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1.
Sci Rep ; 13(1): 881, 2023 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-36650223

RESUMO

We recently reported exacerbated endotoxic signs of neuroinflammation and autonomic defects in offspring of preeclamptic (PE) dams. Here, we investigated whether PE programming similarly modifies hemodynamic and renal vasoconstrictor responsiveness to endotoxemia in PE offspring and whether this interaction is modulated by gestational angiotensin 1-7 (Ang1-7). Preeclampsia was induced by gestational treatment with L-NAME. Adult offspring was challenged with lipopolysaccharides (LPS, 5 mg/kg) and systolic blood pressure (SBP) and renal vasoconstrictions were assessed 4 h later. Male, but not female, offspring of PE rats exhibited SBP elevations that were blunted by LPS. Renal vasoconstrictions induced by angiotensin II (Ang II), but not phenylephrine, were intensified in perfused kidneys of either sex. LPS blunted the heightened Ang II responses in male, but not female, kidneys. While renal expressions of AT1-receptors and angiotensin converting enzyme (ACE) were increased in PE offspring of both sexes, ACE2 was upregulated in female offspring only. These molecular effects were diminished by LPS in male offspring. Gestational Ang1-7 caused sex-unrelated attenuation of phenylephrine vasoconstrictions and preferentially downregulated Ang II responses and AT1-receptor and nuclear factor-kB (NFkB) expressions in females. Together, endotoxemia and Ang1-7 offset in sexually-related manners imbalances in renal vasoconstriction and AT1/ACE/ACE2 signaling in PE offspring.


Assuntos
Endotoxemia , Pré-Eclâmpsia , Animais , Feminino , Masculino , Ratos , Angiotensina II/metabolismo , Enzima de Conversão de Angiotensina 2/metabolismo , Endotoxemia/induzido quimicamente , Endotoxemia/metabolismo , Endotoxinas/metabolismo , Rim/metabolismo , Lipopolissacarídeos/farmacologia , Pré-Eclâmpsia/metabolismo , Sistema Renina-Angiotensina , Vasoconstrição
2.
Sci Rep ; 13(1): 953, 2023 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-36653504

RESUMO

We aimed to assess the systemic and hepatic renin-angiotensin-system (RAS) fingerprint in advanced chronic liver disease (ACLD). This prospective study included 13 compensated (cACLD) and 12 decompensated ACLD (dACLD) patients undergoing hepatic venous pressure gradient (HVPG) measurement. Plasma components (all patients) and liver-local enzymes (n = 5) of the RAS were analyzed using liquid chromatography-tandem mass spectrometry. Patients with dACLD had significantly higher angiotensin (Ang) I, Ang II and aldosterone plasma levels. Ang 1-7, a major mediator of the alternative RAS, was almost exclusively detectable in dACLD (n = 12/13; vs. n = 1/13 in cACLD). Also, dACLD patients had higher Ang 1-5 (33.5 pmol/L versus cACLD: 6.6 pmol/L, p < 0.001) and numerically higher Ang III and Ang IV levels. Ang 1-7 correlated with HVPG (ρ = 0.655; p < 0.001), von Willebrand Factor (ρ = 0.681; p < 0.001), MELD (ρ = 0.593; p = 0.002) and interleukin-6 (ρ = 0.418; p = 0.047). Considerable activity of ACE, chymase, ACE2, and neprilysin was detectable in all liver biopsies, with highest chymase and ACE2 activity in cACLD patients. While liver-local classical and alternative RAS activity was already observed in cACLD, systemic activation of alternative RAS components occurred only in dACLD. Increased Ang 1-7 was linked to severe liver disease, portal hypertension, endothelial dysfunction and inflammation.


Assuntos
Hipertensão Portal , Doenças Vasculares , Humanos , Sistema Renina-Angiotensina/fisiologia , Quimases , Enzima de Conversão de Angiotensina 2 , Estudos Prospectivos , Cirrose Hepática , Angiotensina II/metabolismo , Inflamação , Peptidil Dipeptidase A/metabolismo
3.
Nutrients ; 15(2)2023 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-36678265

RESUMO

Body sodium (Na) levels must be maintained within a narrow range for the correct functioning of the organism (Na homeostasis). Na disorders include not only elevated levels of this solute (hypernatremia), as in diabetes insipidus, but also reduced levels (hyponatremia), as in cerebral salt wasting syndrome. The balance in body Na levels therefore requires a delicate equilibrium to be maintained between the ingestion and excretion of Na. Salt (NaCl) intake is processed by receptors in the tongue and digestive system, which transmit the information to the nucleus of the solitary tract via a neural pathway (chorda tympani/vagus nerves) and to circumventricular organs, including the subfornical organ and area postrema, via a humoral pathway (blood/cerebrospinal fluid). Circuits are formed that stimulate or inhibit homeostatic Na intake involving participation of the parabrachial nucleus, pre-locus coeruleus, medial tuberomammillary nuclei, median eminence, paraventricular and supraoptic nuclei, and other structures with reward properties such as the bed nucleus of the stria terminalis, central amygdala, and ventral tegmental area. Finally, the kidney uses neural signals (e.g., renal sympathetic nerves) and vascular (e.g., renal perfusion pressure) and humoral (e.g., renin-angiotensin-aldosterone system, cardiac natriuretic peptides, antidiuretic hormone, and oxytocin) factors to promote Na excretion or retention and thereby maintain extracellular fluid volume. All these intake and excretion processes are modulated by chemical messengers, many of which (e.g., aldosterone, angiotensin II, and oxytocin) have effects that are coordinated at peripheral and central level to ensure Na homeostasis.


