Intense impact of IL-1ß expressing inflammatory macrophages in acute aortic dissection.

There is no treatment for acute aortic dissection (AAD) targeting inflammatory cells. We aimed to identify the new therapeutic targets associated with inflammatory cells. We characterized the specific distribution of myeloid cells of both human type A AAD samples and a murine AAD model generated using angiotensin II (ANGII) and ß-aminopropionitrile (BAPN) by single-cell RNA sequencing (scRNA-seq). We also examined the effect of an anti-interleukin-1ß (IL-1ß) antibody in the murine AAD model. IL1B+ inflammatory macrophages and classical monocytes were increased in human AAD samples. Trajectory analysis demonstrated that IL1B+ inflammatory macrophages differentiated from S100A8/9/12+ classical monocytes uniquely observed in the aorta of AAD. We found increased infiltration of neutrophils and monocytes with the expression of inflammatory cytokines in the aorta and accumulation of inflammatory macrophages before the onset of macroscopic AAD in the murine AAD model. In blocking experiments using an anti-IL-1ß antibody, it improved survival of murine AAD model by preventing elastin degradation. We observed the accumulation of inflammatory macrophages expressing IL-1ß in both human AAD samples and in a murine AAD model. Anti-IL-1ß antibody could improve the mortality rate in mice, suggesting that it may be a treatment option for AAD.

Graphene Far-Infrared Irradiation Can Effectively Relieve the Blood Pressure Level of Rat Untr-HT in Primary Hypertension.

Graphene, when electrified, generates far-infrared radiation within the wavelength range of 4 µm to 14 µm. This range closely aligns with the far-infrared band (3 µm to 15 µm), which produces unique physiological effects. Contraction and relaxation of vascular smooth muscle play a significant role in primary hypertension, involving the nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate pathway and the renin-angiotensin-aldosterone system. This study utilized spontaneously hypertensive rats (SHRs) as an untr-HT to investigate the impact of far-infrared radiation at specific wavelengths generated by electrified graphene on vascular smooth muscle and blood pressure. After 7 weeks, the blood pressure of the untr-HT group rats decreased significantly with a notable reduction in the number of vascular wall cells and the thickness of the vascular wall, as well as a decreased ratio of vessel wall thickness to lumen diameter. Additionally, blood flow perfusion significantly increased, and the expression of F-actin in vascular smooth muscle myosin decreased significantly. Serum levels of angiotensin II (Ang-II) and endothelin 1 (ET-1) were significantly reduced, while nitric oxide synthase (eNOS) expression increased significantly. At the protein level, eNOS expression decreased significantly, while α-SMA expression increased significantly in aortic tissue. At the gene level, expressions of eNOS and α-SMA in aortic tissue significantly increased. Furthermore, the content of nitric oxide (NO) in the SHR's aortic tissue increased significantly. These findings confirm that graphene far-infrared radiation enhances microcirculation, regulates cytokines affecting vascular smooth muscle contraction, and modifies vascular morphology and smooth muscle phenotype, offering relief for primary hypertension.

The potential role of renin angiotensin system in acute leukemia: a narrative review.

Acute leukemias (ALs) are the most common cancers in pediatric population. There are two types of ALs: acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Some studies suggest that the Renin Angiotensin System (RAS) has a role in ALs. RAS signaling modulates, directly and indirectly, cellular activity in different cancers, affecting tumor cells and angiogenesis. Our review aimed to summarize the role of RAS in ALs and to explore future perspectives for the treatment of these hematological malignancies by modulating RAS molecules. The database including Pubmed, Scopus, Cochrane Library, and Scielo were searched to find articles about RAS molecules in ALL and in pediatric patients. The search terms were "RAS", "Acute Leukemia", "ALL", "Angiotensin-(1-7)", "Pediatric", "Cancer", "Angiotensin II", "AML". In the bone marrow, RAS has been found to play a key role in blood cell formation, affecting several processes including apoptosis, cell proliferation, mobilization, intracellular signaling, angiogenesis, fibrosis, and inflammation. Local tissue RAS modulates tumor growth and metastasis through autocrine and paracrine actions. RAS mainly acts via two molecules, Angiotensin II (Ang II) and Angiotensin (1-7) [Ang-(1-7)]. While Ang II promotes tumor cell growth and stimulates angiogenesis, Ang-(1-7) inhibits the proliferation of neoplastic cells and the angiogenesis, suggesting a potential therapeutic role of this molecule in ALL. The interaction between ALs and RAS reveals a complex network of molecules that can affect the hematopoiesis and the development of hematological cancers. Understanding these interactions could pave the way for innovative therapeutic approaches targeting RAS components.

