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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. [ABSTRACT FROM AUTHOR]

Patients with hyperthyroidism exhibit increased risk of development and progression of cardiac diseases. The activation of the Renin Angiotensin System (RAS) has been indirectly implicated in these cardiac effects observed in hyperthyroidism. Angiotensin-(1-7) (Ang-(1- 7)) has previously been shown to counterbalance pathological effects of Angiotensin II (Ang II). The aim of this study was to investigate the effects of elevated circulating Ang-(1-7) levels on cardiac effects promoted by hyperthyroidism in a transgenic rat (TG) model that constitutively overexpress an Ang-(1-7)-producing fusion protein [TGR(A1-7)3292]. TG and wild-type (WT) rats received daily injections (i.p.) of triiodothyronine (T3; 7μg/100g of body weight) or vehicle for 14 days. In contrast to WT rats, the TG rats did not develop cardiac hypertrophy after T3-treatment. Indeed, TG rats displayed reduced systolic blood pressure and cardiac hyperdynamic condition induced by hyperthyroidism. Moreover, increased plasma levels of Ang II observed in hyperthyroid WT rats were prevented in TG rats. TG rats were protected from glycogen synthase kinase 3β (GSK3β) inactivation and nuclear factor of activated T-cells (NFAT) nuclear accumulation induced by T3. In vitro studies evidenced that Ang-(1-7) prevented cardiomyocyte hypertrophy and GSK3β inactivation induced by T3. Taken together, these data reveal an important cardioprotective action of Ang-(1-7) in experimental model of hyperthyroidism. [ABSTRACT FROM AUTHOR]

Patients with hyperthyroidism exhibit increased risk of development and progression of cardiac diseases. The activation of the renin-angiotensin system (RAS) has been indirectly implicated in these cardiac effects observed in hyperthyroidism. Angiotensin-(1-7) (Ang-(1-7)) has previously been shown to counterbalance pathological effects of angiotensin II (Ang II). The aim of the present study was to investigate the effects of elevated circulating Ang-(1-7) levels on cardiac effects promoted by hyperthyroidism in a transgenic rat (TG) model that constitutively overexpresses an Ang-(1-7)-producing fusion protein [TGR(A1-7)3292]. TG and wild-type (WT) rats received daily injections (i.p.) of triiodothyronine (T3; 7 µg/100 g of body weight (BW)) or vehicle for 14 days. In contrast with WT rats, the TG rats did not develop cardiac hypertrophy after T3 treatment. Indeed, TG rats displayed reduced systolic blood pressure (SBP) and cardiac hyperdynamic condition induced by hyperthyroidism. Moreover, increased plasma levels of Ang II observed in hyperthyroid WT rats were prevented in TG rats. TG rats were protected from glycogen synthase kinase 3β (GSK3β) inactivation and nuclear factor of activated T cells (NFAT) nuclear accumulation induced by T3. In vitro studies evidenced that Ang-(1-7) prevented cardiomyocyte hypertrophy and GSK3β inactivation induced by T3. Taken together, these data reveal an important cardioprotective action of Ang-(1-7) in experimental model of hyperthyroidism. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Cardiac hypertrophy (CH) is an adaptive response to maintain cardiac function; however, persistent stress responses lead to contractile dysfunction and heart failure. Although inflammation is involved in these processes, the mechanisms that control cardiac inflammation and hypertrophy still need to be clarified. The NLRP3 inflammasome is a cytosolic multiprotein complex that mediates IL-1β production. The priming step of NLRP3 is essential for increasing the expression of its components and occurs following NF-κB activation. Hyperthyroidism triggers CH, which can progress to maladaptive CH and even heart failure. We have shown in a previous study that thyroid hormone (TH)-induced CH is linked to the upregulation of S100A8, leading to NF-κB activation. Therefore, we aimed to investigate whether the NLRP3 inflammasome is involved in TH-induced CH and its potential role in CH pathophysiology. Hyperthyroidism was induced in NLRP3 knockout (NLRP3-KO), Caspase-1-KO and Wild Type (WT) male mice of the C57Bl/6J strain, aged 8–12 weeks, by triiodothyronine (7 μg/100 g BW, i.p.) administered daily for 14 days. Morphological and cardiac functional analysis besides molecular assays showed, for the first time, that TH-induced CH is accompanied by reduced NLRP3 expression in the heart and that it occurs independently of the NLRP3 inflammasome and caspase 1-related pathways. However, NLRP3 is important for the maintenance of basal cardiac function since NLRP3-KO mice had impaired diastolic function and reduced heart rate, ejection fraction, and fractional shortening compared with WT mice. [ABSTRACT FROM AUTHOR]

