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All well-known deleterious effects of angiotensin (Ang) II, including vasoconstriction, inflammation, water and salt retention, and vascular remodeling, are mediated via its type 1 (AT1) receptor. This explains why AT1 receptor blockers (ARBs) and inhibitors of Ang II synthesis, such as ACE inhibitors and renin inhibitors, are beneficial for cardiovascular disease. Yet, Ang II has a second receptor, the Ang II type 2 (AT2) receptor, the function of which, even after over 20 years of research, remains largely unknown. In this issue, Marion et al. provide a new chapter to the AT2 receptor story.
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Angiotensinas/metabolismo , Úlcera de Buruli/patologia , Macrolídeos/isolamento & purificação , Mycobacterium ulcerans , Animais , HumanosRESUMO
The concept of local formation of angiotensin II in the kidney has changed over the last 10-15 years. Local synthesis of angiotensinogen in the proximal tubule has been proposed, combined with prorenin synthesis in the collecting duct. Binding of prorenin via the so-called (pro)renin receptor has been introduced, as well as megalin-mediated uptake of filtered plasma-derived renin-angiotensin system (RAS) components. Moreover, angiotensin metabolites other than angiotensin II [notably angiotensin-(1-7)] exist, and angiotensins exert their effects via three different receptors, of which angiotensin II type 2 and Mas receptors are considered renoprotective, possibly in a sex-specific manner, whereas angiotensin II type 1 (AT1) receptors are believed to be deleterious. Additionally, internalized angiotensin II may stimulate intracellular receptors. Angiotensin-converting enzyme 2 (ACE2) not only generates angiotensin-(1-7) but also acts as coronavirus receptor. Multiple, if not all, cardiovascular diseases involve the kidney RAS, with renal AT1 receptors often being claimed to exert a crucial role. Urinary RAS component levels, depending on filtration, reabsorption, and local release, are believed to reflect renal RAS activity. Finally, both existing drugs (RAS inhibitors, cyclooxygenase inhibitors) and novel drugs (angiotensin receptor/neprilysin inhibitors, sodium-glucose cotransporter-2 inhibitors, soluble ACE2) affect renal angiotensin formation, thereby displaying cardiovascular efficacy. Particular in the case of the latter three, an important question is to what degree they induce renoprotection (e.g., in a renal RAS-dependent manner). This review provides a unifying view, explaining not only how kidney angiotensin formation occurs and how it is affected by drugs but also why drugs are renoprotective when altering the renal RAS. SIGNIFICANCE STATEMENT: Angiotensin formation in the kidney is widely accepted but little understood, and multiple, often contrasting concepts have been put forward over the last two decades. This paper offers a unifying view, simultaneously explaining how existing and novel drugs exert renoprotection by interfering with kidney angiotensin formation.