Structural Features Influencing the Bioactive Conformation of Angiotensin II and Angiotensin A: Relationship between Receptor Desensitization, Addiction, and the Blood-Brain Barrier.

The N-terminal portion of the octapeptide angiotensin II (DRVYIHPF; AngII), a vasopressor peptide that favorably binds to, and activates, AngII type 1 receptor (AT1R), has an important role in maintaining bioactive conformation. It involves all three charged groups, namely (i) the N-terminal amino group cation, (ii) the Asp sidechain anion and (iii) the Arg guanidino cation. Neutralization of any one of these three charged groups results in a substantial reduction (<5%) in bioactivity, implicating a specialized function for this cluster. In contrast, angiotensin A (ARVYIHPF; AngA) has reduced bioactivity at AT1R; however, replacement of Asp in AngII with sarcosine (N-methyl-glycine) not only restores bioactivity but increases the activity of agonist, antagonist, and inverse agonist analogues. A bend produced at the N-terminus by the introduction of the secondary amino acid sarcosine is thought to realign the functional groups that chaperone the C-terminal portion of AngII, allowing transfer of the negative charge originating at the C-terminus to be transferred to the Tyr hydroxyl-forming tyrosinate anion, which is required to activate the receptor and desensitizes the receptor (tachyphylaxis). Peptide (sarilesin) and nonpeptide (sartans) moieties, which are long-acting inverse agonists, appear to desensitize the receptor by a mechanism analogous to tachyphylaxis. Sartans/bisartans were found to bind to alpha adrenergic receptors resulting in structure-dependent desensitization or resensitization. These considerations have provided information on the mechanisms of receptor desensitization/tolerance and insights into possible avenues for treating addiction. In this regard sartans, which appear to cross the blood-brain barrier more readily than bisartans, are the preferred drug candidates.

Fluid transitions.

Water is critical for survival and thirst is a powerful way of ensuring that fluid levels remain in balance. Overconsumption, however, can have deleterious effects, therefore optimization requires a need to balance the drive for water with the satiation of that water drive. This review will highlight our current understanding of how thirst is both generated and quenched, with particular focus on the roles of angiotensin II, glucagon like-peptide 1, and estradiol in turning on and off the thirst drive. Our understanding of the roles these bioregulators play has benefited from modern behavioral analyses, which have improved the time resolution of intake measures, allowing for attention to the details of the patterns within a bout of intake. This has led to behavioral interpretation in ways that are helpful in understanding the many controls of water intake and has expanded our understanding beyond the dichotomy that something which increases water intake is simply a "stimulator" while something that decreases water intake is simply a "satiety" factor. Synthesizing the available information, we describe a framework in which thirst is driven directly by perturbations in fluid intake and indirectly modified by several bioregulators. This allows us to better highlight areas that are in need of additional attention to form a more comprehensive understanding of how the system transitions between states of thirst and satiety.

Periostin regulates lysyl oxidase through ERK1/2 MAPK-dependent serum response factor in activated cardiac fibroblasts.

