RESUMO
The gut microbiome is an emerging factor in preventing hypertension, yet the influence of gut bacteriophages, viruses infecting bacteria, on this condition remains unclear. Bacteriophage-bacteria interactions, which impact the gut microbiome, are influenced differentially by temperate and virulent bacteriophages. However, the standard technique for studying viral populations, viral-like particles (VLPs)-metagenomes, often overlook prophages, the intracellular stage of temperate bacteriophages, creating a knowledge gap. To address this, we investigated alterations in extracellular and intracellular bacteriophages, alongside bacterial populations, in the angiotensin II-hypertension model. We sequenced VLPs and bulk DNA from cecal-colonic samples collected from male C57BL/6J mice implanted with minipumps containing saline or angiotensin II. We assembled 106 bacterial and 816 viral genomes and found that gut viral and bacterial populations remained stable between hypertensive and normotensive mice. A higher number of temperate viruses were observed across all treatments. Although temperate viruses outnumbered virulent viruses, sequencing of both VLPs and bulk revealed that virions from virulent viruses were more abundant in the murine gut. We then evaluated the impact of low- and high-fiber intake on gut microbiome composition in the angiotensin II model. Fiber intake significantly influenced the gut microbiome composition and hypertension development. Mice receiving high-fiber had lower blood pressure, a higher bacterial-encoded carbohydrate-associated enzyme, and a higher total relative abundance of temperate viruses than those receiving low-fiber. Our findings suggest that phages are not associated with hypertension development in the angiotensin II model. However, they support a complex diet-bacteria/phage interaction that may be involved in blood pressure regulation.
Assuntos
Bactérias , Bacteriófagos , Fibras na Dieta , Modelos Animais de Doenças , Microbioma Gastrointestinal , Hipertensão , Camundongos Endogâmicos C57BL , Animais , Fibras na Dieta/administração & dosagem , Camundongos , Masculino , Hipertensão/virologia , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Bacteriófagos/fisiologia , Bacteriófagos/genética , Angiotensina II/metabolismo , Genoma ViralRESUMO
Renovascular hypertension (RH), a secondary hypertension, can significantly impact heart health, resulting in heart damage and dysfunction, thereby elevating the risk of cardiovascular diseases. Coniferol (CA), which has vascular relaxation properties, is expected to be able to treat hypertension-related diseases. However, its potential effects on cardiac function after RH remain unclear. In this study, in combination with network pharmacology, the antihypertensive and cardioprotective effects of CA in a two-kidney, one-clip (2K1C) mice model and its ability to mitigate angiotensin II (Ang II)-induced hypertrophy in H9C2 cells were investigated. The findings revealed that CA effectively reduced blood pressure, myocardial tissue damage, and inflammation after RH. The possible targets of CA for RH treatment were screened by network pharmacology. The interleukin-17 (IL-17) and tumor necrosis factor (TNF) signaling pathways were identified using a Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. The inflammatory response was identified using a Gene Ontology (GO) enrichment analysis. Western blot analysis confirmed that CA reduced the expression of IL-17, matrix metallopeptidase 9 (MMP9), cyclooxygenase 2 (COX2), and TNF α in heart tissues and the H9C2 cells. In summary, CA inhibited cardiac inflammation and fibrohypertrophy following RH. This effect was closely linked to the expression of MMP9/COX2/TNF α/IL-17. This study sheds light on the therapeutic potential of CA for treating RH-induced myocardial hypertrophy and provides insights into its underlying mechanisms, positioning CA as a promising candidate for future drug development.
Assuntos
Hipertensão Renovascular , Farmacologia em Rede , Animais , Hipertensão Renovascular/tratamento farmacológico , Hipertensão Renovascular/metabolismo , Hipertensão Renovascular/patologia , Camundongos , Masculino , Modelos Animais de Doenças , Metaloproteinase 9 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Linhagem Celular , Ciclo-Oxigenase 2/metabolismo , Ciclo-Oxigenase 2/genética , Fator de Necrose Tumoral alfa/metabolismo , Ratos , Interleucina-17/metabolismo , Angiotensina II/metabolismo , Transdução de Sinais/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Camundongos Endogâmicos C57BLRESUMO
This study aimed to explore whether m6A modification affects the biogenesis of circRBM33, which is involved in the progression of abdominal aortic aneurysm (AAA). For in vitro experiments, vascular smooth muscle cells (VSMCs) were treated with Ang II. MeRIPâPCR was used to assess m6A modification of circRBM33. Gene expression was measured using RTâqPCR and Western blotting. For in vivo experiments, a mouse model of AAA was established via Ang II infusion. HE, Sirius Red and TUNEL staining was performed to evaluate pathological changes and cell apoptosis in aortic vessels. The results showed that the m6A level of circRBM33 was abnormally increased in Ang II-induced VSMCs. In addition, METTL3 positively regulated circRBM33 expression. YTHDC1 deficiency decreased circRBM33 expression but had no effect on RBM33 mRNA expression. Notably, neither METTL3 nor YTHDC1 influenced the stability of circRBM33 or RBM33 mRNA. The interaction between circRBM33 and METTL3/YTHDC1 was verified by RIP analysis. Moreover, the Ang II-induced increase in circRBM33 expression was reversed by cycloleucine (an inhibitor of m6A methylation). Importantly, the m6A modification and expression of circRBM33 in the circRBM33-m6A-mut2-expressing VSMCs were not altered by METTL3 silencing. Mechanistically, METTL3/YTHDC1 modulates the biogenesis of circRBM33 in an m6A-dependent manner. In addition, circRBM33 knockdown alleviated AAA by reducing ECM degradation in the Ang II-infused mice. In conclusion, this study demonstrated that METTL3/YTHDC1-mediated m6A modification modulates the biogenesis of circRBM33 from exons of the RBM33 gene. Moreover, knockdown of circRBM33 alleviated AAA by reducing ECM degradation, which may provide a novel therapeutic strategy for treating AAA.