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Angiotensinogênio , Doenças Cardiovasculares , Feminino , Humanos , Masculino , Angiotensina II/metabolismo , Enzima de Conversão de Angiotensina 2 , Angiotensinogênio/metabolismo , Doenças Cardiovasculares/metabolismo , Sistemas de Liberação de Medicamentos , Rim/irrigação sanguínea , Rim/metabolismo , Renina/metabolismo , Sistema Renina-Angiotensina , Inibidores do Transportador 2 de Sódio-Glicose/metabolismoRESUMO
Progressive dilation of the infrarenal aortic diameter is a consequence of the ageing process and is considered the main determinant of abdominal aortic aneurysm (AAA). We aimed to investigate the genetic and clinical determinants of abdominal aortic diameter (AAD). We conducted a meta-analysis of genome-wide association studies in 10 cohorts (n = 13 542) imputed to the 1000 Genome Project reference panel including 12 815 subjects in the discovery phase and 727 subjects [Partners Biobank cohort 1 (PBIO)] as replication. Maximum anterior-posterior diameter of the infrarenal aorta was used as AAD. We also included exome array data (n = 14 480) from seven epidemiologic studies. Single-variant and gene-based associations were done using SeqMeta package. A Mendelian randomization analysis was applied to investigate the causal effect of a number of clinical risk factors on AAD. In genome-wide association study (GWAS) on AAD, rs74448815 in the intronic region of LDLRAD4 reached genome-wide significance (beta = -0.02, SE = 0.004, P-value = 2.10 × 10-8). The association replicated in the PBIO1 cohort (P-value = 8.19 × 10-4). In exome-array single-variant analysis (P-value threshold = 9 × 10-7), the lowest P-value was found for rs239259 located in SLC22A20 (beta = 0.007, P-value = 1.2 × 10-5). In the gene-based analysis (P-value threshold = 1.85 × 10-6), PCSK5 showed an association with AAD (P-value = 8.03 × 10-7). Furthermore, in Mendelian randomization analyses, we found evidence for genetic association of pulse pressure (beta = -0.003, P-value = 0.02), triglycerides (beta = -0.16, P-value = 0.008) and height (beta = 0.03, P-value < 0.0001), known risk factors for AAA, consistent with a causal association with AAD. Our findings point to new biology as well as highlighting gene regions in mechanisms that have previously been implicated in the genetics of other vascular diseases.
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Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Exoma/genética , Humanos , Polimorfismo de Nucleotídeo Único/genética , TriglicerídeosRESUMO
OBJECTIVE (S): Circulating angiogenic factors are used for prediction of placenta-related complications, but their associations with first-trimester placental development is unknown. This study investigates associations between maternal angiogenic factors and utero-placental vascular volume (uPVV) and utero-placental vascular skeleton (uPVS) as novel imaging markers of volumetric and morphologic (branching) development of the first-trimester utero-placental vasculature. METHODS: In 185 ongoing pregnancies from the VIRTUAL Placenta study, a subcohort of the ongoing prospective Rotterdam Periconception cohort, three-dimensional power Doppler ultrasounds of the placenta were obtained at 7-9-11 weeks gestational age (GA). The uPVV was measured as a parameter of volumetric development and reported the vascular quantity in cm3. The uPVS was generated as a parameter of morphologic (branching) development and reported the number of end-, bifurcation- crossing- or vessel points and total vascular length. At 11 weeks GA, maternal serum biomarkers suggested to reflect placental (vascular) development were assessed: placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng). sFlt-1/PlGF and sEng/PlGF ratios were calculated. Multivariable linear regression with adjustments was used to estimate associations between serum biomarkers and uPVV and uPVS trajectories. RESULTS: Serum PlGF was positively associated with uPVV and uPVS development (uPVV: ß = 0.39, 95% CI = 0.15;0.64; bifurcation points: ß = 4.64, 95% CI = 0.04;9.25; crossing points: ß = 4.01, 95% CI = 0.65;7.37; total vascular length: ß = 13.33, 95% CI = 3.09;23.58, all p-values < 0.05). sEng/PlGF ratio was negatively associated with uPVV and uPVS development. We observed no associations between sFlt-1, sEng or sFlt-1/PlGF ratio and uPVV and uPVS development. CONCLUSION(S): Higher first-trimester maternal serum PlGF concentration is associated with increased first-trimester utero-placental vascular development as reflected by uPVV and uPVS. Clinical trial registration number Dutch Trial Register NTR6854.
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Vacuolar H+-ATPase (V-ATPase) is a multisubunit protein complex which, along with its accessory proteins, resides in almost every eukaryotic cell. It acts as a proton pump and as such is responsible for regulating pH in lysosomes, endosomes, and the extracellular space. Moreover, V-ATPase has been implicated in receptor-mediated signaling. Although numerous studies have explored the role of V-ATPase in cancer, osteoporosis, and neurodegenerative diseases, research on its involvement in vascular disease remains limited. Vascular diseases pose significant challenges to human health. This review aimed to shed light on the role of V-ATPase in hypertension and atherosclerosis. Furthermore, given that vascular complications are major complications of diabetes, this review also discusses the pathways through which V-ATPase may contribute to such complications. Beginning with an overview of the structure and function of V-ATPase in hypertension, atherosclerosis, and diabetes, this review ends by exploring the pharmacological potential of targeting V-ATPase.
