RESUMEN
Increased mitochondrial reactive oxygen species (ROS) formation is important for the development of right ventricular (RV) hypertrophy (RVH) and failure (RVF) during pulmonary hypertension (PH). ROS molecules are produced in different compartments within the cell, with mitochondria known to produce the strongest ROS signal. Among ROS-forming mitochondrial proteins, outer-mitochondrial-membrane-located monoamine oxidases (MAOs, type A or B) are capable of degrading neurotransmitters, thereby producing large amounts of ROS. In mice, MAO-B is the dominant isoform, which is present in almost all cell types within the heart. We analyzed the effect of an inducible cardiomyocyte-specific knockout of MAO-B (cmMAO-B KO) for the development of RVH and RVF in mice. Right ventricular hypertrophy was induced by pulmonary artery banding (PAB). RV dimensions and function were measured through echocardiography. ROS production (dihydroethidium staining), protein kinase activity (PamStation device), and systemic hemodynamics (in vivo catheterization) were assessed. A significant decrease in ROS formation was measured in cmMAO-B KO mice during PAB compared to Cre-negative littermates, which was associated with reduced activity of protein kinases involved in hypertrophic growth. In contrast to littermates in which the RV was dilated and hypertrophied following PAB, RV dimensions were unaffected in response to PAB in cmMAO-B KO mice, and no decline in RV systolic function otherwise seen in littermates during PAB was measured in cmMAO-B KO mice. In conclusion, cmMAO-B KO mice are protected against RV dilatation, hypertrophy, and dysfunction following RV pressure overload compared to littermates. These results support the hypothesis that cmMAO-B is a key player in causing RV hypertrophy and failure during PH.
Asunto(s)
Hipertensión Pulmonar , Hipertrofia Ventricular Derecha , Monoaminooxidasa , Especies Reactivas de Oxígeno , Animales , Masculino , Ratones , Modelos Animales de Enfermedad , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/patología , Ventrículos Cardíacos/patología , Ventrículos Cardíacos/metabolismo , Hipertensión Pulmonar/genética , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/patología , Hipertrofia Ventricular Derecha/metabolismo , Hipertrofia Ventricular Derecha/genética , Hipertrofia Ventricular Derecha/etiología , Hipertrofia Ventricular Derecha/patología , Ratones Noqueados , Monoaminooxidasa/genética , Monoaminooxidasa/metabolismo , Monoaminooxidasa/deficiencia , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Especies Reactivas de Oxígeno/metabolismo , Disfunción Ventricular Derecha/metabolismo , Disfunción Ventricular Derecha/genética , Disfunción Ventricular Derecha/etiología , Disfunción Ventricular Derecha/patologíaRESUMEN
Right ventricular (RV) function is an important prognostic indicator for pulmonary arterial hypertension (PAH), a vasculopathy that primarily and disproportionally affects women with distinct pre- and postmenopausal clinical outcomes. However, most animal studies have overlooked the impact of sex and ovarian hormones on RV remodeling in PAH. Here, we combined invasive measurements of RV hemodynamics and morphology with computational models of RV biomechanics in sugen-hypoxia (SuHx)-treated male, ovary-intact female, and ovariectomized female rats. Despite similar pressure overload levels, SuHx induced increases in end-diastolic elastance and passive myocardial stiffening, notably in male SuHx animals, corresponding to elevated diastolic intracellular calcium. Increases in end-systolic chamber elastance were largely explained by myocardial hypertrophy in male and ovary-intact female rats, whereas ovariectomized females exhibited contractility recruitment via calcium transient augmentation. Ovary-intact female rats primarily responded with hypertrophy, showing fewer myocardial mechanical alterations and less stiffening. These findings highlight sex-related RV remodeling differences in rats, affecting systolic and diastolic RV function in PAH.NEW & NOTEWORTHY Combining hemodynamic and morphological measurements from male, female, and ovariectomized female pulmonary arterial hypertension (PAH) rats revealed distinct adaptation mechanisms despite similar pressure overload. Males showed the most diastolic stiffening. Ovariectomized females had enhanced myocyte contractility and calcium transient upregulation. Ovary-intact females primarily responded with hypertrophy, experiencing milder passive myocardial stiffening and no changes in myocyte shortening. These findings suggest potential sex-specific pathways in right ventricular (RV) adaptation to PAH, with implications for targeted interventions.
Asunto(s)
Modelos Animales de Enfermedad , Ovariectomía , Hipertensión Arterial Pulmonar , Ratas Sprague-Dawley , Función Ventricular Derecha , Remodelación Ventricular , Animales , Femenino , Masculino , Hipertensión Arterial Pulmonar/fisiopatología , Hipertensión Arterial Pulmonar/metabolismo , Hipertensión Arterial Pulmonar/etiología , Factores Sexuales , Hipertrofia Ventricular Derecha/fisiopatología , Hipertrofia Ventricular Derecha/etiología , Hipertrofia Ventricular Derecha/metabolismo , Hipertrofia Ventricular Derecha/patología , Ratas , Disfunción Ventricular Derecha/fisiopatología , Disfunción Ventricular Derecha/metabolismo , Disfunción Ventricular Derecha/etiología , Arteria Pulmonar/fisiopatología , Arteria Pulmonar/metabolismo , Arteria Pulmonar/patología , Modelos Cardiovasculares , Señalización del Calcio , Hipertensión Pulmonar/fisiopatología , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/etiología , HemodinámicaRESUMEN
BACKGROUND: Pulmonary hypertension and right ventricular (RV) dysfunction are major prognostic determinants in patients with heart failure with preserved ejection fraction (HFpEF). The underlying pathomechanisms remain unknown. In this context, we sought to study the pathogenesis of pulmonary hypertension and RV dysfunction in a rat model of obesity-associated HFpEF. METHODS AND RESULTS: HFpEF was induced in obesity-prone rats fed a high-fat diet (n=13) and compared with obesity-resistant rats fed with standard chow (n=9). After 12 months, the animals underwent echocardiographic and hemodynamic evaluation followed by tissue sampling for pathobiological assessment. HFpEF rats presented mild RV pressure overload (with increased RV systolic pressure and pulmonary vascular resistance). No changes in pulmonary artery medial thickness and ex vivo vasoreactivity (to acetylcholine and endothelin-1) were observed and RNA sequencing analysis failed to identify gene clustering in HFpEF lungs. However, released nitric oxide levels were decreased in HFpEF pulmonary artery, while lung expression of preproendothelin-1 was increased. In HFpEF rats, RV structure and function were altered, with RV enlargement, decreased RV fractional area change and free wall longitudinal fractional shortening, together with altered right ventricle-pulmonary artery coupling (estimated by tricuspid annular plane systolic excursion/systolic pulmonary artery pressure). Hypertrophy and apoptosis (evaluated by transferase biotin- dUTP nick-end labeling staining) were increased in right and left ventricles of HFpEF rats. There was an inverse correlation between tricuspid annular plane systolic excursion/systolic pulmonary artery pressure and RV apoptotic rate. Plasma levels of soluble suppression of tumorigenicity-2, interleukin-1ß, -6 and -17A were increased in HFpEF rats. CONCLUSIONS: Obesity-associated HFpEF in rats spontaneously evolves to pulmonary hypertension-HFpEF associated with impaired right ventricle-pulmonary artery coupling that appears disproportionate to a slight increase in RV afterload.