Collagen crosslinking, mediated by lysyl oxidase, is an adaptive mechanism of the cardiac repair process initiated by cardiac fibroblasts postmyocardial injury. However, excessive crosslinking leads to cardiac wall stiffening, which impairs the contractile properties of the left ventricle and leads to heart failure. In this study, we investigated the role of periostin, a matricellular protein, in the regulation of lysyl oxidase in cardiac fibroblasts in response to angiotensin II and TGFß1. Our results indicated that periostin silencing abolished the angiotensin II and TGFß1-mediated upregulation of lysyl oxidase. Furthermore, the attenuation of periostin expression resulted in a notable reduction in the activity of lysyl oxidase. Downstream of periostin, ERK1/2 MAPK signaling was found to be activated, which in turn transcriptionally upregulates the serum response factor to facilitate the enhanced expression of lysyl oxidase. The periostin-lysyl oxidase association was also positively correlated in an in vivo rat model of myocardial infarction. The expression of periostin and lysyl oxidase was upregulated in the collagen-rich fibrotic scar tissue of the left ventricle. Remarkably, echocardiography data showed a reduction in the left ventricular wall movement, ejection fraction, and fractional shortening, indicative of enhanced stiffening of the cardiac wall. These findings shed light on the mechanistic role of periostin in the collagen crosslinking initiated by activated cardiac fibroblasts. Our findings signify periostin as a possible therapeutic target to reduce excessive collagen crosslinking that contributes to the structural remodeling associated with heart failure.

A new procedure to induce aortic aneurysms in mice.

Aortic aneurysms (AAs) are a major public health challenge, featured by a progressive impairs in aortic wall integrity that drives to aortic dilation and, in end stage, to its rupture. Despite important advances in the surgical treatment of aortic aneurysms, there is currently no pharmacological intervention that prevents their development, reduces their expansion, or avoids their rupture. In addition to classic risk factors such age or gender, several heritable connective tissue disorders have been associated with AA developing, highlighting the role of extracellular matrix (ECM) genes alterations in the developing of AA. In this sense, we have recently demonstrated that global deletion of the cellular communicating network factor 2 (CCN2), previously known as connective tissue growth factor (CTGF) due to its role in the extracellular matrix formation, predisposes to early and lethal AAs development after Angiotensin II (Ang II) infusion in mice. Here, we detail the protocol to induce and detect AAs generation in inducible global CCN2 knockout mice after Ang II infusion which allow the characterization of CCN role in AA development and may help to the development of pharmacological target for AA treatment.

Direct GPCR-EGFR interaction enables synergistic membrane-to-nucleus information transfer.

We addressed the heteromerization of the epidermal growth factor receptor (EGFR) with G-protein coupled receptors (GPCR) on the basis of angiotensin-II-receptor-subtype-1(AT1R)-EGFR interaction as proof-of-concept and show its functional relevance during synergistic nuclear information transfer, beyond ligand-dependent EGFR transactivation. Following in silico modelling, we generated EGFR-interaction deficient AT1R-mutants and compared them to AT1R-wildtype. Receptor interaction was assessed by co-immunoprecipitation (CoIP), Förster resonance energy transfer (FRET) and fluorescence-lifetime imaging microscopy (FLIM). Changes in cell morphology, ERK1/2-phosphorylation (ppERK1/2), serum response factor (SRF)-activation and cFOS protein expression were determined by digital high content microscopy at the single cell level. FRET, FLIM and CoIP confirmed the physical interaction of AT1R-wildtype with EGFR that was strongly reduced for the AT1R-mutants. Responsiveness of cells transfected with AT1R-WT or -mutants to angiotensin II or EGF was similar regarding changes in cell circularity, ppERK1/2 (direct and by ligand-dependent EGFR-transactivation), cFOS-expression and SRF-activity. By contrast, the EGFR-AT1R-synergism regarding these parameters was completely absent for in the interaction-deficient AT1R mutants. The results show that AT1R-EGFR heteromerisation enables AT1R-EGFR-synergism on downstream gene expression regulation, modulating the intensity and the temporal pattern of nuclear AT1R/EGFR-information transfer. Furthermore, remote EGFR transactivation, via ligand release or cytosolic tyrosine kinases, is not sufficient for the complete synergistic control of gene expression.

Expression and significance of pin1 in the wound healing.