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Aterosclerose , Diabetes Mellitus , Hipertensão , ATPases Vacuolares Próton-Translocadoras , Humanos , Aterosclerose/enzimologia , Aterosclerose/metabolismo , ATPases Vacuolares Próton-Translocadoras/metabolismo , Hipertensão/enzimologia , Animais , Diabetes Mellitus/enzimologiaRESUMO
BACKGROUND: Migraine prevalence and levels of calcitonin gene-related peptide (CGRP), a peptide involved in migraine pathophysiology, differ between men and women, and appear to be affected by changes in sex hormones. The present study investigated the sex-specific responses to CGRP in human isolated arteries. METHODS: CGRP-induced relaxation of 62 (28 men and 34 women) human isolated middle meningeal arteries (HMMA) and 139 (69 men and 70 women) human isolated coronary arteries (HCA) was compared between men and women in groups <50 years and ≥50 years of age as a proxy for pre- and postmenopausal status in women, as well as matched-age groups for men. RESULTS: In HCA, no differences were observed between male and female tissue, or between the different age groups. However, in HMMA, the maximum response was significantly smaller and CGRP was less potent in females <50 compared with males <50 years of age. No differences were observed between the older age groups. CONCLUSIONS: Sex differences were observed for CGRP-induced relaxation of HMMA, but not HCA. These differences could arise from differential receptor expression in the vascular beds combined with the effect of sex hormones on CGRP and subsequent receptor desensitization.
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Peptídeo Relacionado com Gene de Calcitonina , Vasos Coronários , Artérias Meníngeas , Transtornos de Enxaqueca , Caracteres Sexuais , Vasodilatação , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Transtornos de Enxaqueca/fisiopatologia , Transtornos de Enxaqueca/metabolismo , Artérias Meníngeas/efeitos dos fármacos , Artérias Meníngeas/fisiologia , Vasodilatação/fisiologia , Vasodilatação/efeitos dos fármacos , Adulto , Vasos Coronários/efeitos dos fármacos , IdosoRESUMO
BACKGROUND AND HYPOTHESIS: Calcineurin inhibitors affect kidney electrolyte handling and blood pressure through an effect on the distal tubule. The second generation calcineurin inhibitor voclosporin causes hypomagnesemia and hypercalciuria less often than tacrolimus. This suggests different effects on the distal tubule, but this has not yet been investigated experimentally. METHODS: Rats were treated with voclosporin, tacrolimus or vehicle for 28 days. Dosing was based on a pilot experiment to achieve clinically therapeutic concentrations. Drug effects were assessed by electrolyte handling at day 18 and 28, thiazide testing at day 20, telemetric blood pressure recordings, and analysis of mRNA and protein levels of distal tubular transporters at day 28. RESULTS: Compared to vehicle, tacrolimus but not voclosporin significantly increased the fractional excretions of calcium (>4-fold), magnesium and chloride (both 1.5-fold) and caused hypomagnesemia. Tacrolimus but not voclosporin significantly reduced distal tubular transporters at mRNA and/or protein level, including the sodium-chloride cotransporter, transient receptor melastatin 6, transient receptor potential vanilloid 5, cyclin M2, sodium-calcium exchanger and calbindin-D28K. Tacrolimus but not voclosporin reduced the mRNA level and urinary excretion of epidermal growth factor. The saluretic response to hydrochlorothiazide at day 20 was similar in the voclosporin and vehicle groups, whereas it was lower in the tacrolimus group. The phosphorylated form of the sodium-chloride cotransporter was significantly higher at day 28 in rats treated with voclosporin than in those treated with tacrolimus. Tacrolimus transiently increased blood pressure, whereas voclosporin caused a gradual but persistent increase in blood pressure which was further characterized by high renin, normal aldosterone, and low endothelin-1. CONCLUSIONS: In contrast to tacrolimus, voclosporin does not cause hypercalciuria and hypomagnesemia, but similarly causes hypertension. Our data reveal differences between the distal tubular effects of tacrolimus and voclosporin and provide a pathophysiological basis for the clinically observed differences between the two calcineurin inhibitors.