Assuntos
Ocitocina , Sódio , Sódio/metabolismo , Homeostase , Rim/metabolismo , Angiotensina II/metabolismo
4.
Cell Mol Life Sci ; 80(2): 38, 2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36629913

RESUMO

BACKGROUND: Vascular endothelial dysfunction is regarded as an early event of hypertension. Galectin-3 (Gal-3) is known to participate in various pathological processes. Whilst previous studies showed that inhibition of Gal-3 effectively ameliorates angiotensin II (Ang II)-induced atherosclerosis or hypertension, it remains unclear whether Ang II regulates Gal-3 expression and actions in vascular endothelium. METHODS: Using techniques of molecular biology and myograph, we investigated Ang II-mediated changes in Gal-3 expression and activity in thoracic aortas and mesenteric arteries from wild-type and Gal-3 gene deleted (Gal-3-/-) mice and cultured endothelial cells. RESULTS: The serum level of Gal-3 was significantly higher in hypertensive patients or in mice with chronic Ang II-infusion. Ang II infusion to wild-type mice enhanced Gal-3 expression in the aortic and mesenteric arteries, elevated systolic blood pressure and impaired endothelium-dependent relaxation of the thoracic aortas and mesenteric arteries, changes that were abolished in Gal-3-/- mice. In human umbilical vein endothelial cells, Ang II significantly upregulated Gal-3 expression by promoting nuclear localization of Yes-associated protein (YAP) and its interaction with transcription factor Tead1 with enhanced YAP/Tead1 binding to Gal-3 gene promoter region. Furthermore, Gal-3 deletion augmented the bioavailability of nitric oxide, suppressed oxidative stress, and alleviated inflammation in the thoracic aorta of Ang II-infused mice or endothelial cells exposed to Ang II. CONCLUSIONS: Our results demonstrate for the first time that Ang II upregulates Gal-3 expression via increment in YAP nuclear localization in vascular endothelium, and that Gal-3 mediates endothelial dysfunction contributing to the development of hypertension.


Assuntos
Angiotensina II , Hipertensão , Camundongos , Humanos , Animais , Angiotensina II/farmacologia , Angiotensina II/metabolismo , Galectina 3/genética , Galectina 3/metabolismo , Hipertensão/metabolismo , Transdução de Sinais , Células Endoteliais da Veia Umbilical Humana/metabolismo , Endotélio Vascular/metabolismo , Pressão Sanguínea
5.
Prog Mol Biol Transl Sci ; 194: 141-157, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36631190

RESUMO

A vasoactive octapeptide angiotensin II (Ang II) hormone is the key regulator of the renin-angiotensin system (RAS). It binds with the two different plasma membrane receptors like angiotensin II type 1 (AT1) and type 2 (AT2) and consequence various biological responses occur. Further, AT1 has two subtypes such as AT1A and AT1B. These angiotensin receptors are classified to be G protein-coupled receptors (GPCRs). The main constituent of RAS is the AT1 receptor (AT1R), and its activation, signal transduction, and regulation have been extensively studied. After Ang II stimulation, the ligand-receptor complexes internalized and trafficked through the early endosome, recycling endosome, and some receptors skipped the recycling endosome and trafficked to the lysosome for metabolic degradation. Moreover, some short sequence motifs located in the carboxyl-terminus (CT) of the receptor play a vital role in the internalization, phosphorylation, subcellular trafficking, signaling, and desensitization. Furthermore, in endocytosis, the various proteins interact with the CT region of the receptor. This chapter highlights the basic mechanism of AT1 receptor internalization, trafficking and signaling in both physiological and pathophysiological conditions.


Assuntos
Angiotensina II , Receptor Tipo 1 de Angiotensina , Humanos , Receptor Tipo 1 de Angiotensina/metabolismo , Angiotensina II/metabolismo , Transdução de Sinais , Endocitose/fisiologia , Proteínas de Transporte/metabolismo
6.
Prog Mol Biol Transl Sci ; 194: 49-65, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36631200

RESUMO

The renin angiotensin system (RAS) plays a major role in blood pressure regulation and electrolyte homeostasis and is mainly composed by two axes mediating opposite effects. The pressor axis, constituted by angiotensin (Ang) II and the Ang II type 1 receptor (AT1R), exerts vasoconstrictor, proliferative, hypertensive, oxidative and pro-inflammatory actions, while the depressor/protective axis, represented by Ang-(1-7), its Mas receptor (MasR) and the Ang II type 2 receptor (AT2R), opposes the actions elicited by the pressor arm. The MasR belongs to the G protein-coupled receptor (GPCR) family. To avoid receptor overstimulation, GPCRs undergo internalization and trafficking into the cell after being stimulated. Then, the receptor may induce other signaling cascades or it may even interact with other receptors, generating distinct biological responses. Thus, control of a GPCR regarding space and time affects the specificity of the signals transduced by the receptor and the ultimate cellular response. The present chapter is focused on the signaling and trafficking pathways of MasR under physiological conditions and its participation in the pathogenesis of numerous brain diseases.