The aim of this study is to delineate the expression patterns of prolyl cis-trans isomerase NIMA-interacting protein 1 (Pin1), Glial cell-derived neurotrophic factor (GDNF), and Angiotensin II (ANG II) during the process of wound repair, and to ascertain the effects of Pin1, GDNF, and ANG II on the healing of wounds in a rat model. A total of 18 rats were allocated into three groups-sham (control), DMSO (vehicle control), and Pin1 inhibitor (treatment with juglone)-with six animals in each group. An animal model of wound healing was established, followed by the intraperitoneal administration of juglone. Tissue samples from the wounds were subsequently collected for histopathological evaluation. Expression levels of Pin1, GDNF, and Ang II were quantified. In addition, an in vitro model of wound healing was created using human umbilical vein endothelial cells (HUVEC), to assess cell proliferation, migration, and tube formation under conditions of juglone pre-treatment. The expression levels of Pin1, GDNF, and ANG II were notably elevated on 7-, and 10- days post-wound compared to those measured on 3-day. Contrastingly, pre-treatment with juglone significantly inhibited the expression of these molecules. Histological analyses, including HE (Hematoxylin and Eosin), Masson's trichrome, and EVG (Elastic van Gieson) staining, demonstrated that vascular angiogenesis, as well as collagen and elastin deposition, were substantially reduced in the juglone pre-treated group when compared to the normal group. Further, immunohistochemical analysis revealed a considerable decrease in CD31 expression in the juglone pre-treatment group relative to the normal control group. Pin1 serves as a pivotal facilitator of wound repair. The findings indicate that the modulation of Pin1, GDNF, and ANG II expression impacts the wound healing process in rats, suggesting potential targets for therapeutic intervention in human wound repair.

Carnosol attenuates angiotensin II-induced cardiac remodeling and inflammation via directly binding to p38 and inhibiting p38 activation.

Chronic inflammation is a significant contributor to hypertensive heart failure. Carnosol (Car), primarily derived from the sage plant (Salvia carnosa), exhibits anti-inflammatory properties in a range of systems. Nevertheless, the influence of angiotensin II (Ang II) on cardiac remodeling remains uncharted. Car was shown to protect mice's hearts against Ang II-induced heart damage at dosages of 20 and 40 mg/kg/d. This protection was evident in a concentration-related decrease in the remodeling of the heart and dysfunction. Examination of the transcriptome revealed that the pivotal roles in mediating the protective effects of Car involved inhibiting Ang II-induced inflammation and the activation of the mitogen-activated protein kinase (MAPK) pathway. Furthermore, Car was found to inhibit p38 phosphorylation, therefore reducing the level of inflammation in cultured cardiomyocytes and mouse hearts. This effect was attributed to the direct binding to p38 and inhibition of p38 protein phosphorylation by Car both in vitro and in vivo. In addition, the effects of Car on inflammation were neutralized when p38 was blocked in cardiomyocytes.

Neutrophil extracellular trap-induced ferroptosis promotes abdominal aortic aneurysm formation via SLC25A11-mediated depletion of mitochondrial glutathione.

BACKGROUND: Neutrophil extracellular traps (NETs) induce oxidative stress, which may initiate ferroptosis, an iron-dependent programmed cell death, during abdominal aortic aneurysm (AAA) formation. Mitochondria regulate the progression of ferroptosis, which is characterized by the depletion of mitochondrial glutathione (mitoGSH) levels. However, the mechanisms are poorly understood. This study examined the role of mitoGSH in regulating NET-induced ferroptosis of smooth muscle cells (SMCs) during AAA formation. METHODS: Concentrations of NET markers were tested in plasma samples. Western blotting and immunofluorescent staining were performed to detect the expression and localization of NET and ferroptosis markers in tissue samples. The role of NETs and SMC ferroptosis during AAA formation was investigated using peptidyl arginine deiminase 4 gene (Padi4) knockout or treatment with a PAD4 inhibitor, ferroptosis inhibitor or activator in an angiotensin II-induced AAA mouse model. The regulatory effect of SLC25A11, a mitochondrial glutathione transporter, on mitoGSH and NET-induced ferroptosis of SMCs was investigated using in vitro and in vivo experiments. Transmission electron microscopy was used to detect mitochondrial damage. Blue native polyacrylamide gel electrophoresis was used to analyze the dimeric and monomeric forms of the protein. RESULTS: Significantly elevated levels of NETosis and ferroptosis markers in aortic tissue samples were observed during AAA formation. Specifically, NETs promoted AAA formation by inducing ferroptosis of SMCs. Subsequently, SLC25A11 was identified as a potential biomarker for evaluating the clinical prognosis of patients with AAA. Furthermore, NETs decreased the stability and dimerization of SLC25A11, leading to the depletion of mitoGSH. This depletion induced the ferroptosis of SMCs and promoted AAA formation. CONCLUSION: During AAA formation, NETs regulate the stability of the mitochondrial carrier protein SLC25A11, leading to the depletion of mitoGSH and subsequent activation of NET-induced ferroptosis of SMCs. Preventing mitoGSH depletion and ferroptosis in SMCs is a potential strategy for treating AAA.