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Blood pressure management involves antihypertensive therapies blocking the renin-angiotensin system (RAS). Yet, it might be inadequate due to poor patient adherence or the so-called RAS escape phenomenon, elicited by the compensatory renin elevation upon RAS blockade. Recently, evidence points toward targeting hepatic AGT (angiotensinogen) as a novel approach to block the RAS pathway that could circumvent the RAS escape phenomenon. Removing AGT, from which all angiotensins originate, should prevent further angiotensin generation, even when renin rises. Furthermore, by making use of a trivalent N-acetylgalactosamine ligand-conjugated small interfering RNA that specifically targets the degradation of hepatocyte-produced mRNAs in a highly potent and specific manner, it may be possible in the future to manage hypertension with therapy that is administered 1 to 2× per year, thereby supporting medication adherence. This review summarizes all current findings on AGT small interfering RNA in preclinical models, making a comparison versus classical RAS blockade with either ACE (angiotensin-converting enzyme) inhibitors or AT1 (angiotensin II type 1) receptor antagonists and AGT suppression with antisense oligonucleotides. It ends with discussing the first-in-human study with AGT small interfering RNA.
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Angiotensinogênio , Hipertensão , Humanos , Acetilgalactosamina , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Angiotensinogênio/genética , Angiotensinogênio/metabolismo , Pressão Sanguínea , Hipertensão/terapia , Hipertensão/tratamento farmacológico , Renina/metabolismo , Sistema Renina-Angiotensina/fisiologia , RNA Interferente Pequeno/farmacologiaRESUMO
Cardiovascular outcome in Marfan syndrome (MFS) patients most prominently depends on aortic aneurysm progression with subsequent aortic dissection. Angiotensin II receptor blockers (ARBs) prevent aneurysm formation in MFS mouse models. In patients, ARBs only slow down aortic dilation. Downstream signalling from the angiotensin II type 1 receptor (AT1R) is mediated by G proteins and ß-arrestin recruitment. AT1R also interacts with the monocyte chemoattractant protein-1 (MCP-1) receptor, resulting in inflammation. In this study, we explore the targeting of ß-arrestin signalling in MFS mice by administering TRV027. Furthermore, because high doses of the ARB losartan, which has been proven beneficial in MFS, cannot be achieved in humans, we investigate a potential additive effect by combining lower concentrations of losartan (25 mg/kg/day and 5 mg/kg/day) with barbadin, a ß-arrestin blocker, and DMX20, a C-C chemokine receptor type 2 (CCR2) blocker. A high dose of losartan (50 mg/kg/day) slowed down aneurysm progression compared to untreated MFS mice (1.73 ± 0.12 vs. 1.96 ± 0.08 mm, p = 0.0033). TRV027, the combination of barbadin with losartan (25 mg/kg/day), and DMX-200 (90 mg/kg/day) with a low dose of losartan (5 mg/kg/day) did not show a significant beneficial effect. Our results confirm that while losartan effectively halts aneurysm formation in Fbn1C1041G/+ MFS mice, neither TRV027 alone nor any of the other compounds combined with lower doses of losartan demonstrate a notable impact on aneurysm advancement. It appears that complete blockade of AT1R function, achieved by administrating a high dosage of losartan, may be necessary for inhibiting aneurysm progression in MFS.
