and improves left ventricular (LV) function and vascular reactivity in the setting of heart failure following MI. OBJECTIVES: The authors investigated the therapeutic efficacy of RF-RDN in a clinically relevant normotensive swine model of heart failure with reduced ejection fraction (HFrEF). METHODS: Yucatan miniswine underwent 75 min of left anterior descending coronary artery balloon occlusion to induce MI followed by reperfusion (R) for 18 weeks. Cardiac function was assessed pre- and post-MI/R by transthoracic echocardiography and every 3 weeks for 18 weeks. HFrEF was classified by an LV ejection fraction <40%. Animals who met inclusion criteria were randomized to receive bilateral RF-RDN (n = 10) treatment or sham-RDN (n = 11) at 6 weeks post-MI/R using an RF-RDN catheter. RESULTS: RF-RDN therapy resulted in significant reductions in renal norepinephrine content and circulating angiotensin I and II. RF-RDN significantly increased circulating B-type natriuretic peptide levels. Following RF-RDN, LV end-systolic volume was significantly reduced when compared with sham-treated animals, leading to a marked and sustained improvement in LV ejection fraction. Furthermore, RF-RDN improved LV longitudinal strain. Simultaneously, RF-RDN reduced LV fibrosis and improved coronary artery responses to vasodilators. CONCLUSIONS: RF-RDN provides a novel therapeutic strategy to reduce renal sympathetic activity, inhibit the renin-angiotensin system, increase circulating B-type natriuretic peptide levels, attenuate LV fibrosis, and improve left ventricular performance and coronary vascular function. These cardioprotective mechanisms synergize to halt the progression of HFrEF following MI/R in a clinically relevant model system.


Asunto(s)
Desnervación Autonómica/métodos , Progresión de la Enfermedad , Insuficiencia Cardíaca/diagnóstico por imagen , Insuficiencia Cardíaca/prevención & control , Riñón/inervación , Sistema Renina-Angiotensina/fisiología , Animales , Relación Dosis-Respuesta a Droga , Ecocardiografía/métodos , Femenino , Insuficiencia Cardíaca/metabolismo , Riñón/diagnóstico por imagen , Riñón/metabolismo , Riñón/cirugía , Arteria Renal/diagnóstico por imagen , Arteria Renal/inervación , Arteria Renal/metabolismo , Arteria Renal/cirugía , Sistema Renina-Angiotensina/efectos de los fármacos , Porcinos , Porcinos Enanos , Vasodilatadores/farmacología , Remodelación Ventricular/efectos de los fármacos , Remodelación Ventricular/fisiología
9.
Circ Res ; 123(5): 590-600, 2018 08 17.
Artículo en Inglés | MEDLINE | ID: mdl-30355137

RESUMEN

Hydrogen sulfide (H2S)-a potent gaseous signaling molecule-has emerged as a critical regulator of cardiovascular homeostasis. H2S is produced enzymatically by 3 constitutively active endogenous enzymes in all mammalian species. Within the past 2 decades, studies administering H2S-donating agents and the genetic manipulation of H2S-producing enzymes have revealed multiple beneficial effects of H2S, including vasodilation, activation of antiapoptotic and antioxidant pathways, and anti-inflammatory effects. More recently, the heightened enthusiasm in this field has shifted to the development of novel H2S-donating agents that exert favorable pharmacological profiles. This has led to the discovery of novel H2S-mediated signaling pathways. This review will discuss recently developed H2S therapeutics, introduce signaling pathways that are influenced by H2S-dependent sulfhydration, and explore the dual-protective effect of H2S in cardiorenal syndrome.


Asunto(s)
Enfermedades Cardiovasculares/tratamiento farmacológico , Sulfuro de Hidrógeno/uso terapéutico , Animales , Enfermedades Cardiovasculares/metabolismo , Humanos , Sulfuro de Hidrógeno/metabolismo , Procesamiento Proteico-Postraduccional , Transducción de Señal
10.
J Am Heart Assoc ; 7(5)2018 03 03.
Artículo en Inglés | MEDLINE | ID: mdl-29502102