Asunto(s)
Modelos Animales de Enfermedad , Insuficiencia Cardíaca , Arteria Pulmonar , Volumen Sistólico , Disfunción Ventricular Derecha , Función Ventricular Derecha , Animales , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/genética , Arteria Pulmonar/fisiopatología , Arteria Pulmonar/metabolismo , Arteria Pulmonar/patología , Volumen Sistólico/fisiología , Disfunción Ventricular Derecha/fisiopatología , Disfunción Ventricular Derecha/etiología , Disfunción Ventricular Derecha/metabolismo , Disfunción Ventricular Derecha/genética , Masculino , Función Ventricular Derecha/fisiología , Ratas , Hipertensión Pulmonar/fisiopatología , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/metabolismo , Ventrículos Cardíacos/fisiopatología , Ventrículos Cardíacos/diagnóstico por imagen , Ventrículos Cardíacos/metabolismo , Ventrículos Cardíacos/patología , Obesidad/fisiopatología , Obesidad/complicaciones , Obesidad/metabolismo , Dieta Alta en GrasaRESUMEN
The specific mechanism of 4-hydroxysesamin (4-HS), a modification of Sesamin, on right ventricular failure due to pulmonary hypertension (PH) is ominous. By creating a rat model of PH in vivo and a model of pulmonary artery smooth muscle cell (PASMC) hypoxia and inflammation in vitro, the current work aimed to investigate in depth the molecular mechanism of the protective effect of 4-HS. In an in vitro model of hypoxia PASMC, changes in cell proliferation and inflammatory factors were detected after treatment with 4-HS, followed by changes in the JNK/p38 MAPK signaling pathway as detected by Western blot signaling pathway. The findings demonstrated that 4-HS was able to minimize PASMC cell death, block the JNK/p38 MAPK signaling pathway, and resist the promoting effect of hypoxia on PASMC cell proliferation. Following that, we found that 4-HS could both mitigate the right ventricular damage brought on by MCT and had a protective impact on rats Monocrotaline (MCT)-induced PH in in vivo investigations. The key finding of this study is that 4-HS may protect against PH by inhibiting the JNK/p38 MAPK signaling pathway.
Asunto(s)
Proliferación Celular , Hipertensión Pulmonar , Sistema de Señalización de MAP Quinasas , Proteínas Quinasas p38 Activadas por Mitógenos , Animales , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/tratamiento farmacológico , Ratas , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Proliferación Celular/efectos de los fármacos , Disfunción Ventricular Derecha/metabolismo , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Lignanos/farmacología , Lignanos/uso terapéutico , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/patología , Arteria Pulmonar/metabolismo , Insuficiencia Cardíaca/metabolismo , Ratas Sprague-Dawley , Monocrotalina , Modelos Animales de EnfermedadRESUMEN
The right ventricle (RV) differs developmentally, anatomically and functionally from the left ventricle (LV). Therefore, characteristics of LV adaptation to chronic pressure overload cannot easily be extrapolated to the RV. Mitochondrial abnormalities are considered a crucial contributor in heart failure (HF), but have never been compared directly between RV and LV tissues and cardiomyocytes. To identify ventricle-specific mitochondrial molecular and functional signatures, we established rat models with two slowly developing disease stages (compensated and decompensated) in response to pulmonary artery banding (PAB) or ascending aortic banding (AOB). Genome-wide transcriptomic and proteomic analyses were used to identify differentially expressed mitochondrial genes and proteins and were accompanied by a detailed characterization of mitochondrial function and morphology. Two clearly distinguishable disease stages, which culminated in a comparable systolic impairment of the respective ventricle, were observed. Mitochondrial respiration was similarly impaired at the decompensated stage, while respiratory chain activity or mitochondrial biogenesis were more severely deteriorated in the failing LV. Bioinformatics analyses of the RNA-seq. and proteomic data sets identified specifically deregulated mitochondrial components and pathways. Although the top regulated mitochondrial genes and proteins differed between the RV and LV, the overall changes in tissue and cardiomyocyte gene expression were highly similar. In conclusion, mitochondrial dysfuntion contributes to disease progression in right and left heart failure. Ventricle-specific differences in mitochondrial gene and protein expression are mostly related to the extent of observed changes, suggesting that despite developmental, anatomical and functional differences mitochondrial adaptations to chronic pressure overload are comparable in both ventricles.