Assuntos
Adenosina , Aneurisma da Aorta Abdominal , Metiltransferases , Músculo Liso Vascular , Animais , Humanos , Masculino , Camundongos , Adenosina/análogos & derivados , Adenosina/metabolismo , Angiotensina II/metabolismo , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/genética , Aneurisma da Aorta Abdominal/patologia , Metiltransferases/metabolismo , Metiltransferases/genética , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , RNA Circular/genética , RNA Circular/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genéticaRESUMO
Every individual at some point encounters the progressive biological process of aging, which is considered one of the major risk factors for common diseases. The main drivers of aging are oxidative stress, senescence, and reactive oxygen species (ROS). The renin-angiotensin-aldosterone system (RAAS) includes several systematic processes for the regulation of blood pressure, which is caused by an imbalance of electrolytes. During activation of the RAAS, binding of angiotensin II (ANG II) to angiotensin II type 1 receptor (AGTR1) activates intracellular nicotinamide adenine dinucleotide phosphate (NADPH) oxidase to generate superoxide anions and promote uncoupling of endothelial nitric oxide (NO) synthase, which in turn decreases NO availability and increases ROS production. Promoting oxidative stress and DNA damage mediated by ANG II is tightly regulated. Individuals with sodium deficiency-associated diseases such as Gitelman syndrome (GS) and Bartter syndrome (BS) show downregulation of inflammation-related processes and have reduced oxidative stress and ROS. Additionally, the histone deacetylase sirtuin-1 (SIRT1) has a significant impact on the aging process, with reduced activity with age. However, GS/BS patients generally sustain higher levels of sirtuin-1 (SIRT1) activity than age-matched healthy individuals. SIRT1 expression in GS/BS patients tends to be higher than in healthy age-matched individuals; therefore, it can be assumed that there will be a trend towards healthy aging in these patients. In this review, we highlight the importance of the hallmarks of aging, inflammation, and the RAAS system in GS/BS patients and how this might impact healthy aging. We further propose future research directions for studying the etiology of GS/BS at the molecular level using patient-derived renal stem cells and induced pluripotent stem cells.
Assuntos
Envelhecimento , Estresse Oxidativo , Sistema Renina-Angiotensina , Sirtuína 1 , Humanos , Sistema Renina-Angiotensina/fisiologia , Envelhecimento/metabolismo , Sirtuína 1/metabolismo , Sirtuína 1/genética , Espécies Reativas de Oxigênio/metabolismo , Síndrome de Gitelman/metabolismo , Síndrome de Gitelman/genética , Síndrome de Bartter/metabolismo , Síndrome de Bartter/genética , Sódio/metabolismo , Angiotensina II/metabolismoRESUMO
Different ligands stabilize specific conformations of the angiotensin II type 1 receptor (AT1R) that direct distinct signaling cascades mediated by heterotrimeric G proteins or ß-arrestin. These different active conformations are thought to engage distinct intracellular transducers because of differential phosphorylation patterns in the receptor C-terminal tail (the "barcode" hypothesis). Here, we identified the AT1R barcodes for the endogenous agonist AngII, which stimulates both G protein activation and ß-arrestin recruitment, and for a synthetic biased agonist that only stimulates ß-arrestin recruitment. The endogenous and ß-arrestin-biased agonists induced two different ensembles of phosphorylation sites along the C-terminal tail. The phosphorylation of eight serine and threonine residues in the proximal and middle portions of the tail was required for full ß-arrestin functionality, whereas phosphorylation of the serine and threonine residues in the distal portion of the tail had little influence on ß-arrestin function. Similarly, molecular dynamics simulations showed that the proximal and middle clusters of phosphorylated residues were critical for stable ß-arrestin-receptor interactions. These findings demonstrate that ligands that stabilize different receptor conformations induce different phosphorylation clusters in the C-terminal tail as barcodes to evoke distinct receptor-transducer engagement, receptor trafficking, and signaling.