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Bloqueadores do Receptor Tipo 1 de Angiotensina II , Aneurisma Aórtico , Losartan , Síndrome de Marfan , Transdução de Sinais , Camundongos , Síndrome de Marfan/tratamento farmacológico , Síndrome de Marfan/patologia , Modelos Animais de Doenças , Aneurisma Aórtico/tratamento farmacológico , Aneurisma Aórtico/prevenção & controle , Oligopeptídeos/administração & dosagem , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/patologia , Pirimidinas/administração & dosagem , Combinação de Medicamentos , Losartan/administração & dosagem , Antagonistas de Receptores de Angiotensina/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Humanos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagemRESUMO
Blood pressure (BP) responses to sodium intake show great variation, discriminating salt-sensitive (SS) from salt-resistant (SR) individuals. The pathophysiology behind salt sensitivity is still not fully elucidated. We aimed to investigate salt-induced effects on body fluid, vascular tone, and autonomic cardiac response with regard to BP change in healthy normotensive individuals. We performed a randomized crossover study in 51 normotensive individuals with normal body mass index and estimated glomerular filtration rate. Subjects followed both a low-Na+ diet (LSD, <50 mmol/day) and a high-Na+ diet (HSD, >200 mmol/day). Cardiac output, systemic vascular resistance (SVR), and cardiac autonomous activity, through heart rate variability and cross-correlation baroreflex sensitivity (xBRS), were assessed with noninvasive continuous finger BP measurements. In a subset, extracellular volume (ECV) was assessed by iohexol measurements. Subjects were characterized as SS if mean arterial pressure (MAP) increased ≥3 mmHg after HSD. After HSD, SS subjects (25%) showed a 6.1-mmHg (SD 1.9) increase in MAP. No differences between SS and SR in body weight, cardiac output, or ECV were found. SVR was positively correlated with Delta BP (r = 0.31, P = 0.03). xBRS and heart rate variability were significantly higher in SS participants compared to SR participants after both HSD and LSD. Sodium loading did not alter heart rate variability within groups. Salt sensitivity in normotensive individuals is associated with an inability to decrease SVR upon high salt intake that is accompanied by alterations in autonomous cardiac regulation, as reflected by decreased xBRS and heart rate variability. No discriminatory changes upon high salt were observed among salt-sensitive individuals in body weight and ECV.NEW & NOTEWORTHY Extracellular fluid expansion in normotensive individuals after salt loading is present in both salt-sensitive and salt-resistant individuals and is not discriminatory to the blood pressure response to sodium loading in a steady-state measurement. In normotensive subjects, the ability to sufficiently vasodilate seems to play a pivotal role in salt sensitivity. In a normotensive cohort, differences in sympathovagal balance are also present in low-salt conditions rather than being affected by salt loading. Whereas treatment and prevention of salt-sensitive blood pressure increase are mostly focused on renal sodium handling and extracellular volume regulation, our study suggests that an inability to adequately vasodilate and altered autonomous cardiac functioning are additional key players in the pathophysiology of salt-sensitive blood pressure increase.
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Hipertensão , Cloreto de Sódio na Dieta , Humanos , Pressão Sanguínea , Cloreto de Sódio na Dieta/efeitos adversos , Frequência Cardíaca/fisiologia , Estudos Cross-Over , Cloreto de Sódio/farmacologia , Sódio/farmacologia , Peso CorporalRESUMO
A high dietary sodium-consumption level is considered the most important lifestyle factor that can be modified to help prevent an increase in blood pressure and the development of hypertension. Despite numerous studies over the past decades, the pathophysiology explaining why some people show a salt-sensitive blood pressure response and others do not is incompletely understood. Here, a brief overview of the latest mechanistic insights is provided, focusing on the mononuclear phagocytic system and inflammation, the gut-kidney axis, and epigenetics. The article also discusses the effects of 3 types of novel drugs on salt-sensitive hypertension-sodium-glucose cotransporter 2 inhibitors, nonsteroidal mineralocorticoid receptor antagonists, and aldosterone synthase inhibitors. The conclusion is that besides kidney-centered mechanisms, vasoconstrictor mechanisms are also relevant for both the understanding and treatment of this blood pressure phenotype.
