RESUMO

Galectin-3 (Gal-3) is a carbohydrate-binding protein with multiple functions. Gal-3 regulates cell growth, proliferation, and apoptosis by orchestrating cell-cell and cell-matrix interactions. It is implicated in the development and progression of cardiovascular disease, and its expression is increased in patients with heart failure. In atherosclerosis, Gal-3 promotes monocyte recruitment to the arterial wall boosting inflammation and atheroma. In acute myocardial infarction (AMI), the expression of Gal-3 increases in infarcted and remote zones from the beginning of AMI, and plays a critical role in macrophage infiltration, differentiation to M1 phenotype, inflammation and interstitial fibrosis through collagen synthesis. Genetic deficiency of Gal-3 delays wound healing, impairs cardiac remodeling and function after AMI. On the contrary, Gal-3 deficiency shows opposite results with improved remodeling and function in other cardiomyopathies and in hypertension. Pharmacologic inhibition with non-selective inhibitors is also protective in cardiac disease. Finally, we recently showed that Gal-3 participates in normal aging. However, genetic absence of Gal-3 in aged mice exacerbates pathological hypertrophy and increases fibrosis, as opposed to reduced fibrosis shown in cardiac disease. Despite some gaps in understanding its precise mechanisms of action, Gal-3 represents a potential therapeutic target for the treatment of cardiovascular diseases and the management of cardiac aging. In this review, we summarize the current knowledge regarding the role of Gal-3 in the pathophysiology of heart failure, atherosclerosis, hypertension, myocarditis, and ischemic heart disease. Furthermore, we describe the physiological role of Gal-3 in cardiac aging.

RESUMO

The involvement of natriuretic peptides was studied during the hypertrophic remodeling transition mediated by sequential exposure to chronic hemodynamic overload. We induced hypertension in rats by pressure (renovascular) or volume overload (DOCA-salt) during 6 and 12 weeks of treatment. We also studied the consecutive combination of both models in inverse sequences: RV 6 weeks/DS 6 weeks and DS 6 weeks/RV 6 weeks. All treated groups developed hypertension. Cardiac hypertrophy and left ventricular ANP gene expression were more pronounced in single DS than in single RV groups. BNP gene expression was positively correlated with left ventricular hypertrophy only in RV groups, while ANP gene expression was positively correlated with left ventricular hypertrophy only in DS groups. Combined models exhibited intermediate values between those of single groups at 6 and 12 weeks. The latter stimulus associated to the second applied overload is less effective than the former to trigger cardiac hypertrophy and to increase ANP and BNP gene expression. In addition, we suggest a correlation of ANP synthesis with volume overload and of BNP synthesis with pressure overload-induced hypertrophy after a prolonged treatment. Volume and pressure overload may be two mechanisms, among others, involved in the differential regulation of ANP and BNP gene expression in hypertrophied left ventricles. Plasma ANP levels reflect a response to plasma volume increase and volume overload, while circulating BNP levels seem to be regulated by cardiac BNP synthesis and ventricular hypertrophy.

RESUMO

ß-Adrenergic blockers are no longer recommended as first-line therapy due to the reduced cardioprotection of traditional ß-blockers compared with other antihypertensive drugs. It is unknown whether third-generation ß-blockers share the limitations of traditional ß-blockers. The aim of the present study was to compare the effects of nebivolol or atenolol on central and peripheral systolic blood pressure (SBP) and its variability and target organ damage (TOD) in N-nitro-L-arginine methyl ester (L-NAME) hypertensive rats. Male Wistar rats were treated with L-NAME for 8 weeks together with oral administration of nebivolol 30 mg/kg (n = 8), atenolol 90 mg/kg (n = 8), or vehicle (n = 8). The control group was composed of vehicle-treated Wistar rats. SBP and its variability, as well as echocardiographic parameters, were assessed during the last 2 weeks of treatment. Tissue levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and transforming growth factor ß (TGF-ß), and histopathological parameters were evaluated in the left ventricle and aorta. Nebivolol had a greater ability than atenolol to decrease central SBP and mid-term and short-term blood pressure variability (BPV) in L-NAME rats. Echocardiographic analysis showed that nebivolol was more effective than atenolol on E/A wave ratio normalization. Compared with atenolol treatment, nebivolol had a greater protective effect on different TOD markers, inducing a decrease in collagen deposition and a reduction in the proinflammatory cytokines IL-6 and TNF-α in the left ventricle and aorta. Our findings suggest that the adverse hemodynamic profile and the reduced cardiovascular protection reported with traditional ß-blockers must not be carried forward to third-generation ß-blockers.

