Cardiac hypertrophy that affects hyperthyroidism occurs independently of the NLRP3 inflammasome.

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-1ß 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.

Genetic deletion of the alamandine receptor MRGD leads to dilated cardiomyopathy in mice.

We have recently described a new peptide of the renin-angiotensin system, alamandine, a derivative of angiotensin-(1-7). Mas-related G protein-coupled receptor member D (MrgD) was identified as its receptor. Although similar cardioprotective effects of alamandine to those of angiotensin-(1-7) have been described, the significance of this peptide in heart function is still elusive. We aimed to evaluate the functional role of the alamandine receptor MrgD in the heart using MrgD-deficient mice. MrgD was localized in cardiomyocytes by immunofluorescence using confocal microscopy. High-resolution echocardiography was performed in wild-type and MrgD-deficient mice (2 and 12 wk old) under isoflurane anesthesia. Standard B-mode images were obtained in the right and left parasternal long and short axes for morphological and functional assessment and evaluation of cardiac deformation. Additional heart function evaluation was performed using Langendorff isolated heart preparations and inotropic measurements of isolated cardiomyocytes. Immunofluorescence indicated that the MrgD receptor is expressed in cardiomyocytes, mainly in the membrane and perinuclear and nuclear regions. Echocardiography showed left ventricular remodeling and severe dysfunction in MrgD-deficient mice. Strikingly, MrgD-deficient mice presented a pronounced dilated cardiomyopathy with a marked decrease in systolic function. Echocardiographic changes were supported by the data obtained in isolated hearts and inotropic measurements in cardiomyocytes. Our data add new evidence for a major role for alamandine/MrgD in the heart. Furthermore, our results indicate that we have identified a new gene implicated in dilated cardiomyopathy, unveiling a new target for translational approaches aimed to treat heart diseases. NEW & NOTEWORTHY The renin-angiotensin system is a key target for cardiovascular therapy. We have recently identified a new vasodepressor/cardioprotective angiotensin, alamandine. Here, we unmasked a key role for its receptor, Mas-related G protein-coupled receptor member D (MrgD), in heart function. The severe dilated cardiomyopathy observed in MrgD-deficient mice warrants clinical and preclinical studies to unveil its potential use in cardiovascular therapy.

Brown adipose tissue transcriptome unveils an important role of the Beta-alanine/alamandine receptor, MrgD, in metabolism.

Alamandine is a recently described heptapeptide component of the renin-angiotensin system (RAS), and its effects are mediated by the receptor Mas-related G protein-coupled receptor D (MrgD) RAS represents an important link between obesity and its consequences by directly modulating the thermogenesis and brown adipose tissue (BAT) function. The alamandine/MrgD metabolic effects and signaling remain unexplored. In this context, the main goal of the present study was to assess the metabolic consequences of MrgD genetic ablation in C57BL6/J mice by evaluating brown adipose tissue RNA sequencing. The main results showed that MrgD-KO mice have diminished brown adipose tissue and that a high-glucose diet (HG) decreased both circulating alamandine levels and MrgD expression in BAT from wild-type mice (WT). BAT transcriptome reveals that MrgD-KO HG mice regulated 45 genes, while WT HG mice regulated 1,148 genes. MrgD-KO mice fed a standard diet (ST) compared with WT ST mice regulated 476 genes, of which 445 genes were downregulated. BAT uses the MrgD receptor to display a normal pattern of gene expression and to respond, like WT mice, to an HG diet. In conclusion, the MrgD signaling is important for the metabolic regulation and manutention of BAT functionality.

Maternal obesity modulates both the renin-angiotensin system in mice dams and fetal adiposity.

Obesity is a chronic multifactorial disease and is currently a public health problem. Maternal obesity during pregnancy is more dangerous as it impairs the health of the mother and future generations. Obesity leads to several metabolic disorders. Since white adipose tissue is an endocrine tissue, obesity often leads to disordered secretion of inflammatory, glycemic, lipid and renin-angiotensin system (RAS) components. The RAS represents a link between obesity and its metabolic consequences. Therefore, our goal was to evaluate the possible changes caused by a high-fat diet in RAS-related receptor expression in the uterus and placenta of pregnant mice and determine the underlying effects of these changes in the fetuses' body composition. Breeding groups were formed after obesity induction by high-fat (HF) diet. Dams and fetuses were euthanized on the 19th day of the gestational period. The HF diet effectively induced obesity, glucose intolerance and insulin resistance in mice. Fetuses born from HF dams showed increased body weight and adiposity. Both results were accompanied by increased AT1R expression in placenta and uterus together with increased angiotensin-converting enzyme expression in the uterus and a decreased expression of MAS1 in placenta of HF dams. These results suggest a link between RAS, maternal obesity induced by HF diet and the fetuses' body adiposity. This new path now can be more thoroughly explored.

Sclareol-loaded lipid nanoparticles improved metabolic profile in obese mice.

Sclareol is a bioactive hydrophobic diterpene in the essential oil isolated from Salvia sclarea (Fam. Lamiaceae). Sclareol has been widely studied due to its anti-inflammatory and antioxidant effects. AIMS: The present study aimed to evaluate the effects of Sclareol in different formulations (solid lipid nanoparticle and free) on the metabolic profile of obese mice. MAIN METHODS: Swiss male mice were randomly divided into two groups: standard diet (STD) and high-fat diet (HFD). After obesity induction, each group was divided into three treatment groups: free Sclareol (Sc), Sclareol-loaded lipid nanoparticle (L-Sc) and blank lipid nanoparticle (L). Treatments were performed every day during 30 days. KEY FINDINGS: L-Sc improves obese mice metabolic profile by decreasing adiposity, ameliorating insulin sensitivity, glucose tolerance and increasing the HDL plasma levels. In addition, L-Sc decreased the expression of NF-KB, MCP-1 and SERBP-1. SIGNIFICANCE: The use of sclareol together with lipid nanocarriers may be promising for the treatment of metabolic disorders by reducing adipose tissue.