Assuntos
Proto-Oncogene Mas , Sistema Renina-Angiotensina , Humanos , Sistema Renina-Angiotensina/fisiologia , Angiotensina II/metabolismo , Angiotensina II/farmacologia , Pressão Sanguínea/fisiologia , Receptores Acoplados a Proteínas G/metabolismo , Endocitose
7.
J Transl Med ; 21(1): 2, 2023 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-36593471

RESUMO

BACKGROUND: There is no available viable treatment for Sepsis-Induced Cardiomyopathy (SIC), a common sepsis complication with a higher fatality risk. The septic patients showed an abnormal activation of the renin angiotensin (Ang) aldosterone system (RAAS). However, it is not known how the Ang II and Ang-(1-7) affect SIC. METHODS: Peripheral plasma was collected from the Healthy Control (HC) and septic patients and Ang II and Ang-(1-7) protein concentrations were measured. The in vitro and in vivo models of SIC were developed using Lipopolysaccharide (LPS) to preliminarily explore the relationship between the SIC state, Ang II, and Ang-(1-7) levels, along with the protective function of exogenous Ang-(1-7) on SIC. RESULTS: Peripheral plasma Ang II and the Ang II/Ang-(1-7) levels in SIC-affected patients were elevated compared to the levels in HC and non-SIC patients, however, the HC showed higher Ang-(1-7) levels. Furthermore, peripheral plasma Ang II, Ang II/Ang-(1-7), and Ang-(1-7) levels in SIC patients were significantly correlated with the degree of myocardial injury. Additionally, exogenous Ang-(1-7) can attenuate inflammatory response, reduce oxidative stress, maintain mitochondrial dynamics homeostasis, and alleviate mitochondrial structural and functional damage by inhibiting nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways, thus alleviating SIC. CONCLUSIONS: Plasma Ang-(1-7), Ang II, and Ang II/Ang-(1-7) levels were regarded as significant SIC biomarkers. In SIC, therapeutic targeting of RAAS, for example with Ang-(1-7), may exert protective roles against myocardial damage.


Assuntos
Cardiomiopatias , Sepse , Humanos , NF-kappa B/metabolismo , Proteínas Quinases Ativadas por Mitógeno , Células Cultivadas , Angiotensina II/metabolismo , Cardiomiopatias/tratamento farmacológico , Cardiomiopatias/etiologia , Sepse/complicações , Sepse/tratamento farmacológico
8.
Nutrients ; 15(1)2023 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-36615902

RESUMO

Perinatal malnutrition affects vascular functions, and calcium is important in vascular regulations. It is unknown whether and how perinatal maternal high-fat diets (MHF)-mediated vascular dysfunction occurs via the angiotensin-PKC-L-type-calcium-channels (LTCC) axis. This study determined angiotensin II (AII) roles in the PKC-LTCC axis in controlling calcium influx in the arteries of offspring after perinatal MHF. Mesenteric arteries (MA) and smooth muscle cells (SMCs) from 5-month-old offspring rats were studied using physiological, ion channel, molecular, and epigenetic analysis. Pressor responses to AII were significantly increased in the free-moving MHF offspring rats. In cell experiments, MA-SMC proliferation was enhanced, and associated with thicker vascular wall in the obese offspring. Imaging analysis showed increase of fluorescence Ca2+ intensity in the SMCs of the MHF group. Angiotensin II receptor (AT1R)-mediated PKC-LTCC axis in vasoconstrictions was altered by perinatal MHF via reduced DNA methylation at specific CpG sites of Agtr1a and Prkcb gene promoters at the transcription level. Accordingly, mRNA and protein expression of AT1R and PKCß in the offspring MA were increased, contributing to enhanced Ca2+ currents and vascular tone. The results showed that DNA methylation resulted in perinatal MHF-induced vascular disorders via altered AT1-PKC-LTCC pathway in resistance arteries of the offspring, providing new insights into the pathogenesis and early prevention/treatments for hypertension in developmental origins.


Assuntos
Angiotensina II , Canais de Cálcio Tipo L , Gravidez , Feminino , Ratos , Animais , Angiotensina II/metabolismo , Canais de Cálcio Tipo L/metabolismo , Cálcio/metabolismo , Metilação de DNA , Artérias Mesentéricas , Dieta , Receptor Tipo 1 de Angiotensina/genética
9.
Sci Rep ; 13(1): 1380, 2023 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-36697439

RESUMO

Aortic aneurysm (AA) is a vascular disorder characterized pathologically by inflammatory cell invasion and extracellular matrix (ECM) degradation. It is known that regulation of the balance between pro-inflammatory M1 macrophages (M1Ms) and anti-inflammatory M2 macrophages (M2Ms) plays a pivotal role in AA stabilization. We investigated the effects of M2M administration in an apolipoprotein E-deficient (apoE-/-) mouse model in which AA was induced by angiotensin II (ATII) infusion. Mice received intraperitoneal administration of 1 million M2Ms 4 weeks after ATII infusion. Compared with a control group that was administered saline, the M2M group exhibited reduced AA expansion; decreased expression levels of interleukin (IL)-1ß, IL-6, tumor necrosis factor-α (TNF-α), and monocyte chemoattractant protein-1 (MCP-1); and a lower M1M/M2M ratio. Moreover, the M2M group exhibited upregulation of anti-inflammatory factors, including IL-4 and IL-10. PKH26-labeled M2Ms accounted for 6.5% of cells in the aneurysmal site and co-expressed CD206. Taken together, intraperitoneal administration of M2Ms inhibited AA expansion by reducing the inflammatory reaction via regulating the M1M/M2M ratio. This study shows that M2M administration might be useful for the treatment of AA.


