RESUMEN
Blood pressure variability (BPV) and baroreflex dysfunction may contribute to end-organ damage process. We investigated the effects of baroreceptor deficit (10 weeks after sinoaortic denervation - SAD) on hemodynamic alterations, cardiac and pulmonary remodeling. Cardiac function and morphology of male Wistar intact rats (C) and SAD rats (SAD) (n=8/group) were assessed by echocardiography and collagen quantification. BP was directly recorded. Ventricular hypertrophy was quantified by the ratio of left ventricular weight (LVW) and right ventricular weight (RVW) to body weight (BW). BPV was quantified in the time and frequency domains. The atrial natriuretic peptide (ANP), alpha-skeletal actin (α-skelectal), collagen type I and type III genes mRNA expression were evaluated by RT-PCR. SAD did not change BP, but increased BPV (11±0.49 vs. 5±0.3 mmHg). As expected, baroreflex was reduced in SAD. Pulmonary artery acceleration time was reduced in SAD. In addition, SAD impaired diastolic function in both LV (6.8±0.26 vs. 5.02±0.21 mmHg) and RV (5.1±0.21 vs. 4.2±0.12 mmHg). SAD increased LVW/BW in 9% and RVW/BW in 20%, and augmented total collagen (3.8-fold in LV, 2.7-fold in RV, and 3.35-fold in pulmonary artery). Also, SAD increased type I (~6-fold) and III (~5-fold) collagen gene expression. Denervation increased ANP expression in LV (75%), in RV (74%) and increased α-skelectal expression in LV (300%) and in RV (546%). Baroreflex function impairment by SAD, despite not changing BP, induced important adjustments in cardiac structure and pulmonary hypertension. These changes may indicate that isolated baroreflex dysfunction can modulate target tissue damage.
Asunto(s)
Barorreflejo/fisiología , Hipertensión Pulmonar/fisiopatología , Hipertrofia Ventricular Izquierda/fisiopatología , Presorreceptores/fisiopatología , Arteria Pulmonar/fisiopatología , Animales , Desnervación Autonómica/efectos adversos , Desnervación Autonómica/métodos , Modelos Animales de Enfermedad , Hipertensión Pulmonar Primaria Familiar , Ventrículos Cardíacos/diagnóstico por imagen , Ventrículos Cardíacos/patología , Ventrículos Cardíacos/fisiopatología , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/patología , Hipertrofia Ventricular Izquierda/etiología , Hipertrofia Ventricular Izquierda/patología , Masculino , Presorreceptores/lesiones , Presorreceptores/cirugía , Arteria Pulmonar/diagnóstico por imagen , Arteria Pulmonar/patología , Ratas , Ratas Wistar , UltrasonografíaRESUMEN
Role of reactive oxygen species (ROS)/nitric oxide (NO) balance and renin-angiotensin system in mediating cardiac hypertrophy in hyperthyroidism was evaluated in an in vivo and in vitro experimental model. Male Wistar rats were divided into four groups: control, thyroid hormone, vitamin E (or Trolox, its hydrosoluble analogue), thyroid hormone+vitamin E. Angiotensin II receptor (AT1/AT2) gene expression, immunocontent of AT1/AT2 receptors, angiotensinogen, NADPH oxidase (Nox2), and nitric oxide synthase isoforms, as well as ROS concentration (hydrogen peroxide and superoxide anion) were quantified in myocardium. Thyroid hormone increased ROS and NO metabolites, iNOS, nNOS and eNOS isoforms and it was accompanied by cardiac hypertrophy. AT1/AT2 expression and the immunocontent of angiotensinogen and Nox2 were enhanced by thyroid hormone. Antioxidants reduced ROS levels, Nox2, AT1/AT2, NOS isoforms and cardiac hypertrophy. In conclusion, ROS/NO balance may play a role in the control of thyroid hormone-induced cardiac hypertrophy mediated by renin-angiotensin system.
Asunto(s)
Cardiomegalia/patología , Especies de Nitrógeno Reactivo/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Sistema Renina-Angiotensina/fisiología , Hormonas Tiroideas/metabolismo , Angiotensinógeno/análisis , Animales , Western Blotting , Cardiomegalia/metabolismo , Células Cultivadas , Cromanos/farmacología , Hipertiroidismo/metabolismo , Masculino , NADPH Oxidasas/análisis , Óxido Nítrico/análisis , Óxido Nítrico Sintasa/genética , Reacción en Cadena de la Polimerasa , Ratas , Ratas Wistar , Receptor de Angiotensina Tipo 1/genética , Receptor de Angiotensina Tipo 1/metabolismo , Receptor de Angiotensina Tipo 2/genética , Receptor de Angiotensina Tipo 2/metabolismo , Receptores de Angiotensina/genética , Hormonas Tiroideas/farmacología , Vitamina E/farmacologíaRESUMEN
Although most of effects of Angiotensin II (Ang II) related to cardiac remodelling can be attributed to type 1 Ang II receptor (AT(1)R), the type 2 receptor (AT(2)R) has been shown to be involved in the development of some cardiac hypertrophy models. In the present study, we investigated whether the thyroid hormone (TH) action leading to cardiac hypertrophy is also mediated by increased Ang II levels or by change on AT(1)R and AT(2)R expression, which could contribute to this effect. In addition, we also evaluated the possible contribution of AT(2)R in the activation of Akt and in the development of TH-induced cardiac hypertrophy. To address these questions, Wistar rats were treated with thyroxine (T(4), 0.1 mg/kg BW/day, i.p.), with or without AT(2)R blocker (PD123319), for 14 days. Cardiac hypertrophy was identified based on heart/body weight ratio and confirmed by analysis of atrial natriuretic factor mRNA expression. Cardiomyocyte cultures were used to exclude the influence of TH-related hemodynamic effects. Our results demonstrate that the cardiac Ang II levels were significantly increased (80%, P < 0.001) as well as the AT(2)R expression (50%, P < 0.05) in TH-induced cardiac hypertrophy. The critical involvement of AT(2)R to the development of this cardiac hypertrophy in vivo was evidenced after administration of AT(2) blocker, which was able to prevent in 40% (P < 0.01) the cardiac mass gain and the Akt activation induced by TH. The role of AT(2)R to the TH-induced cardiomyocyte hypertrophy was also confirmed after using PD123319 in the in vitro studies. These findings improve understanding of the cardiac hypertrophy observed in hyperthyroidism and provide new insights into the generation of future therapeutic strategies.
