Thyroxine-induced cardiac hypertrophy: influence of adrenergic nervous system versus renin-angiotensin system on myocyte remodeling

Abstract

-The present study assessed the possible involvement of the renin-angiotensin system (RAS) and the sympathetic nervous system (SNS) in thyroxine (T 4)-induced cardiac hypertrophy. Hemodynamic parameters, heart weight (HW), ratio of HW to body weight (HW/BW), and myocyte width were evaluated in absence of thyroid hormone (hypothyroidism) and after T 4 administration. Male Wistar rats were used. Some were subjected to thyroidectomies, whereas hyperthyroidism was induced in others via daily intraperitoneal injection of T 4 (25 or 100 g ⅐ 100 g BW Ϫ1 ⅐ day Ϫ1 ) for 7 days. In some cases, T4 administration was combined with the angiotensin I-converting enzyme inhibitor enalapril (Ena), with the angiotensin type 1 (AT1) receptor blocker losartan (Los) or with the ␤-adrenergic blocker propanolol (Prop). Hemodynamics and morphology were then evaluated. Systolic blood pressure (SBP) was not altered by administration of either T4 alone or T4 in combination with the specific inhibitors. However, SBP decreased significantly in hypothyroid rats. An increased heart rate was seen after administration of either T4 alone or T4 in combination with either Los or Ena. Although the higher dose of T 4 significantly increased HW, HW/BW increased in both T 4-treated groups. Ena and Prop inhibited the increase in HW or HW/BW in hyperthyroid rats. Morphologically, both T 4 dose levels significantly increased myocyte width, an occurrence prevented by RAS or SNS blockers. There was a good correlation between changes in HW/BW and myocyte width. These results indicate that T4-induced cardiac hypertrophy is associated with both the SNS and the RAS. cardiac myocytes; thyroid hormone; angiotensin-converting enzyme; angiotensin II receptors CHANGES IN HEMODYNAMIC LOADING appear to be an important stimulus for cardiac growth. However, dissociation between elevated arterial pressure and increased myocardial mass has been demonstrated in hypertensive cardiac hypertrophy in animals and humans (25). This dissociation suggests that, in addition to blood pressure, various stimuli are involved in the development and regression of cardiac hypertrophy (25). Over the past several decades, many neural and hormonal stimuli have been implicated in cardiac muscle growth, including, but not limited to, ␣-and ␤-adrenergic agonists, ANG II, glucocorticoids, insulin, growth hormone, glucagon, and thyroxine (T 4 ) (25).Mechanisms of cardiac hypertrophy produced by elevated T 4 include a direct effect of the hormone on the heart and indirect effects related to stimulation of the adrenergic nervous system or altered left ventricular loading conditions. Decreased systemic vascular resistance and the subsequent increase in cardiac work contribute to this T 4 -induced hypertrophy (15, 25). However, in support of a direct effect of thyroid hormone on heart growth, some authors have observed that T 4 -induced cardiac hypertrophy in isolated heart preparations is accompanied by increased (31) quantity and rate of protein and ribosome synthesis (33).It is well established t...

Cardiac-specific elevations in thyroid hormone enhance contractility and prevent pressure overload-induced cardiac dysfunction

“…Additionally, abnormal TH signaling͞metabolism is reported in both heart disease and after cardiopulmonary bypass surgery (5, 7). Thus, TH therapy has been advocated for treating cardiac disease (12,13), although clear benefit has been difficult to demonstrate, particularly with chronic use, possibly because of adverse extracardiac effects of TH (5,27). The response of our D2-overexpressing mice to AB supports the conclusion that cardiac-restricted T3 production by D2 protects against deterioration of heart function induced by pressure overload.…”

“…Prolonged TH treatment has been shown to impair heart function, possibly because of (peripheral) extracardiac effects (14,27,28). As shown in Tables 1 and 2 (see also Table 3, which is published as supporting information on the PNAS web site), not only was deterioration of heart function not observed, but cardiac contractility and Ca 2ϩ transients remained elevated in Bin-Off mice 9 weeks after being withdrawn from DOX compared with Con-Off mice.…”

“…Previous studies have suggested that impaired TH signaling and altered TH metabolism occur in heart disease and might contribute to disease pathogenesis (8)(9)(10). On the other hand, elevated TH induces heart disease, possibly as a result of peripheral actions (14,27,28). To assess whether cardiac-restricted D2 overexpression is beneficial in heart disease, 8-week-old mice were DOX withdrawn and subjected to AB for 9 weeks.…”

New insight into the mechanisms associated with the rapid effect of T3 on AT1R expression

“…A growing body of evidence indicates that the renin-angiotensin system (RAS) has a critical role in the development of cardiac hypertrophy found in hyperthyroidism and the local RAS, present in the cardiomyocytes, is directly implicated in this process (Diniz et al 2009, Carneiro-Ramos et al 2010. In this sense, the contribution of the RAS in this pathological condition has been demonstrated by several studies reported in the literature, which showed that AT1R receptor blockade and angiotensin-converting enzyme inhibition attenuate or prevent the development of cardiac hypertrophy induced by THs (Kobori et al 1997, Asahi et al 2001, Basset et al 2001, Hu et al 2003, Pantos et al 2005.…”

Participação do receptor AT2 da angiotensina II no relaxamento vascular promovido pelo hormônio tiroideano

“…Ainda, estudos demonstraram que ratos hipertiroideos apresentam aumento da síntese de renina com conseqüente elevação dos níveis plasmáticos de Ang II, independente da participação do sistema nervoso simpático (Kobori, et al, 1997). Neste sentido, Hu, et al, (2003) mostraram que a administração de inibidores do SRA foi capaz de prevenir o desenvolvimento da hipertrofia cardíaca induzida pelo T4, confirmando a interação entre estes dois sistemas hormonais (Hu, et al, 2003).…”