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Hipertensão , Receptores de Mineralocorticoides , Humanos , Aldosterona , Pressão Sanguínea , Hipertensão/genética , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Cloreto de Sódio na Dieta/efeitos adversosRESUMO
STUDY QUESTION: Could circulating maternal prorenin serve as a proxy for oocyte and preimplantation embryo development, assessed by time-lapse parameters and clinical treatment outcomes? SUMMARY ANSWER: High circulating maternal prorenin concentrations after ovarian stimulation associate with a larger oocyte area, faster cleavage divisions from the five-cell stage onwards and increased chance of successful implantation. WHAT IS KNOWN ALREADY: After ovarian stimulation, circulating prorenin (renin's precursor), is largely ovary-derived. Prorenin may contribute to ovarian angiotensin synthesis, which is relevant in reproduction given its role in follicular development and oocyte maturation. STUDY DESIGN, SIZE, DURATION: Prospective observational cohort study including couples requiring fertility treatment from May 2017 as a subcohort of the ongoing Rotterdam Periconception Cohort conducted in a tertiary referral hospital. PARTICIPANTS/MATERIALS, SETTING, METHODS: Between May 2017 and July 2020, 309 couples with an indication for IVF treatment or ICSI were included. Resulting embryos (n = 1024) were submitted to time-lapse embryo culture. Time of fertilization (t0), pronuclear appearance (tPNa), and fading (tPNf) as well as the exact timing of reaching the two- to eight-cell stage (t2-t8), the start of blastulation (tSB), reaching the full (tB), and expanded blastocyst (tEB) were retrospectively recorded. Oocyte area was measured at t0, tPNa, and tPNf. Prorenin was determined at the day of embryo transfer. MAIN RESULTS AND THE ROLE OF CHANCE: After adjustment for patient- and treatment-related factors, linear mixed modeling showed that higher prorenin concentrations associate with a larger oocyte area at tPNa (ß 64.45 µm2, 95% CI 3.26; 125.64, P = 0.04), and faster progression from five-cell stage onwards (e.g. ß8-cell -1.37 h, 95% CI -2.48; -0.26, P = 0.02). Prorenin associated positively with pre-transfer outcomes (e.g. ßfertilized oocytes 2.09, 95% CI 1.43; 2.75, P < 0.001) and implantation (odds ratio+ß-hCG-test: 1.79, 95% CI 1.06; 3.08, P = 0.03), but not with live birth. LIMITATIONS, REASONS FOR CAUTION: This prospective observational study provides associations and therefore residual confounding cannot be excluded and causality has to be shown in intervention studies. WIDER IMPLICATIONS OF THE FINDINGS: Theca cell-derived factors, such as prorenin, may help to clarify the underlying endocrine mechanism of oocyte maturation and embryo development, with a special focus on the (patho)physiological reproductive role of prorenin and the identification of factors influencing its secretion and activity, which is of great added value for improving embryo selection and predicting implantation and pregnancy outcomes. This will bring us to investigate which determinants of oocyte quality and embryo development should take center stage in developing preconception care strategies. STUDY FUNDING/COMPETING INTEREST(S): This research was funded by the Department of Obstetrics and Gynecology of the Erasmus MC, University Medical Center, Rotterdam, the Netherlands, and the Erasmus MC Medical Research Advisor Committee's 'Health Care Efficiency Research' program (OZBS72.16080). The authors have no competing interests to disclose. TRIAL REGISTRATION NUMBER: N/A.