Assuntos
Aneurisma Aórtico , Macrófagos , Animais , Camundongos , Angiotensina II/metabolismo , Anti-Inflamatórios/metabolismo , Aneurisma Aórtico/induzido quimicamente , Aneurisma Aórtico/tratamento farmacológico , Aneurisma Aórtico/metabolismo , Modelos Animais de Doenças , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Fator de Necrose Tumoral alfa/metabolismo
10.
BMC Cardiovasc Disord ; 23(1): 55, 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36710339

RESUMO

OBJECTIVE: Previous studies have revealed associations between hyperuricemia and microvascular diseases, but the association between hyperuricemia and abdominal aortic aneurysm (AAA) remains unclear. The aim of this study was to elucidate the pathogenesis and prove the relationship between AAA and hyperuricemia. METHODS: A retrospective study was performed to validate the growth rates of AAA in humans with different serum uric acid levels. A murine model of angiotensin II-induced AAA was used to assess the effects of hyperuricemia on AAA growth in vivo, and human aortic smooth muscle cells (HASMCs) were used to study the pathways involved in these effects in vitro. RESULTS: We analyzed data from 107 AAA patients and found that patients with serum uric acid levels above 9 mg/dl had higher AAA growth rates than patients with serum uric acid levels between 4 and 7.9 mg/dl. In vivo, induction of hyperuricemia increased the incidence of AAA formation and the abdominal aortic diameter in mice. The hyperuricemic mice exhibited higher levels of urate transporter 1 (URAT1) expression, phospho-extracellular signal-regulated kinase (p-ERK)1/2 expression, reactive oxygen species (ROS) levels and matrix metalloproteinase (MMP)-9 expression in the abdominal aorta than the control mice. Soluble uric acid increased the expression of URAT1, p-ERK1/2, and MMP-9 and the levels of ROS in HASMCs in vitro. CONCLUSIONS: We have provided human evidence that hyperuricemia exacerbates AAA formation. In addition, our murine experimental evidence suggests that hyperuricemia exacerbates AAA formation and reveals that the URAT1/ERK1/2/ROS/MMP-9 pathway is among the pathways activated by uric acid in HASMCs.


Assuntos
Aneurisma da Aorta Abdominal , Hiperuricemia , Humanos , Camundongos , Animais , Sistema de Sinalização das MAP Quinases , Ácido Úrico , Metaloproteinase 9 da Matriz/metabolismo , Hiperuricemia/complicações , Hiperuricemia/diagnóstico , Espécies Reativas de Oxigênio/metabolismo , Estudos Retrospectivos , Aneurisma da Aorta Abdominal/metabolismo , Aorta Abdominal , Transdução de Sinais , Modelos Animais de Doenças , Angiotensina II/metabolismo
11.
J Mol Graph Model ; 118: 108365, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36335829

RESUMO

The structural features that contribute to the efficacy of biased agonists targeting G protein-coupled receptors (GPCRs) towards G proteins or ß-arrestin (ß-arr) signaling pathways is nebulous, although such knowledge is critical in designing biased ligands. The dynamics of the agonist-GPCR complex is one of the critical factors in determining agonist bias. Angiotensin II type I receptor (AT1R) is an ideal model system to study the molecular basis of bias since it has multiple ß-arr2 and Gq protein biased agonists as well as experimentally solved three dimensional structures. Using Molecular Dynamics (MD) simulations for the Angiotensin II type I receptor (AT1R) bound to ten different agonists, we infer that the agonist bound receptor samples conformations with different relative weights, from both the inactive and active state ensembles of the receptor. This concept is perhaps extensible to other class A GPCRs. Such a weighted mixed ensemble recapitulates the inter-residue distance distributions measured for different agonists bound AT1R using DEER experiments. The ratio of the calculated relative strength of the allosteric communication to ß-arr2 vs Gq coupling sites scale similarly to the experimentally measured bias factors. Analysis of the inter-residue distance distributions of the activation microswitches involved in class A GPCR activation suggests that ß-arr2 biased agonists turn on different combination of microswitches with different relative strengths of activation. We put forth a model that activation microswitches behave like rheostats that tune the relative efficacy of the biased agonists toward the two signaling pathways. Finally, based on our data we propose that the agonist specific residue contacts in the binding site elicit a combinatorial response in the microswitches that in turn differentially modulate the receptor conformation ensembles resulting in differences in coupling to Gq and ß-arrestin.