Role of angiotensin II in cellular entry and replication of dengue virus.

Previous studies have demonstrated the relevance of several soluble molecules in the pathogenesis of dengue. In this regard, a possible role for angiotensin II (Ang II) in the pathophysiology of dengue has been suggested by the observation of a blockade of Ang II in patients with dengue, increased expression of molecules related to Ang II production in the plasma of dengue patients, increased expression of circulating cytokines and soluble molecules related to the action of Ang II, and an apparent relationship between DENV, Ang II effects, and miRNAs. In addition, in ex vivo experiments, the blockade of Ang II AT1 receptor and ACE-1 (angiotensin converting enzyme 1), both of which are involved in Ang II production and its function, inhibits infection of macrophages by DENV, suggesting a role of Ang II in viral entry or in intracellular viral replication of the virus. Here, we discuss the possible mechanisms of Ang II in the entry and replication of DENV. Ang II has the functions of increasing the expression of DENV entry receptors, creation of clathrin-coated vesicles, and increasing phagocytosis, all of which are involved in DENV entry. This hormone also modulates the expression of the Rab5 and Rab7 proteins, which are important in the endosomal processing of DENV during viral replication. This review summarizes the data related to the possible involvement of Ang II in the entry of DENV into cells and its replication.

Baicalin alleviates angiotensin II-induced cardiomyocyte apoptosis and autophagy and modulates the AMPK/mTOR pathway.

As a main extraction compound from Scutellaria baicalensis Georgi, Baicalin exhibits various biological activities. However, the underlying mechanism of Baicalin on hypertension-induced heart injury remains unclear. In vivo, mice were infused with angiotensin II (Ang II; 500 ng/kg/min) or saline using osmotic pumps, followed by intragastrically administrated with Baicalin (5 mg/kg/day) for 4 weeks. In vitro, H9C2 cells were stimulated with Ang II (1 µM) and treated with Baicalin (12.5, 25 and 50 µM). Baicalin treatment significantly attenuated the decrease in left ventricular ejection fraction and left ventricular fractional shortening, increase in left ventricular mass, left ventricular systolic volume and left ventricular diastolic volume of Ang II infused mice. Moreover, Baicalin treatment reversed 314 differentially expressed transcripts in the cardiac tissues of Ang II infused mice, and enriched multiple enriched signalling pathways (including apoptosis, autophagy, AMPK/mTOR signalling pathway). Consistently, Baicalin treatment significantly alleviated Ang II-induced cell apoptosis in vivo and in vitro. Baicalin treatment reversed the up-regulation of Bax, cleaved-caspase 3, cleaved-caspase 9, and the down-regulation of Bcl-2. Meanwhile, Baicalin treatment alleviated Ang II-induced increase of autophagosomes, restored autophagic flux, and down-regulated LC3II, Beclin 1, as well as up-regulated SQSTM1/p62 expression. Furthermore, autophagy inhibitor 3-methyladenine treatment alleviated the increase of autophagosomes and the up-regulation of Beclin 1, LC3II, Bax, cleaved-caspase 3, cleaved-caspase 9, down-regulation of SQSTM1/p62 and Bcl-2 expression after Ang II treated, which similar to co-treatment with Baicalin. Baicalin treatment reduced the ratio of p-AMPK/AMPK, while increased the ratio of p-mTOR/mTOR. Baicalin alleviated Ang II-induced cardiomyocyte apoptosis and autophagy, which might be related to the inhibition of the AMPK/mTOR pathway.