Assuntos

RESUMO

We studied the role of galectin-3 (Gal-3) in the expression of alternative activation markers (M2) on macrophage, cytokines, and fibrosis through the temporal evolution of healing, ventricular remodeling, and function after myocardial infarction (MI). C57BL/6J and Gal-3 knockout mice (Lgals3-/-) were subjected to permanent coronary ligation or sham. We studied i) mortality, ii) macrophage infiltration and expression of markers of alternative activation, iii) cytokine, iv) matrix metalloproteinase-2 activity, v) fibrosis, and vi) cardiac function and remodeling. At 1 week post-MI, lack of Gal-3 markedly attenuated F4/80+ macrophage infiltration and significantly increased the expression of Mrc1 and Chil1, markers of M2 macrophages at the MI zone. Levels of IL-10, IL-6, and matrix metalloproteinase-2 were significantly increased, whereas tumor necrosis factor-α, transforming growth factor-ß, and fibrosis were remarkably attenuated at the infarct zone. In Gal-3 knockout mice, scar thinning ratio, expansion, and cardiac remodeling and function were severely affected from the onset of MI. At 4 weeks post-MI, the natural evolution of fibrosis in Gal-3 knockout mice was also affected. Our results suggest that Gal-3 is essential for wound healing because it regulates the dynamics of macrophage infiltration, proinflammatory and anti-inflammatory cytokine expression, and fibrosis along the temporal evolution of MI in mice. The deficit of Gal-3 affected the dynamics of wound healing, thus aggravating the evolution of remodeling and function.

Assuntos

RESUMO

Galectin-1 (Gal-1), an evolutionarily conserved ß-galactoside-binding lectin, controls immune cell homeostasis and tempers acute and chronic inflammation by blunting proinflammatory cytokine synthesis, engaging T-cell apoptotic programs, promoting expansion of T regulatory (Treg) cells, and deactivating antigen-presenting cells. In addition, this lectin promotes angiogenesis by co-opting the vascular endothelial growth factor receptor (VEGFR) 2 signaling pathway. Since a coordinated network of immunomodulatory and proangiogenic mediators controls cardiac homeostasis, this lectin has been proposed to play a key hierarchical role in cardiac pathophysiology via glycan-dependent regulation of inflammatory responses. Here, we discuss the emerging roles of Gal-1 in cardiovascular diseases including acute myocardial infarction, heart failure, Chagas cardiomyopathy, pulmonary hypertension, and ischemic stroke, highlighting underlying anti-inflammatory mechanisms and therapeutic opportunities. Whereas Gal-1 administration emerges as a potential novel treatment option in acute myocardial infarction and ischemic stroke, Gal-1 blockade may contribute to attenuate pulmonary arterial hypertension.

Assuntos

RESUMO

Introducción: Tradicionalmente se ha considerado que el riesgo cardiovascular asociado con la hipertensión es producto de la elevación sostenida de la presión arterial, que lleva al daño de órgano blanco. En los últimos años se ha descripto que otros factores, como la variabilidad de la presión arterial y la presión arterial central, también afectan directamente el daño de órgano blanco. Objetivo: Determinar los efectos de la administración crónica de atenolol o nebivolol sobre la variabilidad de la presión arterial a corto plazo y el daño de órgano blanco a nivel del ventrículo izquierdo y de la aorta. Material y métodos: Se incluyeron ratas espontáneamente hipertensas (REH) que fueron tratadas durante 8 semanas con una única administración diaria de atenolol, nebivolol o vehículo. Se determinaron la presión arterial y su variabilidad a corto plazo y se realizó ecocardiografía. Se extrajeron el ventrículo izquierdo y la aorta torácica para cuantificar la expresión del factor de crecimiento transformante b y realizar estudios histológicos. Resultados: El tratamiento crónico con nebivolol redujo la presión arterial media (PAM) y su variabilidad en mayor medida que el atenolol (PAM WKY: 118,6 ± 8,0 mm Hg; REH: 174,6 ± 2,1ª mm Hg; REH-atenolol: 155,2 ± 2,1a, b mm Hg; REH-nebivolol: 122,3 ± 2,3b, c mm Hg; desviación estándar de la PAM WKY: 3,8 ± 0,2 mm Hg; REH: 6,2 ± 0,3ª mm Hg; REH-atenolol: 5,2 ± 0,3a, b mm Hg; REH-nebivolol: 4,2 ± 0,2b, c mm Hg; ªp < 0,05 vs. ratas WKY; b p < 0,05 vs. REH; c p < 0,05 vs. REH-atenolol). Conclusiones: El análisis del daño de órgano blanco establece que el nebivolol reduce el contenido de fibrosis ventricular, disminuye el espesor de la media aórtica e induce una mayor reducción de la sobreexpresión del factor de crecimiento transformante b en ambos órganos en comparación con REH tratadas con vehículo o atenolol. Estos hallazgos sugieren que la mayor reducción de la presión arterial central, junto con la disminución de la labilidad de la presión arterial, contribuiría en la superior protección del daño de órgano blanco por el nebivolol respecto del atenolol.