Assuntos
Angiotensina II , Receptor Tipo 1 de Angiotensina , Receptor Tipo 1 de Angiotensina/agonistas , Receptor Tipo 1 de Angiotensina/metabolismo , Angiotensina II/química , Angiotensina II/metabolismo , Angiotensina II/farmacologia , Espectroscopia de Ressonância de Spin Eletrônica , beta-Arrestinas/metabolismo , Ligantes , Conformação Proteica
12.
Brain Behav Immun ; 108: 255-268, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36535607

RESUMO

The metabolic syndrome has been associated to chronic peripheral inflammation and related with neuroinflammation and neurodegeneration, including Parkinson's disease. However, the responsible mechanisms are unclear. Previous studies have involved the brain renin-angiotensin system in progression of Parkinson's disease and the angiotensin receptor type 1 (AT1) has been recently revealed as a major marker of dopaminergic vulnerability in humans. Dysregulation of tissue renin-angiotensin system is a key common mechanism for all major components of metabolic syndrome. Circulating AT1 agonistic autoantibodies have been observed in several inflammation-related peripheral processes, and activation of AT1 receptors of endothelial cells, dopaminergic neurons and glial cells have been observed to disrupt endothelial blood -brain barrier and induce neurodegeneration, respectively. Using a rat model, we observed that metabolic syndrome induces overactivity of nigral pro-inflammatory renin-angiotensin system axis, leading to increase in oxidative stress and neuroinflammation and enhancing dopaminergic neurodegeneration, which was inhibited by treatment with AT1 receptor blockers (ARBs). In rats, metabolic syndrome induced the increase in circulating levels of LIGHT and other major pro-inflammatory cytokines, and 27-hydroxycholesterol. Furthermore, the rats showed a significant increase in serum levels of proinflammatory AT1 and angiotensin converting enzyme 2 (ACE2) autoantibodies, which correlated with levels of several metabolic syndrome parameters. We also found AT1 and ACE2 autoantibodies in the CSF of these rats. Effects of circulating autoantibodies were confirmed by chronic infusion of AT1 autoantibodies, which induced blood-brain barrier disruption, an increase in the pro-inflammatory renin-angiotensin system activity in the substantia nigra and a significant enhancement in dopaminergic neuron death in two different rat models of Parkinson's disease. Observations in the rat models, were analyzed in a cohort of parkinsonian and non-parkinsonian patients with or without metabolic syndrome. Non-parkinsonian patients with metabolic syndrome showed significantly higher levels of AT1 autoantibodies than non-parkinsonian patients without metabolic syndrome. However, there was no significant difference between parkinsonian patients with metabolic syndrome or without metabolic syndrome, which showed higher levels of AT1 autoantibodies than non-parkinsonian controls. This is consistent with our recent studies, showing significant increase of AT1 and ACE2 autoantibodies in parkinsonian patients, which was related to dopaminergic degeneration and neuroinflammation. Altogether may lead to a vicious circle enhancing the progression of the disease that may be inhibited by strategies against production of these autoantibodies or AT1 receptor blockers (ARBs).


Assuntos
Síndrome Metabólica , Doença de Parkinson , Animais , Humanos , Ratos , Angiotensina II/metabolismo , Angiotensina II/farmacologia , Antagonistas de Receptores de Angiotensina/metabolismo , Antagonistas de Receptores de Angiotensina/farmacologia , Enzima de Conversão de Angiotensina 2/metabolismo , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Autoanticorpos/metabolismo , Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Células Endoteliais/metabolismo , Inflamação/metabolismo , Síndrome Metabólica/metabolismo , Doenças Neuroinflamatórias , Doença de Parkinson/metabolismo , Receptor Tipo 1 de Angiotensina/metabolismo
13.
Biochem Pharmacol ; 208: 115384, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36549460

RESUMO

Heterotrimeric guanine nucleotide regulatory proteins (G-proteins) through the activation of several signaling mechanisms including adenylyl cyclase/cAMP and phospholipase C (PLC)/phosphatidyl inositol (PI) turnover. regulate a variety of cellular functions, including vascular reactivity, proliferation and hypertrophy of VSMC. Activity of adenylyl cyclase is regulated by two G proteins, stimulatory (Gsα) and inhibitory (Giα). Gsα stimulates adenylyl cyclase activity and increases the levels of cAMP, whereas Giα inhibits the activity of adenylyl cyclase and results in the reduction of cAMP levels. Abnormalities in Giα protein expression and associated adenylyl cyclase\cAMP levels result in the impaired cellular functions and contribute to various pathological states including hypertension. The expression of Giα proteins is enhanced in various tissues including heart, kidney, aorta and vascular smooth muscle cells (VSMC) from genetic (spontaneously hypertensive rats (SHR)) and experimentally - induced hypertensive rats and contribute to the pathogenesis of hypertension. In addition, the enhanced expression of Giα proteins exhibited by VSMC from SHR is also implicated in the hyperproliferation and hypertrophy, the two key players contributing to vascular remodelling in hypertension. The enhanced levels of endogenous vasoactive peptides including angiotensin II (Ang II), endothelin-1 (ET-1) and growth factors contribute to the overexpression of Giα proteins in VSMC from SHR. In addition, enhanced oxidative stress, activation of c-Src, growth factor receptor transactivation and MAP kinase/PI3kinase signaling also contribute to the augmented expression of Giα proteins in VSMC from SHR. This review summarizes the role of Giα proteins, and the underlying molecular mechanisms implicated in the regulation of high blood pressure and vascular remodelling.