RESUMEN

BACKGROUND: There is a paucity of data about the mechanisms by which sacubitril/valsartan (also known as LCZ696) improves outcomes in patients with heart failure. Specifically, the effects of sacubitril/valsartan on vascular function and NO bioavailability have not been investigated. We hypothesized that sacubitril/valsartan therapy increases circulating NO levels and improves vascular function in the setting of heart failure. METHODS AND RESULTS: Male spontaneously hypertensive rats underwent myocardial ischemia/reperfusion surgery to induce heart failure and were followed for up to 12 weeks with serial echocardiography. Rats received sacubitril/valsartan (68 mg/kg), valsartan (31 mg/kg), or vehicle starting at 4 weeks after reperfusion. At 8 or 12 weeks of reperfusion, animals were euthanized and tissues were collected for ex vivo analyses of NO bioavailability, aortic vascular reactivity, myocardial and vascular histology, and cardiac molecular assays. Left ventricular structure and function were improved by both valsartan and sacubitril/valsartan compared with vehicle. Sacubitril/valsartan resulted in superior cardiovascular benefits, as evidenced by sustained improvements in left ventricular ejection fraction and end-diastolic pressure. Ex vivo vascular function, as measured by aortic vasorelaxation responses to acetylcholine and sodium nitroprusside, was significantly improved by valsartan and sacubitril/valsartan, with more sustained improvements afforded by sacubitril/valsartan. Furthermore, myocardial NO bioavailability was significantly enhanced in animals receiving sacubitril/valsartan therapy. CONCLUSIONS: Sacubitril/valsartan offers superior cardiovascular protection in heart failure and improves vascular function to a greater extent than valsartan alone. Sacubitril/valsartan-mediated improvements in cardiac and vascular function are likely related to increases in NO bioavailability and explain, in part, the benefits beyond angiotensin receptor blockade.


Asunto(s)
Aminobutiratos/farmacología , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Aorta Torácica/efectos de los fármacos , Insuficiencia Cardíaca/tratamiento farmacológico , Miocardio/metabolismo , Neprilisina/antagonistas & inhibidores , Óxido Nítrico/metabolismo , Inhibidores de Proteasas/farmacología , Volumen Sistólico/efectos de los fármacos , Tetrazoles/farmacología , Función Ventricular Izquierda/efectos de los fármacos , Animales , Aorta Torácica/metabolismo , Aorta Torácica/fisiopatología , Compuestos de Bifenilo , Modelos Animales de Enfermedad , Combinación de Medicamentos , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/fisiopatología , Hipertensión/complicaciones , Hipertensión/metabolismo , Hipertensión/fisiopatología , Masculino , Miocardio/patología , Péptidos Natriuréticos/sangre , Neprilisina/metabolismo , Ratas Endogámicas SHR , Valsartán
11.
JACC Basic Transl Sci ; 3(6): 796-809, 2018 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-30623139

RESUMEN

Cardioprotective effects of H2S have been well documented. However, the lack of evidence supporting the benefits afforded by delayed H2S therapy warrants further investigation. Using a murine model of transverse aortic constriction-induced heart failure, this study showed that delayed H2S therapy protects multiple organs including the heart, kidney, and blood-vessel; reduces oxidative stress; attenuates renal sympathetic and renin-angiotensin-aldosterone system pathological activation; and ultimately improves exercise capacity. These findings provide further insights into H2S-mediated cardiovascular protection and implicate the benefits of using H2S-based therapies clinically for the treatment of heart failure.

12.
Am J Physiol Heart Circ Physiol ; 314(2): H311-H321, 2018 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-29101177

RESUMEN

Oxidative stress results in mtDNA damage and contributes to myocardial cell death. mtDNA repair enzymes are crucial for mtDNA repair and cell survival. We investigated a novel, mitochondria-targeted fusion protein (Exscien1-III) containing endonuclease III in myocardial ischemia-reperfusion injury and transverse aortic constriction (TAC)-induced heart failure. Male C57/BL6J mice (10-12 wk) were subjected to 45 min of myocardial ischemia and either 24 h or 4 wk of reperfusion. Exscien1-III (4 mg/kg ip) or vehicle was administered at the time of reperfusion. Male C57/BL6J mice were subjected to TAC, and Exscien1-III (4 mg/kg i.p) or vehicle was administered daily starting at 3 wk post-TAC and continued for 12 wk. Echocardiography was performed to assess left ventricular (LV) structure and function. Exscien1-III reduced myocardial infarct size ( P < 0.01) at 24 h of reperfusion and preserved LV ejection fraction at 4 wk postmyocardial ischemia. Exscien1-III attenuated TAC-induced LV dilation and dysfunction at 6-12 wk post-TAC ( P < 0.05). Exscien1-III reduced ( P < 0.05) cardiac hypertrophy and maladaptive remodeling after TAC. Assessment of cardiac mitochondria showed that Exscien1-III localized to mitochondria and increased mitochondrial antioxidant and reduced apoptotic markers. In conclusion, our results indicate that administration of Exscien1-III provides significant protection against myocardial ischemia and preserves myocardial structure and LV performance in the setting of heart failure. NEW & NOTEWORTHY Oxidative stress-induced mitochondrial DNA damage is a prominent feature in the pathogenesis of cardiovascular diseases. In the present study, we demonstrate the efficacy of a novel, mitochondria-targeted fusion protein that traffics endonuclease III specifically for mitochondrial DNA repair in two well-characterized murine models of cardiac injury and failure.