Asunto(s)
Modelos Animales de Enfermedad , Insuficiencia Cardíaca , Mitocondrias Cardíacas , Animales , Mitocondrias Cardíacas/metabolismo , Mitocondrias Cardíacas/patología , Masculino , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/patología , Insuficiencia Cardíaca/genética , Proteómica , Disfunción Ventricular Derecha/fisiopatología , Disfunción Ventricular Derecha/metabolismo , Disfunción Ventricular Derecha/genética , Disfunción Ventricular Derecha/patología , Función Ventricular Derecha , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Ventrículos Cardíacos/metabolismo , Ventrículos Cardíacos/fisiopatología , Ventrículos Cardíacos/patología , Ratas , Función Ventricular Izquierda , Disfunción Ventricular Izquierda/fisiopatología , Disfunción Ventricular Izquierda/metabolismo , Disfunción Ventricular Izquierda/patología , Disfunción Ventricular Izquierda/genética , Transcriptoma , Ratas Sprague-Dawley , Proteínas Mitocondriales/metabolismo , Proteínas Mitocondriales/genéticaRESUMEN
Duchenne muscular dystrophy (DMD) is an X-linked recessive myopathy due to mutations in the dystrophin gene. Diaphragmatic weakness in DMD causes hypoventilation and elevated afterload on the right ventricle (RV). Thus, RV dysfunction in DMD develops early in disease progression. Herein, we deliver a 30-min sustained RV preload/afterload challenge to isolated hearts of wild-type (Wt) and dystrophic (Dmdmdx-4Cv) mice at both young (2-6 month) and middle-age (8-12 month) to test the hypothesis that the dystrophic RV is susceptible to dysfunction with elevated load. Young dystrophic hearts exhibited greater pressure development than wild type under baseline (Langendorff) conditions, but following RV challenge exhibited similar contractile function as wild type. Following the RV challenge, young dystrophic hearts had an increased incidence of premature ventricular contractions (PVCs) compared to wild type. Hearts of middle-aged wild-type and dystrophic mice had similar contractile function during baseline conditions. After RV challenge, hearts of middle-aged dystrophic mice had severe RV dysfunction and arrhythmias, including ventricular tachycardia. Following the RV load challenge, dystrophic hearts had greater lactate dehydrogenase (LDH) release than wild-type mice indicative of damage. Our data indicate age-dependent changes in RV function with load in dystrophin deficiency, highlighting the need to avoid sustained RV load to forestall dysfunction and arrhythmia.
Asunto(s)
Arritmias Cardíacas , Distrofina , Contracción Miocárdica , Animales , Masculino , Distrofina/genética , Distrofina/deficiencia , Ratones , Arritmias Cardíacas/fisiopatología , Arritmias Cardíacas/etiología , Arritmias Cardíacas/genética , Disfunción Ventricular Derecha/fisiopatología , Disfunción Ventricular Derecha/genética , Disfunción Ventricular Derecha/metabolismo , Distrofia Muscular de Duchenne/fisiopatología , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/complicaciones , Distrofia Muscular de Duchenne/metabolismo , Ratones Endogámicos mdx , Ratones Endogámicos C57BLRESUMEN
ABSTRACT: Pulmonary arterial hypertension (PAH) is characterized by increased pulmonary vascular resistance (PVR), imposing overload on the right ventricle (RV) and imbalance of the redox state. Our study investigated the influence of treatment with sulforaphane (SFN), found in cruciferous vegetables, on RV remodeling and redox homeostasis in monocrotaline (MCT)-induced PAH. Male Wistar rats were separated into 4 groups: control (CTR); CTR + SFN; MCT; and MCT + SFN. PAH induction was implemented by a single dose of MCT (60 mg/kg intraperitoneally). Treatment with SFN (2.5 mg/kg/day intraperitoneally) started on the seventh day after the MCT injection and persisted for 2 weeks. After 21 days of PAH induction, echocardiographic, hemodynamic, and oxidative stress evaluation was performed. The MCT group showed an increase in RV hypertrophy, RV systolic area, RV systolic, mean pulmonary artery pressure, and PVR and exhibited a decrease in the RV outflow tract acceleration time/ejection time ratio, RV fractional shortening, and tricuspid annular plane systolic excursion compared to CTR ( P < 0.05). SFN-treated PAH attenuated detrimental changes in tricuspid annular plane systolic excursion, mean pulmonary artery pressure, and PVR parameters. Catalase levels and the glutathione/Glutathione disulfide (GSSG) ratio were diminished in the MCT group compared to CTR ( P < 0.05). SFN increased catalase levels and normalized the glutathione/GSSG ratio to control levels ( P < 0.05). Data express the benefit of SFN treatment on the cardiac function of rats with PAH associated with the cellular redox state.
Asunto(s)
Modelos Animales de Enfermedad , Isotiocianatos , Monocrotalina , Oxidación-Reducción , Estrés Oxidativo , Ratas Wistar , Sulfóxidos , Función Ventricular Derecha , Animales , Sulfóxidos/farmacología , Isotiocianatos/farmacología , Masculino , Función Ventricular Derecha/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Antioxidantes/farmacología , Hipertrofia Ventricular Derecha/fisiopatología , Hipertrofia Ventricular Derecha/metabolismo , Hipertrofia Ventricular Derecha/tratamiento farmacológico , Homeostasis/efectos de los fármacos , Remodelación Ventricular/efectos de los fármacos , Contracción Miocárdica/efectos de los fármacos , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/fisiopatología , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/inducido químicamente , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/fisiopatología , Arteria Pulmonar/metabolismo , Ratas , Presión Arterial/efectos de los fármacos , Hipertensión Arterial Pulmonar/tratamiento farmacológico , Hipertensión Arterial Pulmonar/fisiopatología , Hipertensión Arterial Pulmonar/metabolismo , Disfunción Ventricular Derecha/fisiopatología , Disfunción Ventricular Derecha/tratamiento farmacológico , Disfunción Ventricular Derecha/metabolismoRESUMEN
BACKGROUND: Right ventricular (RV) dysfunction remains a major problem after heart transplantation and may be associated with brain death (BD) in a donor. A calcineurin inhibitor tacrolimus was recently found to have beneficial effects on heart function. Here, we examined whether tacrolimus might prevent BD-induced RV dysfunction and the associated pathobiological changes. METHODS: After randomized tacrolimus (n = 8; 0.05 mg·kg-1·day-1) or placebo (n = 9) pretreatment, pigs were assigned to a BD procedure and hemodynamically investigated 1, 3, 5, and 7 h after the Cushing reflex. After euthanasia, myocardial tissue was sampled for pathobiological evaluation. Seven pigs were used as controls. RESULTS: Calcineurin inhibition prevented increases in pulmonary vascular resistance and RV-arterial decoupling induced by BD. BD was associated with an increased RV pro-apoptotic Bax-to-Bcl2 ratio and RV and LV apoptotic rates, which were prevented by tacrolimus. BD induced increased expression of the pro-inflammatory IL-6-to-IL-10 ratio, their related receptors, and vascular cell adhesion molecule-1 in both the RV and LV. These changes were prevented by tacrolimus. RV and LV neutrophil infiltration induced by BD was partly prevented by tacrolimus. BD was associated with decreased RV expression of the ß-1 adrenergic receptor and sarcomere (myosin heavy chain [MYH]7-to-MYH6 ratio) components, while ß-3 adrenergic receptor, nitric oxide-synthase 3, and glucose transporter 1 expression increased. These changes were prevented by tacrolimus. CONCLUSIONS: Brain death was associated with isolated RV dysfunction. Tacrolimus prevented RV dysfunction induced by BD through the inhibition of apoptosis and inflammation activation.