Angiotensin II participates in mitochondrial thermogenic functions via the activation of glycolysis in chemically induced human brown adipocytes.

Brown adipocytes are potential therapeutic targets for the prevention of obesity-associated metabolic diseases because they consume circulating glucose and fatty acids for heat production. Angiotensin II (Ang II) peptide is involved in the pathogenesis of obesity- and cold-induced hypertension; however, the mechanism underlying the direct effects of Ang II on human brown adipocytes remains unclear. Our transcriptome analysis of chemical compound-induced brown adipocytes (ciBAs) showed that the Ang II type 1 receptor (AGTR1), but not AGTR2 and MAS1 receptors, was expressed. The Ang II/AGTR1 axis downregulated the expression of mitochondrial uncoupling protein 1 (UCP1). The simultaneous treatment with ß-adrenergic receptor agonists and Ang II attenuated UCP1 expression, triglyceride lipolysis, and cAMP levels, although cAMP response element-binding protein (CREB) phosphorylation was enhanced by Ang II mainly through the protein kinase C pathway. Despite reduced lipolysis, both coupled and uncoupled mitochondrial respiration was enhanced in Ang II-treated ciBAs. Instead, glycolysis and glucose uptake were robustly activated upon treatment with Ang II without a comprehensive transcriptional change in glucose metabolic genes. Elevated mitochondrial energy status induced by Ang II was likely associated with UCP1 repression. Our findings suggest that the Ang II/AGTR1 axis participates in mitochondrial thermogenic functions via glycolysis.

DNA methylation-mediated 11ßHSD2 downregulation drives the increases in angiotensin-converting enzyme and angiotensin II within preeclamptic placentas.

Preeclampsia (PE) is a complex human-specific complication frequently associated with placental pathology. The local renin-angiotensin system (RAS) in the human placenta, which plays a crucial role in regulating placental function, has been extensively documented. Glucocorticoids (GCs) are a class of steroid hormones. PE cases often have abnormalities in GCs levels and placental GCs barrier. Despite extensive speculation, there is currently no robust evidence indicating that GCs regulate placental RAS. This study aims to investigate these potential relationships. Plasma and placental samples were collected from both normal and PE pregnancies. The levels of angiotensin-converting enzyme (ACE), angiotensin II (Ang II), cortisol, and 11ß-hydroxysteroid dehydrogenases (11ßHSD) were analyzed. In PE placentas, cortisol, ACE, and Ang II levels were elevated, while 11ßHSD2 expression was reduced. Interestingly, a positive correlation was observed between ACE and cortisol levels in the placenta. A significant inverse correlation was found between the methylation statuses within the 11ßHSD2 gene promoter and its expression, meanwhile, 11ßHSD2 expression was negatively correlated with cortisol and ACE levels. In vitro experiments using placental trophoblast cells confirmed that active GCs can stimulate ACE transcription and expression through the GR pathway. Furthermore, 11ßHSD2 knockdown could enhance this activating effect. An in vivo study using a rat model of intrauterine GCs overexposure during mid-to-late gestation suggested that excess GCs in utero lead to increased ACE and Ang II levels in the placenta. Collectively, this study provides the first evidence of the relationships between 11ßHSD2 expression, GCs barrier, ACE, and Ang II levels in the placenta. It not only contributes to understanding the pathological features of the placental GCs barrier and RAS under PE conditions, also provides important information for revealing the pathological mechanism of PE.

Role of Vasoactive Hormone-Induced Signal Transduction in Cardiac Hypertrophy and Heart Failure.