Assuntos
Receptor Tipo 1 de Angiotensina , Transdução de Sinais , beta-Arrestinas , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor Tipo 1 de Angiotensina/química , Receptor Tipo 1 de Angiotensina/genética , Fosforilação , Humanos , beta-Arrestinas/metabolismo , beta-Arrestinas/genética , Células HEK293 , Simulação de Dinâmica Molecular , Angiotensina II/metabolismoRESUMO
Metabolic dysfunction-associated steatohepatitis (MASH) confers a risk for cardiovascular diseases in patients. Animal models may help exploring the mechanisms linking liver and heart diseases. Hence, we explored the cardiac phenotype in two MASH mouse models: foz/foz mice fed a high-fat diet (HFD) for 24 or 60 weeks and C57BL/6J mice fed a high-fat-, high-cholesterol-, and high-fructose diet for 60 weeks. Angiotensin II (AngII) was used as an additional cardiovascular stressor for 4 weeks in 10 weeks HFD-fed foz/foz mice. Foz/foz mice with fibrosing MASH developed cardiac hypertrophy with adverse cardiac remodelling not seen in WT similarly fed the HFD. AngII caused hypertension and up-regulated the expression of genes contributing to pathological cardiac hypertrophy (Nppa, Myh7) more severely so in foz/foz mice than in controls. After 60 weeks of HFD, while liver disease had progressed to burn-out non steatotic MASH with hepatocellular carcinoma in 50% of the animals, the cardiomyopathy did not. In an independent model (C57BL/6J mice fed a fat-, cholesterol- and fructose-rich diet), moderate fibrosing MASH is associated with cardiac fibrosis and dysregulation of genes involved in pathological remodelling (Col1a1, Col3a1, Vim, Myh6, Slc2a1). Thus, animals with MASH present consistent adverse structural changes in the heart with no patent alteration of cardiac function even when stressed with exogenous AngII. Liver disease, and likely not overfeeding or aging alone, is associated with this cardiac phenotype. Our findings support foz/foz mice as suitable for studying links between MASH and heart structural changes ahead of heart failure.
Assuntos
Cardiomegalia , Dieta Hiperlipídica , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Remodelação Ventricular , Animais , Dieta Hiperlipídica/efeitos adversos , Cardiomegalia/fisiopatologia , Cardiomegalia/patologia , Cardiomegalia/etiologia , Cardiomegalia/metabolismo , Angiotensina II/metabolismo , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Fígado Gorduroso/patologia , Fígado Gorduroso/fisiopatologia , Fígado Gorduroso/metabolismoRESUMO
Myocardial fibroblasts transform into myofibroblasts during the progression of cardiac fibrosis, together with excessive cardiac fibroblast proliferation. Hence, the prevention and treatment of cardiac fibrosis are significant factors for inhibiting the development of heart failure. P-element Induced WImpy testis-interacting RNAs (PiRNA) are widely expressed in the heart, but their involvement in cardiac fibrosis has not yet been confirmed. We identified differentially expressed PiRNAs using Arraystar PiRNA expression profiling in Angiotensin II models of cardiac fibrosis in vivo and in vitro. We then explored cardiac-fibrosis-associated PiRNA-related proteins, RNA-protein interactomes, immunoprecipitation, and pulldown. We detected fibrosis markers and pathway-related proteins using immunofluorescence, qRT-PCR, and Western blot. We uncovered cardiac fibrosis associated PiRNA (CFAPIR) that was obviously dysregulated during cardiac fibrosis, whereas its overexpression reversed fibrosis in vivo and in vitro. Mechanistically, CFAPIR competitively bound muscleblind like protein 2 (MBNL2) and the cyclin-dependent kinase inhibitor P21 to regulate the TGF-ß1/SMAD3 signaling pathway.
Assuntos
Fibrose , RNA Interferente Pequeno , Proteínas de Ligação a RNA , Transdução de Sinais , Proteína Smad3 , Animais , Fibrose/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Camundongos , RNA Interferente Pequeno/metabolismo , RNA Interferente Pequeno/genética , Proteína Smad3/metabolismo , Proteína Smad3/genética , Masculino , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta1/genética , Miocárdio/metabolismo , Miocárdio/patologia , Miofibroblastos/metabolismo , Miofibroblastos/patologia , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/genética , Camundongos Endogâmicos C57BL , Humanos , Angiotensina II/farmacologia , Angiotensina II/metabolismo , RNA de Interação com PiwiRESUMO
Medical procedures, such as radiation therapy, are a vital element in treating many cancers, significantly contributing to improved survival rates. However, a common long-term complication of such exposure is radiation-induced skin fibrosis (RISF), a complex condition that poses substantial physical and psychological challenges. Notably, about 50% of patients undergoing radiation therapy may achieve long-term remission, resulting in a significant number of survivors managing the aftereffects of their treatment. This article delves into the intricate relationship between RISF, reactive oxygen species (ROS), and angiotensin II (Ang II) signaling. It proposes the underlying mechanisms and examines potential treatments for mitigating skin fibrosis. The primary goal is to offer essential insights in order to better care for and improve the quality of life of cancer survivors who face the risk of developing RISF.