RESUMO

Background: Previous studies have shown that endurance training (ET) reduces inotropic, chronotropic and lusitropic reserve in normal mice. Objective: The aim of this study was to evaluate the effect of endurance training on the inotropic and chronotropic reserve of trans-genic mice with sympathetic hyperactivity induced by overexpression of the cardiac GSα protein. Methods: Endurance training consisted in two daily 90-min sessions, 6 days/week, during 4 weeks. Four experimental groups were formed: 1) non-transgenic sedentary (nonTG Sed); 2) transgenic sedentary (TG Sed); 3) nonTG+ET and 4) TG+ET. Results: Endurance training induced myocardial hypertrophy [left ventricular weight (g)/tibial length (mm)] from 5.3±0.3 and 5.5±0.2 in nonTG Sed and TG Sed to 6.8±0.1 and 6.8±0.3 in nonTG+ET and TG+ET, respectively (p<0.05 nonTG Sed vs. nonTG+ET and TG Sed vs. TG+ET). Isoproterenol administration (56 ng/kg) increased +dP/dtmax by 63±10% in nonTG Sed (p<0.05 vs. baseline), 34±2% in TG Sed (p<0.05 vs. baseline and p<0.05 vs. nonTG Sed), 36±7% in non TG+ET (p<0.05 vs. base-line) and 36±7% in TG+ET (p<0.05 vs. baseline). Heart rate (beats/min) increased from 301±15 to 528±37 in nonTG Sed (p<0.05 vs. baseline), from 519±57 to 603±41 in TG Sed, from 300±16 to 375±20 in nonTG+ET (p<0.05 vs. baseline) and from 484±18 to 515±21 in TG+ET. Interstitial collagen was similar among groups. Conclusions: These results suggest that endurance training decreases inotropic and chronotropic reserve without generating struc-tural changes associated to pathological hypertrophy. The presence of sympathetic hyperactivity does not modify this response.

Introducción: En estudios previos mostramos que el ejercicio intenso (EI) reduce la reserva inotrópica, cronotrópica y lusitrópica en ratones normales. Objetivo: Evaluar el efecto del ejercicio intenso sobre la reserva inotrópica y cronotrópica en un modelo de ratones transgénicos con sobreexpresión cardíaca de la proteína Gsα, que induce un cuadro de hiperactividad simpática. Material y métodos: El ejercicio consistió en dos sesiones diarias de 90 minutos de natación, 6 días/semana durante 4 semanas. Se utilizaron cuatro grupos experimentales: 1: sedentario no transgénico (noTG Sed); 2: sedentario TG (TG Sed); 3: noTG+EI y 4: TG+EI. Resultados: El ejercicio indujo el desarrollo de hipertrofia miocárdica [índice peso del ventrículo izquierdo (g)/longitud de la tibia (mm)] desde 5,3±0,3 y 5,5±0,2 en noTG Sed y TG Sed a 6,8±0,1 y 6,8±0,3 en noTG+EI y TG+EI, respectivamente (p<0,05 noTG Sed vs. noTG+EI y TG Sed vs. TG+EI). La administración de isoproterenol (56 ng/kg) incrementó la +dP/dtmáx 63% ±10% en noTG Sed (p<0,05 vs. basal); 34% ±2% en TG Sed (p<0,05 vs.basal y p< 0,05 vs. noTG Sed); 36% ±7% en noTG+EI (p<0,05 vs. basal) y 36% ±7% en TG+EI (p<0,05 vs.basal). La frecuencia cardíaca aumentó de 301±15 a 528±37 latidos/min en noTG Sed (p<0,05 vs. basal), de 519±57 a 603±41 latidos/min en TG Sed, de 300±16 a 375±20 en noTG+EI (p<0,05 vs. basal) y de 484±18 a 515±21 en TG+EI. El colágeno intersticial fue similar entre los grupos. Conclusiones: Estos resultados sugieren que el ejercicio intenso disminuye la reserva inotrópica y cronotrópica sin generar cambios estructurales vinculados a la hipertrofia patológica. La presencia de hiperactividad simpática no modifica esta respuesta.