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. • Endocrine stimuli can lead to increase of cardiomyocyte volume inducing to a cardiac hypertrophic phenotype. • The development of cardiac hypertrophy by endocrine factors occurs by activation of distinct cellular signaling or multiple interconnected signaling pathways. • Here, some endocrine factors and their signaling pathways responsible for physiological or pathological cardiac hypertrophy are addressed. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Obesity is the major risk factor for several cardiovascular and metabolic disorders. Previous studies reported that deletion of Angiotensin II type 2 receptor (AT2R) protects against metabolic dysfunctions induced by high fat (HF) diet. However, the role of AT2R in obesity-induced cardiac hypertrophy remains unclear. Male AT2R knockout (AT2RKO) and wild type (AT2RWT) mice were fed with control or HF diet for 10 weeks. HF diet increased cardiac expression of AT2R in obese mice. Deletion of AT2R did not affect body weight gain, glucose intolerance and fat mass gain induced by HF feeding. However, loss of AT2R prevented HF diet-induced hypercholesterolemia and cardiac remodeling. Mechanistically, we found that pharmacological inhibition or knockdown of AT2R prevented leptin-induced cardiomyocyte hypertrophy in vitro. Collectively, our results suggest that AT2R is involved in obesity-induced cardiac hypertrophy. • Cardiac expression of AT2R is increased in obese mice. • Loss of AT2R prevented high fat diet-induced hypercholesterolemia. • Loss of AT2R prevented high fat diet-induced cardiac remodeling. • Pharmacological blockage or knockdown of AT2R abolished leptin-induced cardiomyocyte hypertrophy in vitro. [ABSTRACT FROM AUTHOR]

It is well-known that increased thyroid hormone (TH) levels induce cardiomyocyte growth. MicroRNAs (miRNAs) have been identified as key players in cardiomyocyte hypertrophy, which is associated with increased risk of heart failure. In this study, we evaluated the miR-1 expression in TH-induced cardiac hypertrophy, as well as the potential involvement of miR-1 in cardiomyocyte hypertrophy elicited by TH in vitro. The possible role of type 1 angiotensin II receptor (AT1R) in the effect promoted by TH in miR-1 expression was also evaluated. Neonatal rat cardiac myocytes (NRCMs) were treated with T3 for 24 hr and Wistar rats were subjected to hyperthyroidism for 14 days combined or not with AT1R blocker. Real Time RT-PCR analysis indicated that miR-1 expression was decreased in cardiac hypertrophy in response to TH in vitro and in vivo, and this effect was unchanged by AT1R blocker. In addition, HDAC4, which is target of miR-1, was increased in NRCMs after T3 treatment. A gain-of-function study revealed that overexpression of miR-1 prevented T3-induced cardiomyocyte hypertrophy and reduced HADC4 mRNA levels in NRCMs. In vivo experiments confirmed the downregulation of miR-1 in cardiac tissue from hyperthyroid animals, which was accompanied by increased HDAC4 mRNA levels. In addition, HDAC inhibitor prevented T3-induced cardiomyocyte hypertrophy. Our data reveal a new mechanistic insight into cardiomyocyte growth in response to TH, suggesting that miR-1 plays a role in cardiomyocyte hypertrophy induced by TH potentially via targeting HADC4. [ABSTRACT FROM AUTHOR]

Thimet oligopeptidase (EC 3.4.24.15; EP24.15; THOP1) is a potential therapeutic target, as it plays key biological functions in processing biologically functional peptides. The structural conformation of THOP1 provides a unique restriction regarding substrate size, in that it only hydrolyzes peptides (optimally, those ranging from eight to 12 amino acids) and not proteins. The proteasome activity of hydrolyzing proteins releases a large number of intracellular peptides, providing THOP1 substrates within cells. The present study aimed to investigate the possible function of THOP1 in the development of diet-induced obesity (DIO) and insulin resistance by utilizing a murine model of hyperlipidic DIO with both C57BL6 wild-type (WT) and THOP1 null (THOP1−/−) mice. After 24 weeks of being fed a hyperlipidic diet (HD), THOP1−/− and WT mice ingested similar chow and calories; however, the THOP1−/− mice gained 75% less body weight and showed neither insulin resistance nor non-alcoholic fatty liver steatosis when compared to WT mice. THOP1−/− mice had increased adrenergic-stimulated adipose tissue lipolysis as well as a balanced level of expression of genes and microRNAs associated with energy metabolism, adipogenesis, or inflammation. Altogether, these differences converge to a healthy phenotype of THOP1−/− fed a HD. The molecular mechanism that links THOP1 to energy metabolism is suggested herein to involve intracellular peptides, of which the relative levels were identified to change in the adipose tissue of WT and THOP1−/− mice. Intracellular peptides were observed by molecular modeling to interact with both pre-miR-143 and pre-miR-222, suggesting a possible novel regulatory mechanism for gene expression. Therefore, we successfully demonstrated the previously anticipated relevance of THOP1 in energy metabolism regulation. It was suggested that intracellular peptides were responsible for mediating the phenotypic differences that are described herein by a yet unknown mechanism of action. [ABSTRACT FROM AUTHOR]