Asunto(s)
Disfunción Ventricular Derecha , Animales , Muerte Encefálica , Miocardio/metabolismo , Porcinos , Tacrolimus/farmacología , Tacrolimus/uso terapéutico , Resistencia Vascular , Disfunción Ventricular Derecha/tratamiento farmacológico , Disfunción Ventricular Derecha/etiología , Disfunción Ventricular Derecha/metabolismoRESUMEN
BACKGROUND AND PURPOSE: Pulmonary hypertension (PH) is a cardiovascular disease characterised by an increase in pulmonary arterial (PA) resistance leading to right ventricular (RV) failure. Reactive oxygen species (ROS) play a major role in PH. OP2113 is a drug with beneficial effects on cardiac injuries that targets mitochondrial ROS. The aim of the study was to address the in vivo therapeutic effect of OP2113 in PH. EXPERIMENTAL APPROACH: PH was induced by 3 weeks of chronic hypoxia (CH-PH) in rats treated with OP2113 or its vehicle via subcutaneous osmotic mini-pumps. Haemodynamic parameters and both PA and heart remodelling were assessed. Reactivity was quantified in PA rings and in RV or left ventricular (LV) cardiomyocytes. Oxidative stress was detected by electron paramagnetic resonance and western blotting. Mitochondrial mass and respiration were measured by western blotting and oxygraphy, respectively. KEY RESULTS: In CH-PH rats, OP2113 reduced the mean PA pressure, PA remodelling, PA hyperreactivity in response to 5-HT, the contraction slowdown in RV and LV and increased the mitochondrial mass in RV. Interestingly, OP2113 had no effect on haemodynamic parameters, both PA and RV wall thickness and PA reactivity, in control rats. Whereas oxidative stress was evidenced by an increase in protein carbonylation in CH-PH, this was not affected by OP2113. CONCLUSION AND IMPLICATIONS: Our study provides evidence for a selective protective effect of OP2113 in vivo on alterations in both PA and RV from CH-PH rats without side effects in control rats.
Asunto(s)
Insuficiencia Cardíaca , Hipertensión Pulmonar , Disfunción Ventricular Derecha , Ratas , Animales , Hipertensión Pulmonar/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Ventrículos Cardíacos/metabolismo , Arteria Pulmonar , Insuficiencia Cardíaca/metabolismo , Hipoxia/complicaciones , Hipoxia/tratamiento farmacológico , Hipoxia/metabolismo , Disfunción Ventricular Derecha/metabolismo , Función Ventricular Derecha , Modelos Animales de EnfermedadRESUMEN
BACKGROUND AND PURPOSE: Pulmonary arterial hypertension (PAH) is a pulmonary vasculature obstructive disease that leads to right heart failure and death. Maresin 1 is an endogenous lipid mediator known to promote inflammation resolution. However, the effect of Maresin 1 on PAH remains unclear. EXPERIMENTAL APPROACH: The serum Maresin 1 concentration was assessed using UPLC. A mouse model of PAH was established by combining the Sugen 5416 injection and hypoxia exposure. After treatment with Maresin 1, the right ventricular systolic pressure (RVSP) and right ventricular function were measured by haemodynamic measurement and echocardiography, respectively. Vascular remodelling was evaluated by histological staining. Confocal microscopy and western blot were used to test related protein expression. In vitro cell migration, proliferation and apoptosis assays were performed in primary rat pulmonary artery smooth muscle cells (PASMCs). Western blotting and siRNA transfection were used to clarify the mechanism of Maresin 1. KEY RESULTS: Endogenous serum Maresin 1 was decreased in PAH patients and mice. Maresin 1 treatment decreased RVSP and attenuated right ventricular dysfunction (RVD) in the murine PAH model. Maresin 1 reversed abnormal changes in pulmonary vascular remodelling, attenuating endothelial to mesenchymal transformation and enhancing apoptosis of α-SMA positive cells. Furthermore, Maresin 1 inhibited PASMC proliferation and promoted apoptosis by inhibiting STAT, AKT, ERK, and FoxO1 phosphorylation via LGR6. CONCLUSION AND IMPLICATIONS: Maresin 1 improved abnormal pulmonary vascular remodelling and right ventricular dysfunction in PAH mice, targeting aberrant PASMC proliferation. This suggests Maresin 1 may have a potent therapeutic effect in vascular disease.