Assuntos
Angiotensina II , Fibrose , Espécies Reativas de Oxigênio , Pele , Humanos , Angiotensina II/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Pele/efeitos da radiação , Pele/patologia , Animais , Lesões por Radiação/etiologia , Radioterapia/efeitos adversos , Transdução de SinaisRESUMO
Baicalin, a flavonoid glycoside from Scutellaria baicalensis Georgi., exerts anti-hypertensive effects. The present study aimed to assess the cardioprotective role of baicalin and explore its potential mechanisms. Network pharmacology analysis pointed out a total of 477 potential targets of baicalin were obtained from the PharmMapper and SwissTargetPrediction databases, while 11,280 targets were identified associating with hypertensive heart disease from GeneCards database. Based on the above 382 common targets, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses revealed enrichment in the regulation of cardiac hypertrophy, cardiac contraction, cardiac relaxation, as well as the mitogen-activated protein kinase (MAPK) and other signaling pathways. Moreover, baicalin treatment exhibited the amelioration of increased cardiac index and pathological alterations in angiotensin II (Ang II)-infused C57BL/6 mice. Furthermore, baicalin treatment demonstrated a reduction in cell surface area and a down-regulation of hypertrophy markers (including atrial natriuretic peptide and brain natriuretic peptide) in vivo and in vitro. In addition, baicalin treatment led to a decrease in the expression of phosphorylated c-Jun N-terminal kinase (p-JNK)/JNK, phosphorylated p38 (p-p38)/p38, and phosphorylated extracellular signal-regulated kinase (p-ERK)/ERK in the cardiac tissues of Ang II-infused mice and Ang II-stimulated H9c2 cells. These findings highlight the cardioprotective effects of baicalin, as it alleviates hypertensive cardiac injury, cardiac hypertrophy, and the activation of the MAPK pathway.
Assuntos
Angiotensina II , Cardiomegalia , Flavonoides , Sistema de Sinalização das MAP Quinases , Camundongos Endogâmicos C57BL , Animais , Flavonoides/farmacologia , Angiotensina II/metabolismo , Cardiomegalia/tratamento farmacológico , Cardiomegalia/induzido quimicamente , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Masculino , Farmacologia em Rede , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Linhagem Celular , Cardiotônicos/farmacologia , Cardiotônicos/uso terapêuticoRESUMO
Albuminuria is characterized by a disruption of the glomerular filtration barrier, which is composed of the fenestrated endothelium, the glomerular basement membrane, and the slit diaphragm. Nephrin is a major component of the slit diaphragm. Apart from hemodynamic effects, Ang II enhances albuminuria by ß-Arrestin2-mediated nephrin endocytosis. Blocking the AT1 receptor with candesartan and irbesartan reduces the Ang II-mediated nephrin-ß-Arrestin2 interaction. The inhibition of MAPK ERK 1/2 blocks Ang II-enhanced nephrin-ß-Arrestin2 binding. ERK 1/2 signaling, which follows AT1 receptor activation, is mediated by G-protein signaling, EGFR transactivation, and ß-Arrestin2 recruitment. A mutant AT1 receptor defective in EGFR transactivation and ß-Arrestin2 recruitment reduces the Ang II-mediated increase in nephrin ß-Arrestin2 binding. The mutation of ß-Arrestin2K11,K12, critical for AT1 receptor binding, completely abrogates the interaction with nephrin, independent of Ang II stimulation. ß-Arrestin2K11R,K12R does not influence nephrin cell surface expression. The data presented here deepen our molecular understanding of a blood-pressure-independent molecular mechanism of AT-1 receptor blockers (ARBs) in reducing albuminuria.
