Angiotensin-(1-7) prevents T3-induced cardiomyocyte hypertrophy by upregulating FOXO3/SOD1/catalase and downregulating NF-ĸB.

Clinical studies have shown a correlation between thyroid disorders and cardiac diseases. High levels of triiodothyronine (T3) induce cardiac hypertrophy, a risk factor for cardiac complications and heart failure. Previous results have demonstrated that angiotensin-(1-7) is able to block T3-induced cardiac hypertrophy; however, the molecular mechanisms involved in this event have not been fully elucidated. Here, we evidenced the contribution of FOXO3 signaling to angiotensin-(1-7) effects. Angiotensin-(1-7) treatment increased nuclear FOXO3 levels and reduced p-FOXO3 levels (inactive form) in isolated cardiomyocytes. Knockdown of FOXO3 by RNA silencing abrogated the antihypertrophic effect of angiotensin-(1-7). Increased expression of antioxidant enzymes superoxide dismutase 1 (SOD1 and catalase) and lower levels of reactive oxygen species and nuclear factor-κB (NF-κB) were observed after angiotensin-(1-7) treatment in vitro. Consistent with these results, transgenic rats overexpressing angiotensin-(1-7) displayed increased nuclear FOXO3 and SOD1 levels and reduced NF-κB levels in the heart. These results provide a new molecular mechanism responsible for the antihypertrophic effect of angiotensin-(1-7), which may contribute to future therapeutic targets.

Renin-angiotensin system overactivation in perivascular adipose tissue contributes to vascular dysfunction in heart failure.

Perivascular adipose tissue (PVAT) dysfunction is associated with vascular damage in cardiometabolic diseases. Although heart failure (HF)-induced endothelial dysfunction is associated with renin-angiotensin system (RAS) activation, no data have correlated this syndrome with PVAT dysfunction. Thus, the aim of the present study was to investigate whether the hyperactivation of the RAS in PVAT participates in the vascular dysfunction observed in rats with HF after myocardial infarction surgery. Wire myograph studies were carried out in thoracic aorta rings in the presence and absence of PVAT. An anticontractile effect of PVAT was observed in the rings of the control rats in the presence (33%) or absence (11%) of endothelium. Moreover, this response was substantially reduced in animals with HF (5%), and acute type 1 angiotensin II receptor (AT1R) and type 2 angiotensin II receptor (AT2R) blockade restored the anticontractile effect of PVAT. In addition, the angiotensin-converting enzyme 1 (ACE1) activity (26%) and angiotensin II levels (51%), as well as the AT1R and AT2R gene expression, were enhanced in the PVAT of rats with HF. Associated with these alterations, HF-induced lower nitric oxide bioavailability, oxidative stress and whitening of the PVAT, which suggests changes in the secretory function of this tissue. The ACE1/angiotensin II/AT1R and AT2R axes are involved in thoracic aorta PVAT dysfunction in rats with HF. These results suggest PVAT as a target in the pathophysiology of vascular dysfunction in HF and provide new perspectives for the treatment of this syndrome.

The endocrinological component and signaling pathways associated to cardiac hypertrophy.

Although myocardial growth corresponds to an adaptive response to maintain cardiac contractile function, the cardiac hypertrophy is a condition that occurs in many cardiovascular diseases and typically precedes the onset of heart failure. Different endocrine factors such as thyroid hormones, insulin, insulin-like growth factor 1 (IGF-1), angiotensin II (Ang II), endothelin (ET-1), catecholamines, estrogen, among others represent important stimuli to cardiomyocyte hypertrophy. Thus, numerous endocrine disorders manifested as changes in the local environment or multiple organ systems are especially important in the context of progression from cardiac hypertrophy to heart failure. Based on that information, this review summarizes experimental findings regarding the influence of such hormones upon signalling pathways associated with cardiac hypertrophy. Understanding mechanisms through which hormones differentially regulate cardiac hypertrophy could open ways to obtain therapeutic approaches that contribute to prevent or delay the onset of heart failure related to endocrine diseases.

AT1 receptor blockage impairs NF-κB activation mediated by thyroid hormone in cardiomyocytes.

We have previously demonstrated that calcium-binding protein S100A8 and myeloid differentiation factor-88 (MyD88) are important mediators of nuclear transcription factor kappa-B (NF-κB) activation in cardiomyocytes and that signalling molecules are involved in the hypertrophic response that is stimulated by thyroid hormones (TH). Angiotensin II (Ang II), the main active peptide of the renin-angiotensin system (RAS), binds to type 1 Ang II receptor (AT1R) and subsequently promotes cardiac hypertrophy and the inflammatory response with NF-κB activation underlying the cardiovascular effects. Considering the amount of evidence that RAS is an important mediator of TH actions on the cardiovascular system, we aimed to investigate whether cardiac expression of NF-κB and upstream associated molecules could be altered in hyperthyroidism, as well as whether AT1R could mediate the effects of TH on cardiac tissue and in cardiomyocytes in culture. Wistar rats were subjected to hyperthyroidism with or without the AT1R blocker losartan. The TH serum levels, haemodynamic parameters and cardiac mass were assessed to confirm the hyperthyroid status. The S100A8, MyD88 and nuclear NF-κB expression levels were increased in the hearts of the hyperthyroid rats, and the losartan treatment attenuated these TH effects. In addition, the cultured cardiomyocytes that had been stimulated with losartan exhibited blunted S100A8 upregulation and NF-κB activation compared with the TH-treated cells. Together, our results suggest that AT1R participates in TH-induced cardiac hypertrophy partly by mediating S100A8, MyD88 and NF-κB activation via TH. These findings indicate the important crosstalk between TH and RAS, highlighting the participation of AT1R in the triggered mechanisms of TH that contribute to the cardiac hypertrophy response.

Cardiac ACE2/angiotensin 1-7/Mas receptor axis is activated in thyroid hormone-induced cardiac hypertrophy.

OBJECTIVES: Thyroid hormone (TH) promotes marked effects on the cardiovascular system, including the development of cardiac hypertrophy. Some studies have demonstrated that the renin-angiotensin system (RAS) is a key mediator of the cardiac growth in response to elevated TH levels. Although some of the main RAS components are changed in cardiac tissue on hyperthyroid state, the potential modulation of the counter regulatory components of the RAS, such as angiotensin-converting enzyme type 2 (ACE2), angiotensin 1-7 (Ang 1-7) levels and Mas receptor induced by hyperthyroidism is unknown. The aim of this study was to investigate the effect of hyperthyroidism on cardiac Ang 1-7, ACE2 and Mas receptor levels. METHODS: Hyperthyroidism was induced in Wistar rats by daily intraperitoneal injections of T4 for 14 days. RESULTS: Although plasma Ang 1-7 levels were unchanged by hyperthyroidism, cardiac Ang 1-7 levels were increased in TH-induced cardiac hypertrophy. ACE2 enzymatic activity was significantly increased in hearts from hyperthyroid animals, which may be contributing to the higher Ang 1-7 levels observed in the T4 group. Furthermore, elevated cardiac levels of Ang 1-7 levels were accompanied by increased Mas receptor protein levels. CONCLUSION: The counter-regulatory components of the RAS are activated in hyperthyroidism and may be contributing to modulate the cardiac hypertrophy in response to TH.