Asunto(s)
Fármacos Cardiovasculares/farmacología , Daño del ADN/efectos de los fármacos , ADN Mitocondrial/efectos de los fármacos , Insuficiencia Cardíaca/tratamiento farmacológico , Hipertrofia Ventricular Izquierda/tratamiento farmacológico , Disfunción Ventricular Izquierda/tratamiento farmacológico , Función Ventricular Izquierda/efectos de los fármacos , Remodelación Ventricular/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Proteínas Reguladoras de la Apoptosis/metabolismo , ADN Mitocondrial/genética , ADN Mitocondrial/metabolismo , Modelos Animales de Enfermedad , Fibrosis , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/patología , Insuficiencia Cardíaca/fisiopatología , Hipertrofia Ventricular Izquierda/metabolismo , Hipertrofia Ventricular Izquierda/patología , Hipertrofia Ventricular Izquierda/fisiopatología , Masculino , Ratones Endogámicos C57BL , Mitocondrias Cardíacas/efectos de los fármacos , Mitocondrias Cardíacas/metabolismo , Mitocondrias Cardíacas/patología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Estrés Oxidativo/efectos de los fármacos , Proteínas Recombinantes de Fusión/farmacología , Transducción de Señal/efectos de los fármacos , Volumen Sistólico/efectos de los fármacos , Disfunción Ventricular Izquierda/metabolismo , Disfunción Ventricular Izquierda/patología , Disfunción Ventricular Izquierda/fisiopatología
13.
J Am Coll Cardiol ; 70(17): 2139-2153, 2017 Oct 24.
Artículo en Inglés | MEDLINE | ID: mdl-29050562

RESUMEN

BACKGROUND: Sustained sympathetic activation contributes to the progression of myocardial cell injury, cardiac fibrosis, and left ventricular (LV) dysfunction in heart failure (HF). OBJECTIVES: This study investigated the effects of radiofrequency renal nerve denervation (RF-RDN) on the pathobiology of HF and the interaction between the renal sympathetic nerves and natriuretic peptide (NP) metabolism. METHODS: Spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) were subjected to 45 min of coronary artery ligation and reperfusion for 12 weeks. At 4 weeks post-reperfusion, SHR and WKY underwent either bilateral RF-RDN or sham-RDN. RESULTS: Following RF-RDN in both strains, LV ejection fraction remained significantly above those levels in respective sham-RDN rats, and at the end of the 12-week study, rats in both strains had significantly reduced LV fibrosis and improved vascular function. RF-RDN therapy significantly improved vascular reactivity to endothelium-dependent and -independent vasodilators as well as vascular compliance in the setting of severe HF. Improvements in LV function were accompanied by significant elevations in circulating NP as compared to those associated with sham-RDN. Further investigation into the cause of increased circulating NP levels demonstrated that RF-RDN significantly inhibited renal neprilysin activity in SHR and WKY with HF. Likewise, chronic treatment with the beta1 antagonist bisoprolol inhibited renal neprilysin activity and increased circulation NP levels in WKY with HF. CONCLUSIONS: This study identifies a novel endogenous pathway by which the renal nerves participate in the degradation of cardioprotective NP. Furthermore, removal of the influence of the renal nerves on kidney function attenuates renal neprilysin activity, augments circulating NP levels, reduces myocardial fibrosis, and improves LV function in the setting of HF.