Asunto(s)
Hipertensión Pulmonar , Hipertensión Arterial Pulmonar , Disfunción Ventricular Derecha , Animales , Proliferación Celular , Ácidos Docosahexaenoicos/farmacología , Ratones , Miocitos del Músculo Liso , Proteínas Proto-Oncogénicas c-akt/metabolismo , Hipertensión Arterial Pulmonar/tratamiento farmacológico , Arteria Pulmonar , ARN Interferente Pequeño/farmacología , Ratas , Remodelación Vascular , Disfunción Ventricular Derecha/metabolismo , Disfunción Ventricular Derecha/patologíaRESUMEN
For the first time, the present study unravels a cardiospecific therapeutic approach for Pulmonary Arterial Hypertension (PAH), a disease with a very poor prognosis and high mortality rates due to right ventricle (RV) dysfunction. We first established a new in vitro model of high-pressure-induced hypertrophy that closely resembles heart defects associated with PAH and validated our in vitro findings on a preclinical in vivo model of monocrotaline (MCT)-induced PAH. Our results showed the in vitro antihypertrophic effect of 1,8-cineole, a monoterpene widely found in several essential oils. Also, a decrease in RV hypertrophy and fibrosis, and an improvement in heart function in vivo was observed, when 1,8-cineole was applied topically. Furthermore, 1,8-cineole restored gap junction protein connexin43 distribution at the intercalated disks and mitochondrial functionality, suggesting it may act by preserving cardiac cell-to-cell communication and bioenergetics. Overall, our results point out a promising therapeutic compound that can be easily applied topically, thus paving the way for the development of effective cardiac-specific therapies to greatly improve PAH outcomes.
Asunto(s)
Cardiomiopatías , Hipertensión Pulmonar , Hipertensión Arterial Pulmonar , Disfunción Ventricular Derecha , Animales , Conexina 43 , Modelos Animales de Enfermedad , Eucaliptol/uso terapéutico , Ventrículos Cardíacos/metabolismo , Homeostasis , Humanos , Hipertensión Pulmonar/tratamiento farmacológico , Hipertrofia Ventricular Derecha/metabolismo , Hipertensión Arterial Pulmonar/tratamiento farmacológico , Disfunción Ventricular Derecha/metabolismoRESUMEN
Right ventricular (RV) failure is a major cause of mortality in pulmonary arterial hypertension (PAH), but its mechanism remains largely unknown. MicroRNA-21 (miR-21) is involved in flow-mediated stress in the vasculature, but its effects on RV remodeling require investigations. Herein, we aim to study the mechanism of miR-21 in the early (compensated) and late (decompensated) phases of PAH-induced RV dysfunction. Using aorto-venous fistula (AVS) surgery, we established a rat model of PAH. To mimic the microenvironment of PAH, we treated cardiomyocytes with flow-mediated shear stress in 6 dyne for 3 and 8 h. To evaluate whether miR-21 could be a biomarker, we prospectively collected the sera of patients with congenital heart disease- (CHD) related PAH. Additionally, clinical, echocardiographic and right heart catheterization information was collected. The primary endpoint was hospitalization for decompensated heart failure (HF). It is of note that, despite an initial increase in miR-21 expression in hypertrophic RV post AVS, miR-21 expression decreased with RV dysfunction thereafter. Likewise, the activation of miR-21 in cardiomyocytes under shear stress at 3 h was downregulated at 6 h. The downregulated miR-21 at the late phase was associated with increased apoptosis in cardiomyocytes while miR-21 mimic rescued it. Among 76 CHD-induced PAH patients, 19 who were hospitalized for heart failure represented with a significantly lower expression of circulating miR-21. Collectively, our study revealed that the upregulation of miR-21 in the early phase (RV hypertrophy) and downregulation in the late phase (RV dysfunction) under PAH triggered a biphasic regulation of cardiac remodeling and cardiomyocyte apoptosis.
Asunto(s)
Cardiopatías Congénitas , Insuficiencia Cardíaca , MicroARNs , Hipertensión Arterial Pulmonar , Disfunción Ventricular Derecha , Animales , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/metabolismo , Humanos , Hipertrofia Ventricular Derecha/metabolismo , MicroARNs/metabolismo , Hipertensión Arterial Pulmonar/genética , Ratas , Disfunción Ventricular Derecha/genética , Disfunción Ventricular Derecha/metabolismoRESUMEN
OBJECTIVES: Right ventricular (RV) failure is a leading cause of death in patients with congenital heart disease. RV failure is kept at bay during childhood. Limited proliferation of cardiomyocytes is present in the postnatal heart. We propose that cardiomyocyte proliferation improves RV adaptation to pressure load (PL). We studied adaptation in response to increased RV PL and the role of increased cardiomyocyte cell cycle activity (CCA) in rat pups growing into adulthood. METHODS: We induced RV PL at day of weaning in rats (3 weeks; 30-40 g) by pulmonary artery banding and followed rats into adulthood (300 g). We performed histological analyses and RNA sequencing analysis. To study the effects of increased cardiomyocyte cell cycle activity, we administered neuregulin-1 (NRG1), a growth factor involved in cardiac development. RESULTS: PL induced an increase in CCA, with subsequent decline of CCA (sham/PL at 4 weeks: 0.14%/0.83%; P = .04 and 8 weeks: 0.00%/0.00%; P = .484) and cardiac function (cardiac index: control/PL 4 weeks: 4.41/3.29; P = .468 and 8 weeks: 3.57/1.44; P = .024). RNA sequencing analysis revealed delayed maturation and increased CCA pathways. NRG1 stimulated CCA (PL vehicle/NRG1 at 2 weeks: 0.62%/2.28%; P = .003), improved cardiac function (cardiac index control vs vehicle/NRG1 at 2 weeks: 4.21 vs 3.07/4.17; P = .009/.705) and postponed fibrosis (control vs vehicle/NRG1 at 4 weeks: 1.66 vs 4.82%/2.97%; P = .009/.078) in RV PL rats during childhood. CONCLUSIONS: RV PL during growth induces a transient CCA increase. Further CCA stimulation improves cardiac function and delays fibrosis. This proof-of-concept study shows that stimulation of CCA can improve RV adaptation to PL in the postnatal developing heart and might provide a new approach to preserve RV function in patients with congenital heart disease.