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Oócitos , Renina , Gravidez , Feminino , Humanos , Estudos Prospectivos , Estudos Retrospectivos , Blastocisto , Fertilização in vitroRESUMO
The development of a wide range of novel antineoplastic therapies has improved the prognosis for patients with a wide range of malignancies, which has increased the number of cancer survivors substantially. Despite the oncological benefit, cancer survivors are exposed to short- and long-term adverse cardiovascular toxicities associated with anticancer therapies. Systemic hypertension, the most common comorbidity among cancer patients, is a major contributor to the increased risk for developing these adverse cardiovascular events. Cancer and hypertension have common risk factors, have overlapping pathophysiological mechanisms and hypertension may also be a risk factor for some tumor types. Many cancer therapies have prohypertensive effects. Although some of the mechanisms by which these antineoplastic agents lead to hypertension have been characterized, further preclinical and clinical studies are required to investigate the exact pathophysiology and the optimal management of hypertension associated with anticancer therapy. In this way, monitoring and management of hypertension before, during, and after cancer treatment can be improved to minimize cardiovascular risks. This is vital to optimize cardiovascular health in patients with cancer and survivors, and to ensure that advances in terms of cancer survivorship do not come at the expense of increased cardiovascular toxicities.
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Antineoplásicos/efeitos adversos , Hipertensão/induzido quimicamente , Neoplasias/tratamento farmacológico , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Sobreviventes de Câncer , Carcinoma de Células Renais/etiologia , Cardiotoxicidade/etiologia , Humanos , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Neoplasias Renais/etiologia , Inibidores de MTOR/efeitos adversos , Neoplasias/etiologia , Compostos de Platina/efeitos adversos , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Inibidores de Proteassoma/efeitos adversos , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-ret/antagonistas & inibidores , Fatores de Risco , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidoresRESUMO
BACKGROUND: The adipokine chemerin regulates adipogenesis and the metabolic function of both adipocytes and liver. Chemerin is elevated in preeclamptic women, and overexpression of chemerin in placental trophoblasts induces preeclampsia-like symptoms in mice. Preeclampsia is known to be accompanied by dyslipidemia, albeit via unknown mechanisms. Here, we hypothesized that chemerin might be a contributor to dyslipidemia. METHODS: Serum lipid fractions as well as lipid-related genes and proteins were determined in pregnant mice with chemerin overexpression in placental trophoblasts and chemerin-overexpressing human trophoblasts. In addition, a phospholipidomics analysis was performed in chemerin-overexpressing trophoblasts. RESULTS: Overexpression of chemerin in trophoblasts increased the circulating and placental levels of cholesterol rather than triglycerides. It also increased the serum levels of lysophosphatidic acid, high-density lipoprotein cholesterol (HDL-C), and and low-density lipoprotein cholesterol (LDL-C), and induced placental lipid accumulation. Mechanistically, chemerin upregulated the levels of peroxisome proliferator-activated receptor g, fatty acid-binding protein 4, adiponectin, sterol regulatory element-binding protein 1 and 2, and the ratio of phosphorylated extracellular signal-regulated protein kinase (ERK)1/2 / total ERK1/2 in the placenta of mice and human trophoblasts. Furthermore, chemerin overexpression in human trophoblasts increased the production of lysophospholipids and phospholipids, particularly lysophosphatidylethanolamine. CONCLUSIONS: Overexpression of placental chemerin production disrupts trophoblast lipid metabolism, thereby potentially contributing to dyslipidemia in preeclampsia.