Heart failure is the common concluding pathway for a majority of cardiovascular diseases and is associated with cardiac dysfunction. Since heart failure is invariably preceded by adaptive or maladaptive cardiac hypertrophy, several biochemical mechanisms have been proposed to explain the development of cardiac hypertrophy and progression to heart failure. One of these includes the activation of different neuroendocrine systems for elevating the circulating levels of different vasoactive hormones such as catecholamines, angiotensin II, vasopressin, serotonin and endothelins. All these hormones are released in the circulation and stimulate different signal transduction systems by acting on their respective receptors on the cell membrane to promote protein synthesis in cardiomyocytes and induce cardiac hypertrophy. The elevated levels of these vasoactive hormones induce hemodynamic overload, increase ventricular wall tension, increase protein synthesis and the occurrence of cardiac remodeling. In addition, there occurs an increase in proinflammatory cytokines and collagen synthesis for the induction of myocardial fibrosis and the transition of adaptive to maladaptive hypertrophy. The prolonged exposure of the hypertrophied heart to these vasoactive hormones has been reported to result in the oxidation of catecholamines and serotonin via monoamine oxidase as well as the activation of NADPH oxidase via angiotensin II and endothelins to promote oxidative stress. The development of oxidative stress produces subcellular defects, Ca2+-handling abnormalities, mitochondrial Ca2+-overload and cardiac dysfunction by activating different proteases and depressing cardiac gene expression, in addition to destabilizing the extracellular matrix upon activating some metalloproteinases. These observations support the view that elevated levels of various vasoactive hormones, by producing hemodynamic overload and activating their respective receptor-mediated signal transduction mechanisms, induce cardiac hypertrophy. Furthermore, the occurrence of oxidative stress due to the prolonged exposure of the hypertrophied heart to these hormones plays a critical role in the progression of heart failure.

The mechanical mechanism of angiotensin II induced activation of hepatic stellate cells promoting portal hypertension.

In the development of chronic liver disease, the hepatic stellate cell (HSC) plays a pivotal role in increasing intrahepatic vascular resistance (IHVR) and inducing portal hypertension (PH) in cirrhosis. Our research demonstrated that HSC contraction, prompted by angiotensin II (Ang II), significantly contributed to the elevation of type I collagen (COL1A1) expression. This increase was intimately associated with enhanced cell tension and YAP nuclear translocation, mediated through α-smooth muscle actin (α-SMA) expression, microfilaments (MF) polymerization, and stress fibers (SF) assembly. Further investigation revealed that the Rho/ROCK signaling pathway regulated MF polymerization and SF assembly by facilitating the phosphorylation of cofilin and MLC, while Ca2+ chiefly governed SF assembly via MLC. Inhibiting α-SMA-MF-SF assembly changed Ang II-induced cell contraction, YAP nuclear translocation, and COL1A1 expression, findings corroborated in cirrhotic mice models. Overall, our study offers insights into mitigating IHVR and PH through cell mechanics, heralding potential breakthroughs.

Mechanism of Astragalus membranaceus (Huangqi, HQ) for treatment of heart failure based on network pharmacology and molecular docking.

Heart failure is a leading cause of death in the elderly. Traditional Chinese medicine, a verified alternative therapeutic regimen, has been used to treat heart failure, which is less expensive and has fewer adverse effects. In this study, a total of 15 active ingredients of Astragalus membranaceus (Huangqi, HQ) were obtained; among them, Isorhamnetin, Quercetin, Calycosin, Formononetin, and Kaempferol were found to be linked to heart failure. Ang II significantly enlarged the cell size of cardiomyocytes, which could be partially reduced by Quercetin, Isorhamnetin, Calycosin, Kaempferol, or Formononetin. Ang II significantly up-regulated ANP, BNP, ß-MHC, and CTGF expressions, whereas Quercetin, Isorhamnetin, Calycosin, Kaempferol or Formononetin treatment partially downregulated ANP, BNP, ß-MHC and CTGF expressions. Five active ingredients of HQ attenuated inflammation in Ang II-induced cardiomyocytes by inhibiting the levels of TNF-α, IL-1ß, IL-18 and IL-6. Molecular docking shows Isorhamnetin, Quercetin, Calycosin, Formononetin and Kaempferol can bind with its target protein ESR1 in a good bond by intermolecular force. Quercetin, Calycosin, Kaempferol or Formononetin treatment promoted the expression levels of ESR1 and phosphorylated ESR1 in Ang II-stimulated cardiomyocytes; however, Isorhamnetin treatment had no effect on ESR1 and phosphorylated ESR1 expression levels. In conclusion, our results comprehensively illustrated the bioactives, potential targets, and molecular mechanism of HQ against heart failure. Isorhamnetin, Quercetin, Calycosin, Formononetin and Kaempferol might be the primary active ingredients of HQ, dominating its cardioprotective effects against heart failure through regulating ESR1 expression, which provided a basis for the clinical application of HQ to regulate cardiac hypertrophy and heart failure.