Asunto(s)
Insuficiencia Cardíaca , Disfunción Ventricular Derecha , Ratas , Animales , Hipertrofia Ventricular Derecha/metabolismo , Disfunción Ventricular Derecha/etiología , Disfunción Ventricular Derecha/prevención & control , Disfunción Ventricular Derecha/metabolismo , Presión Ventricular/fisiología , Neurregulina-1/genética , Neurregulina-1/metabolismo , Neurregulina-1/farmacología , Función Ventricular Derecha , Miocitos Cardíacos/metabolismo , Fibrosis , Insuficiencia Cardíaca/metabolismo , Ciclo Celular , Modelos Animales de EnfermedadRESUMEN
AIMS: Research on the pathophysiology of right ventricular (RV) failure has, in spite of the associated high mortality and morbidity, lagged behind compared to the left ventricle (LV). Previous work from our lab revealed that the embryonic basic helix-loop-helix transcription factor heart and neural crest derivatives expressed-2 (Hand2) is re-expressed in the adult heart and activates a 'foetal gene programme' contributing to pathological cardiac remodelling under conditions of LV pressure overload. As such, ablation of cardiac expression of Hand2 conferred protection to cardiac stress and abrogated the maladaptive effects that were observed upon increased expression levels. In this study, we aimed to understand the contribution of Hand2 to RV remodelling in response to pressure overload induced by pulmonary artery banding (PAB). METHODS AND RESULTS: In this study, Hand2F/F and MCM- Hand2F/F mice were treated with tamoxifen (control and knockout, respectively) and subjected to six weeks of RV pressure overload induced by PAB. Echocardiographic- and MRI-derived haemodynamic parameters as well as molecular remodelling were assessed for all experimental groups and compared to sham-operated controls. Six weeks after PAB, levels of Hand2 expression increased in the control-banded animals but, as expected, remained absent in the knockout hearts. Despite the dramatic differences in Hand2 expression, pressure overload resulted in impaired cardiac function independently of the genotype. In fact, Hand2 depletion seems to sensitize the RV to pressure overload as these mice develop more hypertrophy and more severe cardiac dysfunction. Higher expression levels of HAND2 were also observed in RV samples of human hearts from patients with pulmonary hypertension. In turn, the LV of RV pressure-overloaded hearts was also dramatically affected as reflected by changes in shape, decreased LV mass, and impaired cardiac function. RNA-sequencing revealed a distinct set of genes that are dysregulated in the pressure-overloaded RV, compared to the previously described pressure-overloaded LV. CONCLUSION: Cardiac-specific depletion of Hand2 is associated with severe cardiac dysfunction in conditions of RV pressure overload. While inhibiting Hand2 expression can prevent cardiac dysfunction in conditions of LV pressure overload, the same does not hold true for conditions of RV pressu re overload. This study highlights the need to better understand the molecular mechanisms driving pathological remodelling of the RV in contrast to the LV, in order to better diagnose and treat patients with RV or LV failure.
Asunto(s)
Insuficiencia Cardíaca , Disfunción Ventricular Derecha , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/metabolismo , Ventrículos Cardíacos/metabolismo , Humanos , Ratones , ARN/metabolismo , Tamoxifeno/metabolismo , Factores de Transcripción/metabolismo , Disfunción Ventricular Derecha/genética , Disfunción Ventricular Derecha/metabolismo , Función Ventricular Derecha , Presión Ventricular , Remodelación VentricularRESUMEN
Pulmonary hypertension (PH) is a global health issue with a prevalence of 10% in ages >65 years. Right heart failure (RHF) is the main cause of death in PH. We have previously shown that monocrotaline (MCT)-induced PH and RHF are due to an increase in oxidative stress. In this study, probucol (PROB), a strong antioxidant with a lipid-lowering property, versus lovastatin (LOV), a strong lipid-lowering drug with some antioxidant effects, were evaluated for their effects on the MCT-induced RHF. Rats were treated (I.P.) with PROB (10 mg/kg ×12) or LOV (4 mg/kg ×12), daily 6 days before and 6 days after a single MCT injection (60 mg/kg). Serial echocardiography was performed and at 4-week post-MCT, lung wet-to-dry weight, hemodynamics, RV glutathione peroxidase (GSHPx), superoxide dismutase (SOD), catalase, lipid peroxidation, and myocardial as well as plasma lipids were examined. MCT increased RV systolic and diastolic pressures, wall thickness, RV end diastolic diameter, mortality, and decreased ejection fraction as well as pulmonary artery acceleration time. These changes were mitigated by PROB while LOV had no effect. Furthermore, PROB prevented lipid peroxidation, lowered lipids, and increased GSHPx and SOD in RV myocardium. LOV did decrease the lipids but had no effect on antioxidants and lipid peroxidation. A reduction in oxidative stress and not the lipid-lowering effect of PROB may explain the prevention of MCT-induced PH, RHF, and mortality. Thus targeting of oxidative stress as an adjuvant therapy is suggested.