Assuntos
Angiotensina II , Endocitose , Proteínas de Membrana , Receptor Tipo 1 de Angiotensina , Endocitose/efeitos dos fármacos , Endocitose/fisiologia , Animais , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Angiotensina II/farmacologia , Angiotensina II/metabolismo , Humanos , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor Tipo 1 de Angiotensina/genética , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Camundongos , Albuminúria/metabolismo , Podócitos/metabolismo , Podócitos/efeitos dos fármacos , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/genética , Compostos de Bifenilo/farmacologia , Irbesartana/farmacologia , Células HEK293 , beta-Arrestina 2/metabolismo , beta-Arrestina 2/genética , Benzimidazóis , TetrazóisRESUMO
There is evidence that tumor necrosis factor alpha (TNFα) influences autonomic processes coordinated within the hypothalamic paraventricular nucleus (PVN), however, the signaling mechanisms subserving TNFα's actions in this brain area are unclear. In non-neuronal cell types, TNFα has been shown to play an important role in canonical NADPH oxidase (NOX2)-mediated production of reactive oxygen species (ROS), molecules also known to be critically involved in hypertension. However, little is known about the role of TNFα in NOX2-dependent ROS production in the PVN within the context of hypertension. Using dual labeling immunoelectron microscopy and dihydroethidium (DHE) microfluorography, we provide structural and functional evidence for interactions between TNFα and NOX2 in the PVN. The TNFα type 1 receptor (TNFR1), the major mediator of TNFα signaling in the PVN, was commonly co-localized with the catalytic gp91phox subunit of NOX2 in postsynaptic sites of PVN neurons. Additionally, there was an increase in dual labeled dendritic profiles following fourteen-day slow-pressor angiotensin II (AngII) infusion. Using DHE microfluorography, it was also shown that TNFα application resulted in a NOX2-dependent increase in ROS in isolated PVN neurons projecting to the spinal cord. Further, TNFα-mediated ROS production was heightened after AngII infusion. The finding that TNFR1 and gp91phox are positioned for rapid interactions, particularly in PVN-spinal cord projection neurons, provides a molecular substrate by which inflammatory signaling and oxidative stress may jointly contribute to AngII hypertension.
Assuntos
Angiotensina II , NADPH Oxidase 2 , Neurônios , Núcleo Hipotalâmico Paraventricular , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio , Fator de Necrose Tumoral alfa , Animais , Núcleo Hipotalâmico Paraventricular/metabolismo , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Angiotensina II/farmacologia , Angiotensina II/metabolismo , NADPH Oxidase 2/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Masculino , NADPH Oxidases/metabolismo , Ratos , Glicoproteínas de Membrana/metabolismoRESUMO
An over-active renin-angiotensin system (RAS) is characterized by elevated angiotensin II (Ang II). While Ang II can promote metabolic and mitochondrial dysfunction in tissues, little is known about its role in the gastrointestinal system (GI). Here, we treated rat primary colonic epithelial cells with Ang II (1-5000 nM) to better define their role in the GI. We hypothesized that Ang II would negatively affect mitochondrial bioenergetics as these organelles express Ang II receptors. Ang II increased cellular ATP production but reduced the mitochondrial membrane potential (MMP) of colonocytes. However, cells maintained mitochondrial oxidative phosphorylation and glycolysis with treatment, reflecting metabolic compensation with impaired MMP. To determine whether lipid dysregulation was evident, untargeted lipidomics were conducted. A total of 1949 lipids were detected in colonocytes spanning 55 distinct (sub)classes. Ang II (1 nM) altered the abundance of some sphingosines [So(d16:1)], ceramides [Cer-AP(t18:0/24:0)], and phosphatidylcholines [OxPC(16:0_20:5(2O)], while 100 nM Ang II altered some triglycerides and phosphatidylserines [PS(19:0_22:1). Ang II did not alter the relative expression of several enzymes in lipid metabolism; however, the expression of pyruvate dehydrogenase kinase 2 (PDK2) was increased, and PDK2 can be protective against dyslipidemia. This study is the first to investigate the role of Ang II in colonic epithelial cell metabolism.
Assuntos
Angiotensina II , Colo , Células Epiteliais , Metabolismo dos Lipídeos , Potencial da Membrana Mitocondrial , Animais , Angiotensina II/farmacologia , Angiotensina II/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Colo/metabolismo , Colo/efeitos dos fármacos , Colo/citologia , Ratos , Células Epiteliais/metabolismo , Células Epiteliais/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Lipidômica , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Ratos Sprague-DawleyRESUMO
The renin-angiotensin system plays a key role in regulating blood pressure, which has motivated many investigations of associated mouse models of hypertensive arterial remodelling. Such studies typically focus on histological and cell biological changes, not wall mechanics. This study explores tissue-level ramifications of chronic angiotensin II infusion in wild-type (WT) and type 1b angiotensin II (AngII) receptor null (Agtr1b -/-) mice. Biaxial biomechanical and immunohistological changes were quantified and compared in the thoracic and abdominal aorta in these mice following 14 and 28 days of angiotensin II infusion. Preliminary results showed that changes were largely independent of sex. Associated thickening and stiffening of the aortic wall in male mice differed significantly between thoracic and abdominal regions and between genotypes. Notwithstanding multiple biomechanical changes in both WT and Agtr1b -/- mice, AngII infusion caused distinctive wall thickening and inflammation in the descending thoracic aorta of WT, but not Agtr1b -/-, mice. Our study underscores the importance of exploring differential roles of receptor-dependent angiotensin II signalling along the aorta and its influence on distinct cell types involved in regional histomechanical remodelling. Disrupting the AT1b receptor primarily affected inflammatory cell responses and smooth muscle contractility, suggesting potential therapeutic targets.