RESUMO

Introducción: La galectina-3 (Gal-3) es una lectina que regula la respuesta inmune. Sin embargo, su rol en la remodelación y la función ventricular posinfarto de miocardio (IM) se desconoce. Objetivo: Estudiar si el déficit de Gal-3 empeora la remodelación y la función ventricular pos-IM en ratones. Material y métodos: Se utilizaron ratones machos Gal-3 KO y su respectivo control C57 con ligadura de la coronaria descendente anterior o sham. Se conformaron cuatro grupos experimentales: C57 sham, Gal-3 KO sham, C57 IM y Gal-3 KO IM. A los 7 días poscirugía se les realizó ecocardiografía seguida de eutanasia y autopsia; se cuantificó el tamaño del IM y la fibrosis en cortes teñidos con tricrómico de Masson y picrosirius red, respectivamente, el infiltrado de macrófagos y la expresión de IL-6. Resultados: Los diámetros del ventrículo izquierdo se incrementaron significativamente en el grupo C57 IM respecto del sham y dicho incremento fue aún mayor en el grupo Gal-3 KO IM. Además, la fracción de eyección disminuyó desde 47% ± 2% a 37% ± 3% en C57 IM y Gal-3 KO IM, respectivamente (p < 0,02). El tamaño del IM aumentó desde 39,4% ± 5% en los ratones C57 IM a 66,8% ± 5% en los animales Gal-3 KO (p = 0,002). El infiltrado de macrófagos y la fibrosis en el área del IM se redujeron en los ratones Gal-3 KO IM (p < 0,001 C57 IM vs. Gal-3 KO IM), mientras que la concentración de IL-6 en la pared libre del ventrículo izquierdo fue similar entre grupos (p = ns). Conclusiones: La deleción de Gal-3 es un factor importante para la cinética del proceso reparativo regulando el infiltrado de macrófagos y el grado de fibrosis de la zona infartada, como también en la evolución temprana de la remodelación pos-IM.

Background: Galectin-3 (Gal-3) is a lectin that regulates the immune response. However, its role in remodeling and ventricular function after myocardial infarction (MI) is unknown. Objective: The purpose of this study was to analyze whether Gal-3 deficit impairs remodeling and ventricular function after MI in mice. Methods: Male Gal-3 KO mice and their respective C57 controls underwent anterior descending coronary artery ligation or sham operation. Animals were then divided into four experimental groups: 1) C57 sham; 2) Gal-3 KO sham; 3) C57 MI and 4) Gal-3 KO MI. Seven days after surgery, an echocardiography was performed followed by euthanasia. Heart samples were collected to measure MI size and fibrosis using Masson's trichrome and picrosirius red, respectively, and assess macrophage infiltration and IL-6 expression. Results: Left ventricular diameters were significantly increased in the C57 MI group compared with sham animals and the increase was even higher in the Gal-3 KO MI group. Moreover, ejection fraction decreased to 47%±2% in C57 MI and 37%±3% in Gal-3 KO MI mice (p<0.02), and infarct size increased from 39.4%±5% in C57 MI to 66.8%±5% in Gal-3 KO MI animals (p=0.002). Macrophage infiltration and fibrosis in the MI area were significantly reduced in Gal-3 KO MI mice (p<0.001 C57 MI vs. Gal-3KO MI) without changes of IL-6 concentration in the left ventricular free wall (p=ns). Conclusions: Gal-3 gene deletion is an important factor in repair kinetics, regulating macrophage infiltration and the degree of fibrosis in the infarct area, as well as early remodeling after MI.

RESUMO

Introducción El ejercicio leve a moderado reduce los factores de riesgo cardiovascular, mejora estados patológicos previamente establecidos y produce el desarrollo de hipertrofia cardíaca adaptativa. Sin embargo, la respuesta del miocardio frente a un tipo de ejercicio intenso no es del todo conocida. Objetivo Estudiar la función ventricular basal y la reserva miocárdica (respuesta inotrópica, cronotró-pica y lusitrópica frente a un agonista ß-adrenérgico como el isoproterenol) luego de un tipo de ejercicio intenso tanto in vivo como in vitro en ratones. Material y métodos Se utilizaron ratones macho de tres meses de edad de la cepa FVB. El protocolo de ejercicio consistió en dos sesiones diarias de 90 minutos de natación, 6 días/semana durante 4 semanas. Se conformaron dos grupos experimentales: 1) Sedentario: no realiza ejercicio y 2) Ejercicio: realiza protocolo completo de natación intenso. Resultados Al finalizar el protocolo hubo un incremento de la masa ventricular izquierda del 27,9% ± 4%, con función ventricular basal conservada. Sin embargo, hubo una disminución de la respuesta miocárdica al isoproterenol tanto in vivo como in vitro, sin observarse modificaciones en el colágeno intersticial. Conclusiones En nuestras condiciones experimentales, el protocolo de natación, con características de ejercicio intenso, produjo una hipertrofia cardíaca moderada con características mixtas de hipertrofia adaptativa y no adaptativa. Si bien la función basal se mantuvo conservada y no hubo cambios en el colágeno intersticial, se observó una disminución en la reserva inotrópica, cronotrópica y lusitrópica.