Asunto(s)
Anticolesterolemiantes/farmacología , Antioxidantes/farmacología , Insuficiencia Cardíaca/metabolismo , Corazón/efectos de los fármacos , Hipertensión Pulmonar/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Lovastatina/farmacología , Miocardio/metabolismo , Estrés Oxidativo/efectos de los fármacos , Probucol/farmacología , Animales , Catalasa/efectos de los fármacos , Catalasa/metabolismo , Ecocardiografía , Glutatión Peroxidasa/efectos de los fármacos , Glutatión Peroxidasa/metabolismo , Insuficiencia Cardíaca/inducido químicamente , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/fisiopatología , Hemodinámica , Hipertensión Pulmonar/inducido químicamente , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/fisiopatología , Pulmón/efectos de los fármacos , Monocrotalina/toxicidad , Tamaño de los Órganos/efectos de los fármacos , Ratas , Superóxido Dismutasa/efectos de los fármacos , Superóxido Dismutasa/metabolismo , Disfunción Ventricular Derecha/inducido químicamente , Disfunción Ventricular Derecha/tratamiento farmacológico , Disfunción Ventricular Derecha/metabolismo , Disfunción Ventricular Derecha/fisiopatologíaRESUMEN
Pulmonary hypertension (PH) is a life-threatening disease characterized by vascular remodeling. Exploring new therapy target is urgent. The purpose of the present study is to investigate whether and how spliced x-box binding protein 1 (xbp1s), a key component of endoplasmic reticulum stress (ERS), contributes to the pathogenesis of PH. Forty male SD rats were randomly assigned to four groups: Control, Monocrotaline (MCT), MCT+AAV-CTL (control), and MCT+AAV-xbp1s. The xbp1s protein levels were found to be elevated in lung tissues of the MCT group. Intratracheal injection of adeno-associated virus serotype 1 carrying xbp1s shRNA (AAV-xbp1s) to knock down the expression of xbp1s effectively ameliorated the MCT-induced elevation of right ventricular systolic pressure (RVSP), total pulmonary resistance (TPR), right ventricular hypertrophy and medial wall thickness of muscularized distal pulmonary arterioles. The abnormally increased positive staining rates of proliferating cell nuclear antigen (PCNA) and Ki67 and decreased positive staining rates of terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) in pulmonary arterioles were also reversed in the MCT+AAV-xbp1s group. For mechanistic exploration, bioinformatics prediction of the protein network was performed on the STRING database, and further verification was performed by qRT-PCR, Western blots and co-immunoprecipitation (Co-IP). DNA damage-inducible transcript 3 (Ddit3) was identified as a downstream protein that interacted with xbp1s. Overexpression of Ddit3 restored the decreased proliferation, migration and cell viability caused by silencing of xbp1s. The protein level of Ddit3 was also highly consistent with xbp1s in the animal model. Taken together, our study demonstrated that xbp1s-Ddit3 may be a potential target to interfere with vascular remodeling in PH.
Asunto(s)
Presión Arterial , Hipertensión Pulmonar/metabolismo , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Factor de Transcripción CHOP/metabolismo , Remodelación Vascular , Proteína 1 de Unión a la X-Box/metabolismo , Animales , Apoptosis , Movimiento Celular , Proliferación Celular , Células Cultivadas , Modelos Animales de Enfermedad , Hipertensión Pulmonar/inducido químicamente , Hipertensión Pulmonar/genética , Hipertensión Pulmonar/fisiopatología , Hipertrofia Ventricular Derecha/inducido químicamente , Hipertrofia Ventricular Derecha/metabolismo , Hipertrofia Ventricular Derecha/fisiopatología , Masculino , Monocrotalina , Músculo Liso Vascular/fisiopatología , Arteria Pulmonar/metabolismo , Arteria Pulmonar/fisiopatología , Ratas Sprague-Dawley , Transducción de Señal , Factor de Transcripción CHOP/genética , Disfunción Ventricular Derecha/inducido químicamente , Disfunción Ventricular Derecha/metabolismo , Disfunción Ventricular Derecha/fisiopatología , Función Ventricular Derecha , Proteína 1 de Unión a la X-Box/genéticaRESUMEN
Pulmonary hypertension (PH) initially results in compensatory right ventricular (RV) hypertrophy, but eventually in RV failure. This transition is poorly understood, but may be triggered by hypoxia. Measurements of RV oxygen tension (pO2) in PH are lacking. We hypothesized that RV hypoxia occurs in monocrotaline-induced PH in rats and that myo-inositol trispyrophosphate (ITPP), facilitating oxygen dissociation from hemoglobin, can relieve it. Rats received monocrotaline (PH) or saline (control) and 24 days later echocardiograms, pressure-volume loops were obtained and myocardial pO2 was measured using a fluorescent probe. In PH mean pulmonary artery pressure more than doubled (35 ± 5 vs. 15 ± 2 in control), RV was hypertrophied, though its contractility was augmented. RV and LV pO2 was 32 ± 5 and 15 ± 8 mmHg, respectively, in control rats. In PH RV pO2 was reduced to 18 ± 9 mmHg, while LV pO2 was unchanged. RV pO2 correlated with RV diastolic wall stress (negatively) and LV systolic pressure (positively). Acute ITPP administration did not affect RV or LV pO2 in control animals, but increased RV pO2 to 26 ± 5 mmHg without affecting LV pO2 in PH. RV oxygen balance is impaired in PH and as such can be an important target for PH therapy. ITPP may be one of such potential therapies.
Asunto(s)
Cardiotónicos/farmacología , Hipertensión Pulmonar/tratamiento farmacológico , Hipertrofia Ventricular Derecha/tratamiento farmacológico , Hipoxia/tratamiento farmacológico , Fosfatos de Inositol/farmacología , Disfunción Ventricular Derecha/tratamiento farmacológico , Animales , Cardiotónicos/administración & dosificación , Modelos Animales de Enfermedad , Hemoglobinas/metabolismo , Hipertensión Pulmonar/inducido químicamente , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/fisiopatología , Hipertrofia Ventricular Derecha/inducido químicamente , Hipertrofia Ventricular Derecha/metabolismo , Hipertrofia Ventricular Derecha/fisiopatología , Hipoxia/inducido químicamente , Hipoxia/metabolismo , Hipoxia/fisiopatología , Masculino , Monocrotalina/administración & dosificación , Contracción Miocárdica/efectos de los fármacos , Contracción Miocárdica/fisiología , Ratas , Ratas Wistar , Resultado del Tratamiento , Disfunción Ventricular Derecha/inducido químicamente , Disfunción Ventricular Derecha/metabolismo , Disfunción Ventricular Derecha/fisiopatología , Función Ventricular Derecha/fisiologíaRESUMEN
BACKGROUND: Dysfunction and inflammation of hearts subjected to cold ischemic preservation may differ between left and right ventricles, suggesting distinct strategies for amelioration. METHODS AND RESULTS: Explanted murine hearts subjected to cold ischemia for 0, 4, or 8 h in preservation solution were assessed for function during 60 min of warm perfusion and then analyzed for cell death and inflammation by immunohistochemistry and western blotting and total RNA sequencing. Increased cold ischemic times led to greater left ventricle (LV) dysfunction compared to right ventricle (RV). The LV experienced greater cell death assessed by TUNEL+ cells and cleaved caspase-3 expression (n = 4). While IL-6 protein levels were upregulated in both LV and RV, IL-1ß, TNFα, IL-10, and MyD88 were disproportionately increased in the LV. Inflammasome components (NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3), adaptor molecule apoptosis-associated speck-like protein containing a CARD (ASC), cleaved caspase-1) and products (cleaved IL-1ß and gasdermin D) were also more upregulated in the LV. Pathway analysis of RNA sequencing showed increased signaling related to tumor necrosis factor, interferon, and innate immunity with ex-vivo ischemia, but no significant differences were found between the LV and RV. Human donor hearts showed comparable inflammatory responses to cold ischemia with greater LV increases of TNFα, IL-10, and inflammasomes (n = 3). CONCLUSIONS: Mouse hearts subjected to cold ischemia showed time-dependent contractile dysfunction and increased cell death, inflammatory cytokine expression and inflammasome expression that are greater in the LV than RV. However, IL-6 protein elevations and altered transcriptional profiles were similar in both ventricles. Similar changes are observed in human hearts.