Assuntos
Angiotensina II , Camundongos Knockout , Receptor Tipo 1 de Angiotensina , Remodelação Vascular , Animais , Angiotensina II/farmacologia , Angiotensina II/metabolismo , Camundongos , Masculino , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor Tipo 1 de Angiotensina/genética , Feminino , Aorta Torácica/metabolismo , Aorta Torácica/patologiaRESUMO
BACKGROUND: Mesenchymal stromal cell (MSC)-derived exosomes (MSC-Exo) have been recognized for their significant role in regulating macrophage polarization, a process crucial to the pathogenesis of abdominal aortic aneurysm (AAA). However, the therapeutic effects of MSC-Exo on AAA remain largely unexplored. Therefore, this study aimed to investigate the functional and mechanistic aspects of MSC-Exo in the progression of AAA. METHODS: The MSC-derived exosomes were characterized using Transmission Electron Microscopy, Nanoparticle Tracking Analysis, and Western blotting. An experimental mouse model of AAA was established through the administration of angiotensin II (Ang II) in male apoe-/- mice and calcium chloride (CaCl2) in male C57/B6 mice, with subsequent tail vein injection of exosomes to evaluate their efficacy against AAA. Macrophage polarization was assessed using immunofluorescence staining and WB analysis. Mechanistic analysis was performed using 4D Label-free Proteomics analysis. RESULTS: We found that intravenous administration of MSC-Exo induced M2 polarization of macrophages within an inflammatory environment, effectively impeding AAA development in Ang II or CaCl2-induced AAA model. The therapeutic efficacy of MSC-Exo treatment was dependent on the presence of macrophages. Mechanistically, MSC-Exo suppressed the levels of cluster of differentiation 74 (CD74), modulating macrophage polarization through the TSC2-mTOR-AKT pathway. These findings highlight the potential of MSC-Exo as a therapeutic strategy for AAA by modulating macrophage polarization.
Assuntos
Aneurisma da Aorta Abdominal , Exossomos , Macrófagos , Células-Tronco Mesenquimais , Camundongos Endogâmicos C57BL , Animais , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/induzido quimicamente , Exossomos/metabolismo , Camundongos , Células-Tronco Mesenquimais/metabolismo , Macrófagos/metabolismo , Macrófagos/imunologia , Masculino , Modelos Animais de Doenças , Angiotensina II/metabolismo , Antígenos de Histocompatibilidade Classe II/metabolismo , Antígenos de Histocompatibilidade Classe II/genética , Cloreto de CálcioRESUMO
Dengue is a disease caused by a flavivirus (DENV) and transmitted by the bite of a mosquito, primarily the Aedes aegypti and Aedes albopictus species. Previous studies have demonstrated a relationship between the host gut microbiota and the evolution of dengue. It seems to be a bidirectional relationship, in which the DENV can affect the microbiota by inducing alterations related to intestinal permeability, leading to the release of molecules from microbiota dysbiosis that can influence the evolution of dengue. The role of angiotensin II (Ang II) in the microbiota/dengue relationship is not well understood, but it is known that the renin-angiotensin system (RAS) is present in the intestinal tract and interacts with the gut microbiota. The possible effect of Ang II on the microbiota/Ang II/dengue relationship can be summarised as follows: the presence of Ang II induced hypertension, the increase in angiotensinogen, chymase, and microRNAs during the disease, the induction of vascular dysfunction, the production of trimethylamine N-oxide and the brain/microbiota relationship, all of which are elements present in dengue that could be part of the microbiota/Ang II/dengue interactions. These findings suggest the potential use of Ang II synthesis blockers and the use of AT1 receptor antagonists as therapeutic drugs in dengue.