Assuntos
Hipertensão , Remodelação Vascular , Ratos , Animais , Pressão Sanguínea , Adenilil Ciclases/metabolismo , Músculo Liso Vascular/metabolismo , Ratos Endogâmicos SHR , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo , Hipertensão/metabolismo , Angiotensina II/metabolismo
14.
Anal Chem ; 95(2): 730-738, 2023 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-36574961

RESUMO

The mechanisms by which angiotensin II type 1 receptor is distributed and the diffusional pattern in the plasma membrane (PM) remain unclear, despite their crucial role in cardiovascular homeostasis. In this work, we obtained quantitative information of angiotensin II type 1 receptor (AT1R) lateral dynamics as well as changes in the diffusion properties after stimulation with ligands in living cells using photoactivated localization microscopy (PALM) combined with image spatial-temporal correlation analysis. To study the organization of the receptor at the nanoscale, expansion microscopy (ExM) combined with PALM was performed. This study revealed that AT1R lateral diffusion increased after binding to angiotensin II (Ang II) and the receptor diffusion was transiently confined in the PM. In addition, ExM revealed that AT1R formed nanoclusters at the PM and the cluster size significantly decreased after Ang II treatment. Taking these results together suggest that Ang II binding and activation cause reorganization and changes in the dynamics of AT1R at the PM.


Assuntos
Angiotensina II , Receptor Tipo 1 de Angiotensina , Receptor Tipo 1 de Angiotensina/metabolismo , Angiotensina II/farmacologia , Angiotensina II/metabolismo , Microscopia , Membrana Celular/metabolismo
15.
Eur J Pharmacol ; 940: 175475, 2023 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-36563952

RESUMO

Vascular endothelial dysfunction plays a central role in the most dreadful human diseases, including stroke, tumor metastasis, and the coronavirus disease 2019 (COVID-19). Strong evidence suggests that angiotensin II (Ang II)-induced mitochondrial dysfunction is essential for endothelial dysfunction pathogenesis. However, the precise molecular mechanisms remain obscure. Here, polymerase-interacting protein 2 (Poldip 2) was found in the endothelial mitochondrial matrix and no effects on Poldip 2 and NADPH oxidase 4 (NOX 4) expression treated by Ang II. Interestingly, we first found that Ang II-induced NOX 4 binds with Poldip 2 was dependent on cyclophilin D (CypD). CypD knockdown (KD) significantly inhibited the binding of NOX 4 to Poldip 2, and mitochondrial ROS generation in human umbilical vein endothelial cells (HUVECs). Similar results were also found in cyclosporin A (CsA) treated HUVECs. Our previous study suggested a crosstalk between extracellular regulated protein kinase (ERK) phosphorylation and CypD expression, and gallic acid (GA) inhibited mitochondrial dysfunction in neurons depending on regulating the ERK-CypD axis. Here, we confirmed that GA inhibited Ang II-induced NOX 4 activation and mitochondrial dysfunction via ERK/CypD/NOX 4/Poldip 2 pathway, which provide novel mechanistic insight into CypD act as a key regulator of the NOX 4/Poldip 2 axis in Ang II-induced endothelial mitochondrial dysfunction and GA might be beneficial in the treatment of wide variety of diseases, such as COVID-19, which is worthy further research.


Assuntos
COVID-19 , Doenças Vasculares , Humanos , NADPH Oxidase 4/metabolismo , Angiotensina II/farmacologia , Angiotensina II/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Ciclofilina D/metabolismo , Ciclofilina D/farmacologia , NADPH Oxidases/metabolismo , Estresse Oxidativo , Ácido Gálico/farmacologia , COVID-19/metabolismo , Mitocôndrias , Células Endoteliais da Veia Umbilical Humana
16.
Zhongguo Zhong Yao Za Zhi ; 47(21): 5900-5907, 2022 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-36472009