Asunto(s)
Insuficiencia Cardíaca/terapia , Riñón/inervación , Neprilisina/antagonistas & inhibidores , Simpatectomía , Aminobutiratos/farmacología , Angiotensina II/sangre , Animales , Compuestos de Bifenilo , Bisoprolol/farmacología , Presión Sanguínea , Combinación de Medicamentos , Ecocardiografía , Miocardio/química , Miocardio/patología , Neprilisina/fisiología , Nitritos/análisis , Norepinefrina/sangre , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Arteria Renal/inervación , Renina/sangre , Daño por Reperfusión/fisiopatología , Tetrazoles/farmacología , Valsartán , Función Ventricular Izquierda/fisiología
14.
Circulation ; 134(19): 1467-1483, 2016 Nov 08.
Artículo en Inglés | MEDLINE | ID: mdl-27660293

RESUMEN

BACKGROUND: Bone marrow cell (BMC)-based treatment for critical limb ischemia in diabetic patients yielded a modest therapeutic effect resulting from cell dysfunction. Therefore, approaches that improve diabetic stem/progenitor cell functions may provide therapeutic benefits. Here, we tested the hypothesis that restoration of hydrogen sulfide (H2S) production in diabetic BMCs improves their reparative capacities. METHODS: Mouse BMCs were isolated by density-gradient centrifugation. Unilateral hind limb ischemia was conducted in 12- to 14-week-old db/+ and db/db mice by ligation of the left femoral artery. The H2S level was measured by either gas chromatography or staining with florescent dye sulfidefluor 7 AM. RESULTS: Both H2S production and cystathionine γ-lyase (CSE), an H2S enzyme, levels were significantly decreased in BMCs from diabetic db/db mice. Administration of H2S donor diallyl trisulfide (DATS) or overexpression of CSE restored H2S production and enhanced cell survival and migratory capacity in high glucose (HG)-treated BMCs. Immediately after hind limb ischemia surgery, the db/+ and db/db mice were administered DATS orally and/or given a local intramuscular injection of green fluorescent protein-labeled BMCs or red fluorescent protein-CSE-overexpressing BMCs (CSE-BMCs). Mice with hind limb ischemia were divided into 6 groups: db/+, db/db, db/db+BMCs, db/db+DATS, db/db+DATS+BMCs, and db/db+CSE-BMCs. DATS and CSE overexpression greatly enhanced diabetic BMC retention in ischemic hind limbs followed by improved blood perfusion, capillary/arteriole density, skeletal muscle architecture, and cell survival and decreased perivascular CD68+ cell infiltration in the ischemic hind limbs of diabetic mice. It is interesting to note that DATS or CSE overexpression rescued high glucose-impaired migration, tube formation, and survival of BMCs or mature human cardiac microvascular endothelial cells. Moreover, DATS restored nitric oxide production and decreased endothelial nitric oxide synthase phosphorylation at threonine 495 levels in human cardiac microvascular endothelial cells and improved BMC angiogenic activity under high glucose condition. Last, silencing CSE by siRNA significantly increased endothelial nitric oxide synthase phosphorylation at threonine 495 levels in human cardiac microvascular endothelial cells. CONCLUSIONS: Decreased CSE-mediated H2S bioavailability is an underlying source of BMC dysfunction in diabetes mellitus. Our data indicate that H2S and overexpression of CSE in diabetic BMCs may rescue their dysfunction and open novel avenues for cell-based therapeutics of critical limb ischemia in diabetic patients.


Asunto(s)
Trasplante de Médula Ósea , Diabetes Mellitus Experimental , Angiopatías Diabéticas , Miembro Posterior/irrigación sanguínea , Sulfuro de Hidrógeno/sangre , Isquemia , Aloinjertos , Animales , Células de la Médula Ósea/metabolismo , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/terapia , Angiopatías Diabéticas/sangre , Angiopatías Diabéticas/terapia , Humanos , Isquemia/sangre , Isquemia/terapia , Masculino , Ratones
15.
J Am Heart Assoc ; 5(7)2016 07 05.
Artículo en Inglés | MEDLINE | ID: mdl-27381758