Assuntos
Dengue , Microbioma Gastrointestinal , Humanos , Microbioma Gastrointestinal/efeitos dos fármacos , Dengue/virologia , Animais , Disbiose/microbiologia , Angiotensina II/metabolismo , Vírus da Dengue/fisiologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Aedes/microbiologia , Aedes/virologiaRESUMO
Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome characterised by multiple risk factors touching various organs outside the heart. Using a murine HFpEF model, we studied cardiac reverse remodelling (RR) after stopping the causing metabolic-hypertensive stress (MHS; Angiotensin II [AngII] and a high-fat diet [HFD]) after 28 days and introducing voluntary exercise (VE) for four more weeks. We measured the effects of MHS and RR on the plasma and myocardial microRNA (miR) profile (miRNome) to characterise better cardiac and non-cardiac responses to HFpEF-inducing risk factors and their reversibility. AngII alone, the HFD or the MHS caused cardiac hypertrophy (CH), left ventricular (LV) concentric remodelling and left atrial enlargement in females. Only AngII and the MHS, but not HFD, did in males. After RR, CH, LV concentric remodelling and atrial enlargement were normalised. Among the 25 most abundant circulating miRs, 10 were modulated by MHS. Plasma miRNomes from AngII, HFD or MHS mice shared 31 common significantly modulated miRs (24 upregulated and 7 downregulated), suggesting that the response of organs producing the bulk of those circulating miRs was similar even for seemingly different stress. In the LV, 19 out of 25 most expressed miRs were modulated. RR restored normality for the plasma miRNome but not for the LV miRNome, which remained mostly unchanged. Our results suggest that abnormalities persist in the myocardium of the HFpEF mice and that the normalisation of circulatory markers may be falsely reassuring after recovery.
Assuntos
Modelos Animais de Doenças , Insuficiência Cardíaca , MicroRNAs , Miocárdio , Volume Sistólico , Remodelação Ventricular , Animais , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/metabolismo , Camundongos , MicroRNAs/genética , MicroRNAs/sangue , MicroRNAs/metabolismo , Masculino , Miocárdio/metabolismo , Miocárdio/patologia , Feminino , Angiotensina II/sangue , Angiotensina II/metabolismo , Camundongos Endogâmicos C57BL , Dieta Hiperlipídica/efeitos adversosRESUMO
Cardiac arrhythmias are often linked to the overactivity of cardiac fibroblasts (CFs). Investigating the impact of poly (ADP-ribose) polymerase 9 (PARP9) on Angiotensin II (Ang II)-induced fibroblast activation and the therapeutic effects of pirfenidone (PFD) offers valuable insights into cardiac arrhythmias. This study utilized weighted gene co-expression network analysis (WGCNA), differential gene expression (DEG) analysis, protein-protein interaction (PPI), and receiver operating characteristic (ROC) analysis on the GSE42955 dataset to identify the hub gene with a significant diagnostic value. The ImmuCellAI tool revealed an association between PARP9 and immune cell infiltration. Our in vitro assessments focused on the influence of PFD on myofibroblast differentiation, transforming growth factor-beta (TGF-ß) expression, and Ang II-induced proliferation and migration in CFs. Additionally, we explored the impact on fibrosis markers and the TGF-ß/Smad signaling pathway in the context of PARP9 overexpression. Analysis of the GSE42955 dataset revealed PARP9 as a central gene with high clinical diagnostic value, linked to seven types of immune cells. The in vitro studies demonstrated that PFD significantly mitigates Ang II-induced CF proliferation, migration, and fibrosis. It also reduces Ang II-induced PARP9 expression and decreases fibrosis markers, including TGF-ß, collagen I, collagen III, and α-SMA. Notably, PARP9 overexpression can partially counteract PFD's inhibitory effects on CFs and modify the expression of fibronectin, CTGF, α-SMA, collagen I, collagen III, MMP2, MMP9, TGF-ß, and p-Smad2/3 in the TGF-ß/Smad signaling pathway. In summary, our findings suggest that PFD effectively counteracts the adverse effects of Ang II-induced CF proliferation and fibrosis, and modulates the TGF-ß/Smad signaling pathway and PARP9 expression. This identifies a potential therapeutic approach for managing myocardial fibrosis.
Assuntos
Angiotensina II , Miocárdio , Piridonas , Transdução de Sinais , Proteínas Smad , Fator de Crescimento Transformador beta , Piridonas/farmacologia , Piridonas/uso terapêutico , Fator de Crescimento Transformador beta/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad/metabolismo , Miocárdio/metabolismo , Miocárdio/patologia , Angiotensina II/farmacologia , Angiotensina II/metabolismo , Humanos , Poli(ADP-Ribose) Polimerases/metabolismo , Poli(ADP-Ribose) Polimerases/genética , Fibrose/metabolismo , Animais , Proliferação de Células/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Movimento Celular/efeitos dos fármacos , Miofibroblastos/efeitos dos fármacos , Miofibroblastos/metabolismo , Miofibroblastos/patologia , Diferenciação Celular/efeitos dos fármacos , RatosRESUMO
Invasion and adhesion of neutrophils into tissues and their concomitant secretion play an important role in the development of vascular pathologies, including abdominal aortic aneurysm (AAA). Chronic administration of angiotensin II is used to initiate AAA formation in mice. The role of aldosterone in this process is being studied. We conducted for the first time a complex comparative study of the effects of angiotensin II and aldosterone on the adhesion of human neutrophils to fibronectin and the concomitant secretion of proteins, free amino acids as well as reactive oxygen (ROS) and nitrogen (NO) species. Neither angiotensin II nor aldosterone affected the attachment of neutrophils to fibronectin and the concomitant production of ROS. We showed for the first time that aldosterone stimulated the release of amino acid hydroxylysine, a product of lysyl hydroxylase, the activity of which is positively correlated with cell invasiveness. Aldosterone also initiates the secretion of matrix metalloproteinase 9 (MMP-9) and cathepsin G, which may reorganize the extracellular matrix and stimulate the recruitment and adhesion of neutrophils to the aortic walls. Angiotensin II did not affect protein secretion. It may contribute to neutrophil-induced vascular injury by inhibiting the production of NO or by increasing the secretion of isoleucine. Our results suggest that it is aldosterone-induced neutrophil secretion that may play a significant role in neutrophil-induced vascular wall destruction in angiotensin II-induced AAA or other vascular complications.