Asunto(s)
Ventrículos Cardíacos/metabolismo , Mediadores de Inflamación/metabolismo , Isquemia Miocárdica/metabolismo , Soluciones Preservantes de Órganos/administración & dosificación , Disfunción Ventricular Izquierda/metabolismo , Disfunción Ventricular Derecha/metabolismo , Animales , Frío/efectos adversos , Femenino , Trasplante de Corazón/métodos , Ventrículos Cardíacos/efectos de los fármacos , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Isquemia Miocárdica/fisiopatología , Donantes de TejidosRESUMEN
Pulmonary arterial hypertension (PAH) is a debilitating condition of the pulmonary circulatory system that occurs in patients of all ages and if untreated, eventually leads to right heart failure and death. Despite existing medical treatment options that improve survival and quality of life, the disease remains incurable. Thus, there is an urgent need to develop novel therapies to treat this disease. Emerging evidence suggests that long non-coding RNAs (lncRNAs) play critical roles in pulmonary vascular remodeling and PAH. LncRNAs are implicated in pulmonary arterial endothelial dysfunction by modulating endothelial cell proliferation, angiogenesis, endothelial mesenchymal transition, and metabolism. LncRNAs are also involved in inducing different pulmonary arterial vascular smooth muscle cell phenotypes, such as cell proliferation, apoptosis, migration, regulation of the phenotypic switching, and cell cycle. LncRNAs are essential regulators of gene expression that affect various diseases at the chromatin, transcriptional, post-translational, and even post-translational levels. Here, we focus on the role of LncRNAs and their molecular mechanisms in the pathogenesis of PAH. We also discuss the current research challenge and potential biomarker and therapeutic potentials of lncRNAs in PAH.
Asunto(s)
Hipertensión Arterial Pulmonar/metabolismo , Arteria Pulmonar/metabolismo , ARN Largo no Codificante/metabolismo , Remodelación Vascular , Animales , Biomarcadores/metabolismo , Edición Génica , Regulación de la Expresión Génica , Humanos , Oligonucleótidos Antisentido/uso terapéutico , Hipertensión Arterial Pulmonar/genética , Hipertensión Arterial Pulmonar/fisiopatología , Hipertensión Arterial Pulmonar/terapia , Arteria Pulmonar/fisiopatología , ARN Largo no Codificante/genética , Tratamiento con ARN de Interferencia , Transducción de Señal , Disfunción Ventricular Derecha/metabolismo , Disfunción Ventricular Derecha/fisiopatología , Función Ventricular Derecha , Remodelación VentricularRESUMEN
In non-ischemic dilated cardiomyopathy (DC) patients at risk of developing right heart failure (RHF), early depiction of congestive heart failure (CHF) is pivotal to inform about the hemodynamic status and tailor medical therapy. We hypothesized increased liver relaxation times measured at routine cardiovascular magnetic resonance (CMR), reflecting passive hepatic congestion, may be a valuable imaging biomarker to depict congestive heart failure. The study cohort consisted of DC patients with LV dysfunction (i.e., ejection fraction <35%) with (nâ¯=â¯48) and without (nâ¯=â¯46) right ventricular dysfunction (RVD), defined as a right ventricular ejection fraction <35%, and >45%, respectively, and a control group (nâ¯=â¯40). Native T1, T2, and extracellular volume (ECV) liver values were measured on routinely acquired cardiac maps. DC+RVD patients had higher C-reactive protein, troponin I and NT-pro BNP values, and worse LV functional parameters than DC-RVD patients (all p <0.001). T1, T2 and ECV Liver values were significantly higher in DC+RVD compared to DC-RVD patients and controls, that is, T1: 675 ± 88 ms verses 538 ± 39 ms and 540 ± 34 ms; T2: 54± 8 ms versus 45 ± 5 ms and 46 ± 4 ms; ECV: 36 ± 7% versus 29 ± 4% and 30 ± 3% (all p <0.001). Gamma-glutamyltranspeptidase (GGT) correlated moderately but significantly with native T1 (r2â¯=â¯0.34), T2 (r2â¯=â¯0.27), and ECV liver (r2â¯=â¯0.23) (all p <0.001). Using right atrial (RA) pressure, as surrogate measure of RHF (i.e., RA pressure >5 mm Hg), native T1 liver yielded at ROC analysis the highest area under the curve (0.906), significantly higher than ECV liver (0.813), GGT (0.806), T2 liver (0.797), total bilirubin (0.737) and alkaline phosphatase (0.561)(pâ¯=â¯0.04). A T1 value of 617 ms yielded a sensitivity of 79.5% and specificity of 91.0% to depict RHF. Excellent intra-/inter-observer agreement was found for assessment of native T1/T2/ECV liver values. In conclusion, in DC patients, assessment of liver relaxation times acquired on a cardiovascular magnetic resonance exam, may provide valuable information with regard to the presence of RHF.