RESUMO

This study was designed to determine the inhibitory effect of astragaloside Ⅳ(AS-Ⅳ), a principal bioactive component extracted from the Chinese medicinal Astragali Radix, on the inflammatory response of vascular endothelial cells induced by angiotensin Ⅱ(Ang Ⅱ), the most major pathogenic factor for cardiovascular diseases, and to clarify the role of calcium(Ca~(2+))/phosphatidylinosi-tol-3-kinase(PI3K)/protein kinase B(Akt)/endothelial nitric oxide synthase(eNOS)/nitric oxide(NO) pathway in the process. To be specific, human umbilical vein endothelial cells(HUVECs) were cultured in the presence of AS-Ⅳ with or without the specific inhibitor of NO synthase(NG-monomethyl-L-arginine, L-NMMA), inhibitor of PI3K/Akt signaling pathway(LY294002), or Ca~(2+)-chelating agent(ethylene glycol tetraacetic acid, EGTA) prior to Ang Ⅱ stimulation. The inhibitory effect of AS-Ⅳ on Ang Ⅱ-induced inflammatory response and the involved mechanism was determined with enzyme-linked immunosorbent assay(ELISA), cell-based ELISA assay, Western blot, and monocyte adhesion assay which determined the fluorescently labeled human monocytic cell line(THP-1) adhered to Ang Ⅱ-stimulated endothelial cells. AS-Ⅳ increased the production of NO by HUVECs in a dose-and time-dependent manner(P<0.05) and raised the level of phosphorylated eNOS(P<0.05). The above AS-Ⅳ-induced changes were abolished by pretreatment with L-NMMA, LY294002, or EGTA. Compared with the control group, Ang Ⅱ obviously enhanced the production and release of cytokines(tumor necrosis factor-α, interleukin-6), chemokines(monocyte chemoattractant protein-1) and adhesion molecules(intercellular adhesion molecule-1, vascular cellular adhesion molecule-1), and the number of monocytes adhered to HUVECs(P<0.05), which were accompanied by the enhanced levels of phosphorylated inhibitor of nuclear factor-κBα protein and activities of nuclear factor-κB(NF-κB)(P<0.05). This study also demonstrated that Ang Ⅱ-induced inflammatory response was inhibited by pretreatment with AS-Ⅳ(P<0.05). In addition, the inhibitory effect of AS-Ⅳ was abrogated by pretreatment with L-NMMA, LY294002, or EGTA(P<0.05). This study provides a direct link between AS-Ⅳ and Ca~(2+)/PI3K/Akt/eNOS/NO pathway in AS-Ⅳ-mediated anti-inflammatory actions in endothelial cells exposed to Ang Ⅱ. The results indicate that AS-Ⅳ attenuates endothelial cell-mediated inflammatory response induced by Ang Ⅱ via the activation of Ca~(2+)/PI3K/Akt/eNOS/NO signaling pathway.


Assuntos
Angiotensina II , Proteínas Proto-Oncogênicas c-akt , Humanos , Angiotensina II/metabolismo , Angiotensina II/farmacologia , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , ômega-N-Metilarginina/metabolismo , ômega-N-Metilarginina/farmacologia , Ácido Egtázico/metabolismo , Ácido Egtázico/farmacologia , Células Endoteliais da Veia Umbilical Humana , NF-kappa B/genética , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Células Cultivadas
17.
Front Biosci (Landmark Ed) ; 27(11): 299, 2022 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-36472099

RESUMO

BACKGROUND: To investigate the effect and potential molecular mechanisms of Dipsacoside B (DB), an herb monomer extracted from Dipsacusasper or Lonicera macranthoides, on the migration and proliferation of vascular smooth muscle cells (VSMCs) and balloon-induced neointimal formation. METHODS: In vivo, rat abdominal aorta balloon injury model was utilized to investigate the effect of DB on the neointimal formation. In vitro, cultured VSMCs were used to investigate the effect of DB on Angiotensin-II (Ang-II)-induced migration and proliferation of VSMCs. Western blot and immunofluorescence were used to measure PTEN expression. RESULTS: As compared to vehicle control balloon-injury group, DB treatment significantly inhibited the neointimal formation together up-regulated the expression of phosphatase and tension homolog deleted on chromosome 10 (PTEN). Cell proliferations (MTT and Edu incorporation) assays and wound migration measurement further revealed that treatment with DB significantly blunted Ang-II-induced proliferation and migration potential of VSMCs. Western blot analysis exhibited that DB upregulated the expression of PTEN in vivo and in vitro. CONCLUSIONS: DB treatment suppresses the proliferation and migration of VSMCs and reduces neointimal formation by the mechanisms involving regulating the phenotype switch of VSMCs via upregulating PTEN expression.


Assuntos
Músculo Liso Vascular , Miócitos de Músculo Liso , Ratos , Animais , Movimento Celular , Neointima/metabolismo , Proliferação de Células , Angiotensina II/metabolismo , Angiotensina II/farmacologia , Células Cultivadas , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo
18.
Redox Biol ; 58: 102521, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36459715

RESUMO

Aortic aneurysms are prevalent and severe vascular diseases with high mortality from unpredicted ruptures, while the only treatment option is surgical correction of large aneurysms with considerable risk. We have shown that folic acid (FA) is highly effective in alleviating development of aneurysms although not sufficient to completely attenuate aneurysm formation. Here, we examined therapeutic effects on aneurysms of combining FA with Nifedipine as novel and potentially more effective oral medication. Oral administration with FA (15 mg/kg/day) significantly reduced incidence of AAA from 85.71% to 18.75% in Ang II-infused apolipoprotein E (apoE) null mice, while combination of FA with Nifedipine (1.5, 5.0 or 20 mg/kg/day) substantially and completely further reduced incidence of AAA to 12.5%, 11.76% and 0.00% respectively in a dose-dependent manner. The combinatory therapy substantially and completely further alleviated enlargement of abdominal aortas defined by ultrasound, vascular remodeling characterized by elastin degradation and adventitial hypertrophy, as well as aortic superoxide production and eNOS uncoupling activity also in a dose-dependent manner, with combination of FA with 20 mg/kg/day Nifedipine attenuating all of these features by 100% to control levels. Aortic NO and H4B bioavailabilities were also dose-dependently further improved by combining FA with Nifedipine. These data establish entirely innovative and robust therapeutic regime of FA combined with Nifedipine for the treatment of aortic aneurysms. The comminatory therapy can serve as a first-in-class and most effective oral medication for aortic aneurysms, which can be rapidly translated into clinical practice to revolutionize management of the devastating vascular diseases of aortic aneurysms known as silent killers.