RESUMEN

BACKGROUND: Zofenopril, a sulfhydrylated angiotensin-converting enzyme inhibitor (ACEI), reduces mortality and morbidity in infarcted patients to a greater extent than do other ACEIs. Zofenopril is a unique ACEI that has been shown to increase hydrogen sulfide (H2S) bioavailability and nitric oxide (NO) levels via bradykinin-dependent signaling. Both H2S and NO exert cytoprotective and antioxidant effects. We examined zofenopril effects on H2S and NO bioavailability and cardiac damage in murine and swine models of myocardial ischemia/reperfusion (I/R) injury. METHODS AND RESULTS: Zofenopril (10 mg/kg PO) was administered for 1, 8, and 24 hours to establish optimal dosing in mice. Myocardial and plasma H2S and NO levels were measured along with the levels of H2S and NO enzymes (cystathionine ß-synthase, cystathionine γ-lyase, 3-mercaptopyruvate sulfur transferase, and endothelial nitric oxide synthase). Mice received 8 hours of zofenopril or vehicle pretreatment followed by 45 minutes of ischemia and 24 hours of reperfusion. Pigs received placebo or zofenopril (30 mg/daily orally) 7 days before 75 minutes of ischemia and 48 hours of reperfusion. Zofenopril significantly augmented both plasma and myocardial H2S and NO levels in mice and plasma H2S (sulfane sulfur) in pigs. Cystathionine ß-synthase, cystathionine γ-lyase, 3-mercaptopyruvate sulfur transferase, and total endothelial nitric oxide synthase levels were unaltered, while phospho-endothelial nitric oxide synthase(1177) was significantly increased in mice. Pretreatment with zofenopril significantly reduced myocardial infarct size and cardiac troponin I levels after I/R injury in both mice and swine. Zofenopril also significantly preserved ischemic zone endocardial blood flow at reperfusion in pigs after I/R. CONCLUSIONS: Zofenopril-mediated cardioprotection during I/R is associated with an increase in H2S and NO signaling.


Asunto(s)
Antihipertensivos/farmacología , Captopril/análogos & derivados , Corazón/efectos de los fármacos , Sulfuro de Hidrógeno/metabolismo , Daño por Reperfusión Miocárdica/prevención & control , Miocardio/metabolismo , Óxido Nítrico/metabolismo , Animales , Disponibilidad Biológica , Western Blotting , Captopril/farmacología , Cistationina betasintasa/efectos de los fármacos , Cistationina betasintasa/genética , Cistationina betasintasa/metabolismo , Cistationina gamma-Liasa/efectos de los fármacos , Cistationina gamma-Liasa/genética , Cistationina gamma-Liasa/metabolismo , Ratones , Infarto del Miocardio/patología , Miocardio/patología , Óxido Nítrico Sintasa de Tipo III/efectos de los fármacos , Óxido Nítrico Sintasa de Tipo III/genética , Óxido Nítrico Sintasa de Tipo III/metabolismo , Ramipril/farmacología , Distribución Aleatoria , Flujo Sanguíneo Regional , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sulfurtransferasas/efectos de los fármacos , Sulfurtransferasas/genética , Sulfurtransferasas/metabolismo , Porcinos , Porcinos Enanos , Troponina I/efectos de los fármacos , Troponina I/metabolismo
16.
Circ Res ; 119(3): 470-80, 2016 07 22.
Artículo en Inglés | MEDLINE | ID: mdl-27296507

RESUMEN

RATIONALE: Catheter-based renal denervation (RDN) is currently under development for the treatment of resistant hypertension and is thought to reduce blood pressure via interruption of sympathetic pathways that modulate cardiovascular function. The sympathetic nervous system also plays a critical role in the pathogenesis of acute myocardial infarction and heart failure. OBJECTIVE: We examined whether treatment with radiofrequency (RF)-RDN would protect the heart against subsequent myocardial ischemia/reperfusion injury via direct effects on the myocardium. METHODS AND RESULTS: Spontaneously hypertensive rats received either bilateral RF-RDN or sham-RDN. At 4 weeks after RF-RDN (n=14) or sham-RDN (n=14) treatment, spontaneously hypertensive rats were subjected to 30 minutes of transient coronary artery occlusion and 24 hours -7 days reperfusion. Four weeks after RF-RDN, myocardial oxidative stress was markedly attenuated, and transcription and translation of antioxidants, superoxide dismutase 1 and glutathione peroxidase-1, were significantly upregulated compared with sham-RDN spontaneously hypertensive rats. RF-RDN also inhibited myocardial G protein-coupled receptor kinase 2 pathological signaling and enhanced myocardial endothelial nitric oxide synthase function and nitric oxide signaling. RF-RDN therapy resulted in a significant reduction in myocardial infarct size per area at risk compared with sham-RDN (26.8 versus 43.9%; P<0.01) at 24 hours postreperfusion and significantly improved left ventricular function at 7 days after myocardial ischemia/reperfusion. CONCLUSIONS: RF-RDN reduced oxidative stress, inhibited G protein-coupled receptor kinase 2 signaling, increased nitric oxide bioavailability, and ameliorated myocardial reperfusion injury in the setting of severe hypertension. These findings provide new insights into the remote cardioprotective effects of RF-RDN acting directly on cardiac myocytes to attenuate cell death and protect against ischemic injury.