Assuntos
Aldosterona , Angiotensina II , Adesão Celular , Neutrófilos , Espécies Reativas de Oxigênio , Humanos , Angiotensina II/metabolismo , Angiotensina II/farmacologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Neutrófilos/metabolismo , Aldosterona/metabolismo , Adesão Celular/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Fibronectinas/metabolismo , Células Cultivadas , Catepsina G/metabolismo , Aminoácidos/metabolismo , Espécies Reativas de Nitrogênio/metabolismo , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologiaRESUMO
Cardiac tissue remodeling is characterized by altered heart tissue architecture and dysfunction, leading to heart failure. Sustained activation of the renin-angiotensin-aldosterone system (RAAS) greatly promotes the development of myocardial remodeling. Angiotensin II (Ang II), which is the major component of RAAS, can directly lead to cardiac remodeling by inducing an inflammatory response. Schisandrin B (Sch B), the active component extracted from the fruit of Schisandra chinensis (Turcz.) Baill has been shown to exhibit anti-inflammatory activity through its ability to target TLR4 and its adaptor protein, MyD88. In this study, we explored whether Sch B alleviates Ang II-induced myocardial inflammation and remodeling via targeting MyD88. Sch B significantly suppressed Ang II-induced inflammation as well as increased the expression of several genes of tissue remodeling (ß-Mhc, Tgfb, Anp, α-Ska) both in vivo and in vitro. These protective effects of Sch B were due to the inhibition of recruitment of MyD88 to TLR2 and TLR4, suppressing the Ang II-induced NF-κB activation and reducing the following inflammatory responses. Moreover, the knockdown of Myd88 in cardiomyocytes abrogated the Ang II-induced increases in the production of inflammatory cytokines and expression of remodeling genes. These findings provide new evidence that the mechanism of Sch B protection was attributed to selective inhibition of MyD88 signaling. This finding could pave the way for novel therapeutic strategies for myocardial inflammatory diseases.
Assuntos
Angiotensina II , Ciclo-Octanos , Lignanas , Camundongos Endogâmicos C57BL , Fator 88 de Diferenciação Mieloide , Miócitos Cardíacos , Compostos Policíclicos , Receptor 4 Toll-Like , Animais , Ciclo-Octanos/farmacologia , Ciclo-Octanos/uso terapêutico , Lignanas/farmacologia , Lignanas/uso terapêutico , Fator 88 de Diferenciação Mieloide/metabolismo , Compostos Policíclicos/farmacologia , Compostos Policíclicos/uso terapêutico , Angiotensina II/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Receptor 4 Toll-Like/metabolismo , Receptor 4 Toll-Like/genética , Camundongos , Masculino , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Receptor 2 Toll-Like/metabolismo , Receptor 2 Toll-Like/genética , Remodelação Ventricular/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Células Cultivadas , NF-kappa B/metabolismoRESUMO
The mechanism by which aging induces aortic aneurysm and dissection (AAD) remains unclear. A total of 430 participants were recruited for the screening of differentially expressed plasma microRNAs (miRNAs). We found that miR-1204 is significantly increased in both the plasma and aorta of elder patients with AAD and is positively correlated with age. Cell senescence induces the expression of miR-1204 through p53 interaction with plasmacytoma variant translocation 1, and miR-1204 induces vascular smooth muscle cell (VSMC) senescence to form a positive feedback loop. Furthermore, miR-1204 aggravates angiotensin II-induced AAD formation, and inhibition of miR-1204 attenuates ß-aminopropionitrile monofumarate-induced AAD development in mice. Mechanistically, miR-1204 directly targets myosin light chain kinase (MYLK), leading to the acquisition of a senescence-associated secretory phenotype (SASP) by VSMCs and loss of their contractile phenotype. MYLK overexpression reverses miR-1204-induced VSMC senescence, SASP and contractile phenotypic changes, and the decrease of transforming growth factor-ß signaling pathway. Our findings suggest that aging aggravates AAD via the miR-1204-MYLK signaling axis.