The roles of angiotensin-converting enzyme 2 inhibitor, melatonin and its agonist on angiotensin II reactivity in intact and denuded rat aortic rings.

BACKGROUND: The pineal product melatonin (MEL) modulates blood vessels through G protein-coupled receptors (GPCRs) called melatonin type 1 receptor (MT1R) and melatonin type 2 receptor (MT2R), in that order. The renin-angiotensin system (RAS), which breaks down angiotensin II (Ang II) to create Ang 1-7, is thought to be mostly controlled by angiotensin-converting enzyme-2 (ACE2). AIM: The current work examines the involvement of ACE2 inhibitor, MEL, and ramelteon (RAM) in the vascular response to Ang II activities in the endothelial denuded (E-) and intact (E+) rat isolated thoracic aortic rings. METHOD: The isometric tension was measured to evaluate the vascular Ang II contractility using dose response curve (DRC). RESULTS: MEL and RAM caused a rightward shift of Ang II in endothelium E + and endothelium E- aorta. CONCLUSION: According to the current study, the distribution of MEL receptors and the endothelium's condition are related to the vasomodulatory effect of MEL and ACE2 on Ang II attenuation. These physiological interactions can control vascular tone and increase Ang II reactivity denude endothelial layaer.

Apelin-13: a novel approach to suppressing renin production in RVHT.

Renovascular hypertension (RVHT) is characterized by renal artery stenosis and overactivated renin-angiotensin system (RAS). Apelin, known for its negative modulation of RAS, has protective effects against cardiovascular diseases. The role and mechanisms of the primary active form of apelin, apelin-13, in RVHT are unclear. In this study, male Sprague-Dawley rats were divided into control, two-kidney one-clip (2K1C) model, and 2K1C with apelin-13 treatment groups. Renin expression was analyzed using immunohistochemistry and molecular techniques. Full-length (pro)renin receptor (fPRR) and soluble PRR (sPRR) levels were assessed via Western blotting, and cAMP levels were measured using ELISA. Plasma renin content, plasma renin activity (PRA), angiotensin II (ANG II), and sPRR levels were determined by ELISA. Human Calu-6 and mouse As4.1 cells were used to investigate renin production mechanisms. The 2K1C model exhibited increased systolic blood pressure, plasma renin content, PRA, sPRR, and ANG II levels, while apelin-13 treatment reduced these elevations. Apelin-13 inhibited cAMP production, renin mRNA expression, protein synthesis, and PRR/sPRR protein expression in renal tissue. In Calu-6 cells, cAMP-induced fPRR and site-1 protease (S1P)-derived sPRR expression, which was blocked by cAMP-responsive element-binding protein (CREB) inhibition. Apelin-13 suppressed cAMP elevation, CREB phosphorylation, fPRR/sPRR protein expression, and renin production. Recombinant sPRR (sPRR-His) stimulated renin production, which was inhibited by the PRR decoy peptide PRO20 and S1P inhibitor PF429242. These findings suggest that apelin-13 inhibits plasma renin expression through the cAMP/PKA/sPRR pathway, providing a potential therapeutic approach for RVHT. Understanding the regulation of renin production is crucial for developing effective treatments.NEW & NOTEWORTHY Our research elucidated that apelin-13 inhibits renin production through the cAMP/PKA/soluble (pro)renin receptor pathway, presenting a promising therapeutic approach for renovascular hypertension (RVHT) by targeting renin expression mechanisms. These findings underscore the potential of apelin-13 as a novel strategy to address RVHT.