Asunto(s)
Ablación por Catéter/métodos , Quinasa 2 del Receptor Acoplado a Proteína-G/metabolismo , Riñón/metabolismo , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/prevención & control , Óxido Nítrico/biosíntesis , Animales , Desnervación/métodos , Quinasa 2 del Receptor Acoplado a Proteína-G/antagonistas & inhibidores , Riñón/inervación , Riñón/cirugía , Masculino , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/prevención & control , Estrés Oxidativo/fisiología , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Transducción de Señal/fisiología
17.
JACC Cardiovasc Interv ; 9(7): 728-41, 2016 Apr 11.
Artículo en Inglés | MEDLINE | ID: mdl-27056313

RESUMEN

OBJECTIVES: The purpose of this study was to assess and compare in vivo the restoration of vasomotor function following Absorb bioresorbable vascular scaffold (BVS) (Abbott Vascular, Santa Clara, California) and metallic Xience V (XV) (Abbott Vascular, Santa Clara, California) stent implantations in porcine coronary arteries at 1 and 2 years. BACKGROUND: Drug-eluting metallic coronary stents induce sustained vasomotor dysfunction, and preliminary observations from arteries with bioresorbable scaffolds have indicated partially restored vasoreactivity. METHODS: A total of 15 Absorb BVS (3.0 × 18.0 mm) and 14 XV (3.0 × 18.0 mm or 3.0 × 12.0 mm) stents were randomly implanted in the main coronaries of 12 nonatherosclerotic swine. The effect of implant on vasomotor performance (constrictive and expansive) was measured in the stented/scaffolded segments and the 5-mm proximal and distal adjacent segments in vivo by angiography assessing mean luminal diameter changes following infusion of vasoactive agents at 1 year (n = 6) and 2 years (n = 6) as well as ex vivo at 2 years using a tissue chamber apparatus. Endothelial cell function and smooth muscle cell phenotype gene marker levels were evaluated with quantitative real-time polymerase chain reaction. RESULTS: The scaffolded Absorb BVS segments showed fully restored constrictive response compared with XV implanted vessels at 1 year: -24.30 ± 14.31% versus -1.79 ± 6.57% (p < 0.004) and at 2 years: -28.13 ± 14.60% versus -3.90 ± 6.44% (p < 0.004). The early restoration of vasomotor function within the scaffolded segments reached a peak at 1 year and did not significantly change up to 2 years. The vasoactive responses of Absorb BVS-implanted vessels within the scaffolded segments were similar to those observed within the proximal and distal edge segments at both time points. Conversely, the stented XV segments demonstrated significantly impaired constrictive response compared with the distal XV edges at 1 year: -1.79 ± 6.57% versus -21.89 ± 7.17% (p < 0.0002) and at 2 years: -3.90 ± 6.44% versus -21.93 ± 15.60% (p < 0.03). Ex vivo assessment of contraction induced by PGF2α and relaxation induced by substance P of isolated BVS segments compared with XV-treated segments generated greater contraction force of 3.94 ± 0.97 g versus 1.83 ± 1.03 g (p < 0.05), and endothelial-dependent relaxation reached 35.91 ± 24.74% versus 1.20 ± 3.79% (p < 0.01). Quantitative real-time polymerase chain reaction gene analysis at 2 years demonstrated increased Connexin 43 messenger ribonucleic acid levels of Absorb BVS-treated vessels compared with XV-treated vessels: 1.92 ± 0.23 versus 0.77 ± 12 (p < 0.05). CONCLUSIONS: Absorb BVS-implanted coronary arteries demonstrate early functional restoration of the scaffolded and adjacent segments at 1 year, which is preserved up to 2 years.