Asunto(s)
Bloqueadores del Receptor Tipo 2 de Angiotensina II , Cardiopatías/inducido químicamente , Cardiopatías/prevención & control , Miocardio/patología , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Tiroxina/efectos adversos , Angiotensina II/fisiología , Animales , Células Cultivadas , Modelos Animales de Enfermedad , Cardiopatías/fisiopatología , Hipertiroidismo/fisiopatología , Hipertrofia/inducido químicamente , Hipertrofia/fisiopatología , Hipertrofia/prevención & control , Imidazoles/farmacología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patología , Proteínas Proto-Oncogénicas c-akt/fisiología , Piridinas/farmacología , Ratas , Ratas Wistar , Receptor de Angiotensina Tipo 1/fisiología , Receptor de Angiotensina Tipo 2/fisiología , Transducción de Señal/fisiologíaRESUMEN
This study assessed the behaviour of angiotensin II (Ang II) receptors in an experimental hypothyroidism model in male Wistar rats. Animals were subjected to thyroidectomy and resting for 14 days. The alteration of cardiac mass was evaluated by total heart weight (HW), right ventricle weight (RVW), left ventricle weight (LVW), ratio of HW, RVW and LVW to body weight (BW) and atrial natriuretic factor (ANF) expression. Cardiac and plasma Ang II levels and serum T3 and T4 were determined. The mRNA and protein levels of Ang II receptors were investigated by RT-PCR and Western blotting, respectively. Functional analyses were performed using binding assays. T3 and T4 levels and the haemodynamic parameters confirmed the hypothyroid state. HW/BW, RVW/BW and LVW/BW ratios and the ANF expression were lower than those of control animals. No change was observed in cardiac or plasma Ang II levels. Both AT1/AT2 mRNA and protein levels were increased in the heart of hypothyroid animals due to a significant increase of these receptors in the RV. Experiments performed in cardiomyocytes showed a direct effect promoted by low thyroid hormone levels upon AT1 and AT2 receptors, discarding possible influence of haemodynamic parameters. Functional assays showed that both receptors are able to bind Ang II. Herein, we have identified, for the first time, a close and direct relation of elevated Ang II receptor levels in hypothyroidism. Whether the increase in these receptors in hypothyroidism is an alternative mechanism to compensate the atrophic state of heart or whether it may represent a potential means to the progression of heart failure remains unknown.
Asunto(s)
Hipotiroidismo/metabolismo , Miocitos Cardíacos/metabolismo , Receptor de Angiotensina Tipo 1/metabolismo , Receptor de Angiotensina Tipo 2/metabolismo , Angiotensina II/metabolismo , Animales , Factor Natriurético Atrial , Presión Sanguínea/fisiología , Células Cultivadas , Regulación de la Expresión Génica , Hipotiroidismo/patología , Masculino , Miocardio/metabolismo , Miocardio/patología , Miocitos Cardíacos/patología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Distribución Aleatoria , Ratas , Ratas Wistar , Hormonas Tiroideas/sangre , TiroidectomíaRESUMEN
Increased thyroid hormone (TH) levels are known to induce cardiac hypertrophy. Some studies have provided evidence for a functional link between angiotensin II (ANG II) and transforming growth factor beta1 (TGF-beta1) in the heart, both being able to also induce cardiac hypertrophy. However, the contribution of this growth factor activated directly by TH or indirectly by ANG II in cardiac hypertrophy development remains unknown. To analyze the possible role of TGF-beta1 in cardiac hypertrophy induced by TH and also to evaluate if the TGF-beta1 effect is mediated by ANG II receptors, we employed Wistar rats separated into control, hypothyroid (hypo) and hyperthyroid (T4 - 10) groups combined or not with ANG II receptor blockers (losartan or PD123319). Serum levels of T3 and T4, systolic pressure and heart rate confirmed the thyroid state of the groups. The T4 - 10 group presented a significant increase in cardiac TGF-beta1 levels; however, TGF-beta1 levels in the hypo group did not change in relation to the control. Inhibition of the increase in cardiac TGF-beta1 levels was observed in the groups treated with T4 in association with losartan or PD123319 when compared to the T4 - 10 group. These results demonstrate for the first time the TH-modulated induction of cardiac TGF-beta1 in cardiac hypertrophy, and that this effect is mediated by ANG II receptors.