Mild to moderate exercise reduces cardiovascular risk factors, improves pre-existing pathologic conditions and develops adaptive cardiac hypertrophy. However, the myocardial response to strenuous exercise is scarcely known. Objective The aim of this study was to evaluate baseline ventricular function and myocardial reserve (inotropic, chronotropic and lusitropic response to the ß-adrenergic agonist isoproterenol) in vivo and in vitro in mice following strenuous exercise. Methods Adult male FVB mice (3 months old) were used. The protocol exercise consisted in 90 min swimming sessions twice a day, 6 days/week for 4 weeks. Two experimental groups were evaluated: 1) sedentary group, with no exercise; and 2) exercise group, with full strenuous swimming protocol. Results At the end of the protocol, left ventricular mass increased by 27.9±4% with preserved baseline left ventricular function. In vivo and in vitro myocardial response to isoproterenol decreased with no changes in interstitial collagen. Conclusions Under our experimental conditions, a strenuous swimming protocol produced moderate cardiac hypertrophy with adaptive and maladaptive hypertrophic characteristics. Although baseline ventricular function was preserved with no changes in interstitial collagen, inotropic, chronotropic and lusitropic reserve decreased.

RESUMO

Introducción El ejercicio leve a moderado reduce los factores de riesgo cardiovascular, mejora estados patológicos previamente establecidos y produce el desarrollo de hipertrofia cardíaca adaptativa. Sin embargo, la respuesta del miocardio frente a un tipo de ejercicio intenso no es del todo conocida. Objetivo Estudiar la función ventricular basal y la reserva miocárdica (respuesta inotrópica, cronotró-pica y lusitrópica frente a un agonista ß-adrenérgico como el isoproterenol) luego de un tipo de ejercicio intenso tanto in vivo como in vitro en ratones. Material y métodos Se utilizaron ratones macho de tres meses de edad de la cepa FVB. El protocolo de ejercicio consistió en dos sesiones diarias de 90 minutos de natación, 6 días/semana durante 4 semanas. Se conformaron dos grupos experimentales: 1) Sedentario: no realiza ejercicio y 2) Ejercicio: realiza protocolo completo de natación intenso. Resultados Al finalizar el protocolo hubo un incremento de la masa ventricular izquierda del 27,9% ± 4%, con función ventricular basal conservada. Sin embargo, hubo una disminución de la respuesta miocárdica al isoproterenol tanto in vivo como in vitro, sin observarse modificaciones en el colágeno intersticial. Conclusiones En nuestras condiciones experimentales, el protocolo de natación, con características de ejercicio intenso, produjo una hipertrofia cardíaca moderada con características mixtas de hipertrofia adaptativa y no adaptativa. Si bien la función basal se mantuvo conservada y no hubo cambios en el colágeno intersticial, se observó una disminución en la reserva inotrópica, cronotrópica y lusitrópica.(AU)

Mild to moderate exercise reduces cardiovascular risk factors, improves pre-existing pathologic conditions and develops adaptive cardiac hypertrophy. However, the myocardial response to strenuous exercise is scarcely known. Objective The aim of this study was to evaluate baseline ventricular function and myocardial reserve (inotropic, chronotropic and lusitropic response to the ß-adrenergic agonist isoproterenol) in vivo and in vitro in mice following strenuous exercise. Methods Adult male FVB mice (3 months old) were used. The protocol exercise consisted in 90 min swimming sessions twice a day, 6 days/week for 4 weeks. Two experimental groups were evaluated: 1) sedentary group, with no exercise; and 2) exercise group, with full strenuous swimming protocol. Results At the end of the protocol, left ventricular mass increased by 27.9±4% with preserved baseline left ventricular function. In vivo and in vitro myocardial response to isoproterenol decreased with no changes in interstitial collagen. Conclusions Under our experimental conditions, a strenuous swimming protocol produced moderate cardiac hypertrophy with adaptive and maladaptive hypertrophic characteristics. Although baseline ventricular function was preserved with no changes in interstitial collagen, inotropic, chronotropic and lusitropic reserve decreased.(AU)