Asunto(s)
Catéteres Cardíacos , Fármacos Cardiovasculares/administración & dosificación , Materiales Biocompatibles Revestidos , Angiografía Coronaria , Vasos Coronarios/efectos de los fármacos , Stents Liberadores de Fármacos , Everolimus/administración & dosificación , Metales , Intervención Coronaria Percutánea/instrumentación , Vasoconstricción/efectos de los fármacos , Vasodilatación/efectos de los fármacos , Animales , Vasos Coronarios/diagnóstico por imagen , Vasos Coronarios/metabolismo , Vasos Coronarios/fisiopatología , Regulación de la Expresión Génica , Técnicas In Vitro , Modelos Animales , Intervención Coronaria Percutánea/efectos adversos , Fenotipo , Reacción en Cadena en Tiempo Real de la Polimerasa , Recuperación de la Función , Porcinos , Porcinos Enanos , Factores de Tiempo
18.
J Cardiovasc Pharmacol Ther ; 21(5): 478-85, 2016 09.
Artículo en Inglés | MEDLINE | ID: mdl-26746429

RESUMEN

BACKGROUND AND PURPOSE: Published data on nebivolol reveal selective ß1 adrenergic selectively along with novel nitric oxide (NO)-dependent vasodilatory properties. However, the exact molecular mechanism is unknown. Protein S-nitrosylation constitutes a large part of the ubiquitous influence of NO on cellular signal transduction and is involved in a number of human diseases. More recently, protein denitrosylation has been shown to play a major role in controlling cellular S-nitrosylation (SNO). Several enzymes have been reported to catalyze the reduction of SNOs and are viewed as candidate denitrosylases. One of the first described is known as S-nitrosoglutathione reductase (GSNOR). Importantly, GSNOR has been shown to play a role in regulating SNO signaling downstream of the ß-adrenergic receptor and is therefore operative in cellular signal transduction. Pharmacological inhibition or genetic deletion of GSNOR leads to enhanced vasodilation and characteristic of known effects of nebivolol. Structurally, nebivolol is similar to known inhibitors of GSNOR. Therefore, we hypothesize that some of the known effects of nebivolol may occur through this mechanism. EXPERIMENTAL APPROACH: Using cell culture systems, tissue organ bath, and intact animal models, we report that nebivolol treatment leads to a dose-dependent accumulation of nitrosothiols in cells, and this is associated with an enhanced vasodilation by S-nitrosoglutathione. KEY RESULTS: These data suggest a new mechanism of action of nebivolol that may explain in part the reported NO activity. CONCLUSIONS AND IMPLICATIONS: Because exogenous mediators of protein SNO or denitrosylation can substantially affect the development or progression of disease, this may call for new utility of nebivolol.


Asunto(s)
Aldehído Oxidorreductasas/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Nebivolol/farmacología , Procesamiento Proteico-Postraduccional/efectos de los fármacos , S-Nitrosoglutatión/metabolismo , Vasodilatación/efectos de los fármacos , Vasodilatadores/farmacología , Aldehído Oxidorreductasas/metabolismo , Animales , Relación Dosis-Respuesta a Droga , Células Endoteliales/efectos de los fármacos , Células Endoteliales/enzimología , Macrófagos/efectos de los fármacos , Macrófagos/enzimología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/enzimología , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo III/deficiencia , Óxido Nítrico Sintasa de Tipo III/genética , Oxidación-Reducción , Células RAW 264.7 , Ratas Sprague-Dawley
19.
Circ Heart Fail ; 9(1): e002314, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26699388