Assuntos
Aneurisma da Aorta Abdominal , Aneurisma Aórtico , Camundongos , Animais , Nifedipino/farmacologia , Nifedipino/uso terapêutico , Ácido Fólico , Angiotensina II/metabolismo , Aneurisma da Aorta Abdominal/etiologia , Apolipoproteínas E/genética , Aneurisma Aórtico/tratamento farmacológico , Aneurisma Aórtico/complicações , Camundongos Knockout , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL
19.
Clin Sci (Lond) ; 136(24): 1831-1849, 2022 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-36540030

RESUMO

Isorhamnetin, a natural flavonoid, has strong antioxidant and antifibrotic effects, and a regulatory effect against Ca2+-handling. Atrial remodeling due to fibrosis and abnormal intracellular Ca2+ activities contributes to initiation and persistence of atrial fibrillation (AF). The present study investigated the effect of isorhamnetin on angiotensin II (AngII)-induced AF in mice. Wild-type male mice (C57BL/6J, 8 weeks old) were assigned to three groups: (1) control group, (2) AngII-treated group, and (3) AngII- and isorhamnetin-treated group. AngII (1000 ng/kg/min) and isorhamnetin (5 mg/kg) were administered continuously via an implantable osmotic pump for two weeks and intraperitoneally one week before initiating AngII administration, respectively. AF induction and electrophysiological studies, Ca2+ imaging with isolated atrial myocytes and HL-1 cells, and action potential duration (APD) measurements using atrial tissue and HL-1 cells were performed. AF-related molecule expression was assessed and histopathological examination was performed. Isorhamnetin decreased AF inducibility compared with the AngII group and restored AngII-induced atrial effective refractory period prolongation. Isorhamnetin eliminated abnormal diastolic intracellular Ca2+ activities induced by AngII. Isorhamnetin also abrogated AngII-induced APD prolongation and abnormal Ca2+ loading in HL-1 cells. Furthermore, isorhamnetin strongly attenuated AngII-induced left atrial enlargement and atrial fibrosis. AngII-induced elevated expression of AF-associated molecules, such as ox-CaMKII, p-RyR2, p-JNK, p-ERK, and TRPC3/6, was improved by isorhamnetin treatment. The findings of the present study suggest that isorhamnetin prevents AngII-induced AF vulnerability and arrhythmogenic atrial remodeling, highlighting its therapeutic potential as an anti-arrhythmogenic pharmaceutical or dietary supplement.


Assuntos
Fibrilação Atrial , Remodelamento Atrial , Masculino , Camundongos , Animais , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/prevenção & controle , Cálcio/metabolismo , Camundongos Endogâmicos C57BL , Átrios do Coração/patologia , Miócitos Cardíacos/metabolismo , Angiotensina II/metabolismo
20.
Int J Mol Sci ; 23(24)2022 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-36555438

RESUMO

The roles of angiotensin II (Ang II) AT1 (AT1a) receptors and its downstream target Na+/H+ exchanger 3 (NHE3) in the proximal tubules in the development of two-kidney, 1-clip (2K1C) Goldblatt hypertension have not been investigated previously. The present study tested the hypothesis that deletion of the AT1a receptor or NHE3 selectively in the proximal tubules of the kidney attenuates the development of 2K1C hypertension using novel mouse models with proximal tubule-specific deletion of AT1a receptors or NHE3. 2K1C Goldblatt hypertension was induced by placing a silver clip (0.12 mm) on the left renal artery for 4 weeks in adult male wild-type (WT), global Agtr1a-/-, proximal tubule (PT)-specific PT-Agtr1a-/- or PT-Nhe3-/- mice, respectively. As expected, telemetry blood pressure increased in a time-dependent manner in WT mice, reaching a maximal response by Week 3 (p < 0.01). 2K1C hypertension in WT mice was associated with increases in renin expression in the clipped kidney and decreases in the nonclipped kidney (p < 0.05). Plasma and kidney Ang II were significantly increased in WT mice with 2K1C hypertension (p < 0.05). Tubulointerstitial fibrotic responses were significantly increased in the clipped kidney (p < 0.01). Whole-body deletion of AT1a receptors completely blocked the development of 2K1C hypertension in Agtr1a-/- mice (p < 0.01 vs. WT). Likewise, proximal tubule-specific deletion of Agtr1a in PT-Agtr1a-/- mice or NHE3 in PT-Nhe3-/- mice also blocked the development of 2K1C hypertension (p < 0.01 vs. WT). Taken together, the present study provides new evidence for a critical role of proximal tubule Ang II/AT1 (AT1a)/NHE3 axis in the development of 2K1C Goldblatt hypertension.


Assuntos
Hipertensão Renovascular , Hipertensão , Receptor Tipo 1 de Angiotensina , Trocador 3 de Sódio-Hidrogênio , Animais , Masculino , Camundongos , Angiotensina II/metabolismo , Pressão Sanguínea , Hipertensão/metabolismo , Hipertensão Renovascular/genética , Rim/metabolismo , Túbulos Renais Proximais/metabolismo , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , Trocador 3 de Sódio-Hidrogênio/genética , Trocador 3 de Sódio-Hidrogênio/metabolismo , Deleção de Genes , Camundongos Knockout
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