RESUMEN

BACKGROUND: Trimethylamine N-oxide (TMAO), a gut microbe-dependent metabolite of dietary choline and other trimethylamine-containing nutrients, is both elevated in the circulation of patients having heart failure and heralds worse overall prognosis. In animal studies, dietary choline or TMAO significantly accelerates atherosclerotic lesion development in ApoE-deficient mice, and reduction in TMAO levels inhibits atherosclerosis development in the low-density lipoprotein receptor knockout mouse. METHODS AND RESULTS: C57BL6/J mice were fed either a control diet, a diet containing choline (1.2%) or a diet containing TMAO (0.12%) starting 3 weeks before surgical transverse aortic constriction. Mice were studied for 12 weeks after transverse aortic constriction. Cardiac function and left ventricular structure were monitored at 3-week intervals using echocardiography. Twelve weeks post transverse aortic constriction, myocardial tissues were collected to evaluate cardiac and vascular fibrosis, and blood samples were evaluated for cardiac brain natriuretic peptide, choline, and TMAO levels. Pulmonary edema, cardiac enlargement, and left ventricular ejection fraction were significantly (P<0.05, each) worse in mice fed either TMAO- or choline-supplemented diets when compared with the control diet. In addition, myocardial fibrosis was also significantly greater (P<0.01, each) in the TMAO and choline groups relative to controls. CONCLUSIONS: Heart failure severity is significantly enhanced in mice fed diets supplemented with either choline or the gut microbe-dependent metabolite TMAO. The present results suggest that additional studies are warranted examining whether gut microbiota and the dietary choline → TMAO pathway contribute to increased heart failure susceptibility.


Asunto(s)
Bacterias/metabolismo , Colina/toxicidad , Dieta/efectos adversos , Insuficiencia Cardíaca/inducido químicamente , Intestinos/microbiología , Metilaminas/toxicidad , Animales , Cardiomegalia/sangre , Cardiomegalia/inducido químicamente , Cardiomegalia/patología , Colina/metabolismo , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Fibrosis , Insuficiencia Cardíaca/sangre , Insuficiencia Cardíaca/patología , Insuficiencia Cardíaca/fisiopatología , Masculino , Metilaminas/sangre , Ratones Endogámicos C57BL , Miocardio/metabolismo , Miocardio/patología , Edema Pulmonar/sangre , Edema Pulmonar/inducido químicamente , Factores de Riesgo , Índice de Severidad de la Enfermedad , Volumen Sistólico , Factores de Tiempo , Disfunción Ventricular Izquierda/sangre , Disfunción Ventricular Izquierda/inducido químicamente , Disfunción Ventricular Izquierda/fisiopatología , Función Ventricular Izquierda
20.
Am J Physiol Heart Circ Physiol ; 309(5): H835-43, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-26116713

RESUMEN

Hydrogen sulfide (H2S) is a biologically active endogenous gasotransmitter formed in penile tissue that has been shown to relax isolated cavernosal smooth muscle. In the present study, erectile responses to the H2S donors sodium sulfide (Na2S) and sodium hydrosulfide (NaHS) were investigated in the anesthetized rat. Intracavernosal injections of Na2S in doses of 0.03-1 mg/kg increased intracavernosal pressure and transiently decreased mean arterial pressure in a dose-dependent manner. Blood pressure responses to Na2S were rapid in onset and short in duration. Responses to Na2S and NaHS were similar at doses up to 0.3 mg/kg, after which a plateau in the erectile response to NaHS was reached. Increases in intracavernosal pressure in response to Na2S were attenuated by tetraethylammonium (K(+) channel inhibitor) and iberiotoxin (large-conductance Ca(2+)-activated K(+) channel inhibitor), whereas glybenclamide [ATP-sensitive K(+) (KATP) channel inhibitor] and inhibitors of nitric oxide (NO) synthase, cyclooxygenase, and cytochrome P-450 epoxygenase had no effect. These data indicate that erectile responses to Na2S are mediated by a tetraethylammonium- and iberiotoxin-sensitive mechanism and that KATP channels, NO, or arachidonic acid metabolites are not involved. Na2S did not alter erectile responses to sodium nitroprusside (NO donor) or cavernosal nerve stimulation, indicating that neither NO nor cGMP metabolism are altered. Thus, Na2S has erectile activity mediated by large-conductance Ca(2+)-activated K(+) channels. It is suggested that strategies that increase H2S formation in penile tissue may be useful in the treatment of erectile dysfunction when NO bioavailability, KATP channel function, or poor responses to PGE1 are present.


Asunto(s)
Sulfuro de Hidrógeno/farmacología , Erección Peniana/efectos de los fármacos , Anestesia , Animales , Ácido Araquidónico/metabolismo , Canales KATP/metabolismo , Masculino , Músculo Liso/efectos de los fármacos , Músculo Liso/metabolismo , Óxido Nítrico/metabolismo , Canales de Potasio Calcio-Activados/metabolismo , Ratas , Ratas Sprague-Dawley , Sulfuros/farmacología
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