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Quimiocinas , Dislipidemias , Pré-Eclâmpsia , Feminino , Humanos , Gravidez , Adipocinas/metabolismo , Colesterol/metabolismo , Dislipidemias/genética , Dislipidemias/metabolismo , Placenta/metabolismo , Triglicerídeos/metabolismo , Trofoblastos/metabolismo , Animais , Camundongos , Quimiocinas/genéticaRESUMO
Cardiovascular diseases are the leading cause of death globally. Within cardiovascular aging, arterial aging holds significant importance, as it involves structural and functional alterations in arteries that contribute substantially to the overall decline in cardiovascular health during the aging process. As arteries age, their ability to respond to stress and injury diminishes, while their luminal diameter increases. Moreover, they experience intimal and medial thickening, endothelial dysfunction, loss of vascular smooth muscle cells, cellular senescence, extracellular matrix remodeling, and deposition of collagen and calcium. This aging process also leads to overall arterial stiffening and cellular remodeling. The process of genomic instability plays a vital role in accelerating vascular aging. Progeria syndromes, rare genetic disorders causing premature aging, exemplify the impact of genomic instability. Throughout life, our DNA faces constant challenges from environmental radiation, chemicals, and endogenous metabolic products, leading to DNA damage and genome instability as we age. The accumulation of unrepaired damages over time manifests as an aging phenotype. To study vascular aging, various models are available, ranging from in vivo mouse studies to cell culture options, and there are also microfluidic in vitro model systems known as vessels-on-a-chip. Together, these models offer valuable insights into the aging process of blood vessels.
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Senilidade Prematura , Envelhecimento , Camundongos , Animais , Envelhecimento/genética , Senescência Celular/genética , Artérias , Instabilidade GenômicaRESUMO
Maternal circulating levels of the adipokine chemerin are elevated in preeclampsia, but its origin and contribution to preeclampsia remain unknown. We therefore studied (1) placental chemerin expression and release in human pregnancy, and (2) the consequences of chemerin overexpression via lentivirus-mediated trophoblast-specific gene manipulation in both mice and immortalized human trophoblasts. Placental chemerin expression and release were increased in women with preeclampsia, and their circulating chemerin levels correlated positively with the soluble Fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) ratio, a well-known biomarker of preeclampsia severity. Placental trophoblast chemerin overexpression in mice induced a preeclampsia-like syndrome, involving hypertension, proteinuria, and endotheliosis, combined with diminished trophoblast invasion, a disorganized labyrinth layer, and up-regulation of sFlt-1 and the inflammation markers nuclear factor-κB (NFκB), tumor necrosis factor (TNF)-α, and interleukin (IL)-1ß. It also led to embryo resorption, while maternal serum chemerin levels correlated negatively with fetal weight in mice. Chemerin overexpression in human trophoblasts up-regulated sFlt-1, reduced vascular endothelial factor-A, and inhibited migration and invasion, as well as tube formation during co-culture with human umbilical vein endothelial cells (HUVECs). The chemokine-like receptor 1 (CMKLR1) antagonist α-NETA prevented the latter phenomenon, although it did not reverse the chemerin-induced down-regulation of the phosphoinositide 3-kinase/Akt pathway. In conclusion, up-regulation of placental chemerin synthesis disturbs normal placental development via its CMKLR1 receptor, thereby contributing to fetal growth restriction/resorption and the development of preeclampsia. Chemerin might be a novel biomarker of preeclampsia, and inhibition of the chemerin/CMKLR1 pathway is a promising novel therapeutic strategy to treat preeclampsia.
Assuntos
Quimiocinas/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Pré-Eclâmpsia/etiologia , Trofoblastos/patologia , Animais , Linhagem Celular , Quimiocinas/genética , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Camundongos , Placenta/metabolismo , Placenta/patologia , Fator de Crescimento Placentário/metabolismo , Gravidez , Resultado da Gravidez , Trofoblastos/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
Vascular endothelial growth factor antagonism with angiogenesis inhibitors in cancer patients induces a 'preeclampsia-like' syndrome including hypertension, proteinuria and elevated endothelin (ET)-1. Cyclo-oxygenase (COX) inhibition with aspirin is known to prevent the onset of preeclampsia in high-risk patients. In the present study, we hypothesised that treatment with aspirin would prevent the development of angiogenesis inhibitor-induced hypertension and kidney damage. Our aims were to compare the effects of low-dose (COX-1 inhibition) and high-dose (dual COX-1 and COX-2 inhibition) aspirin on blood pressure, vascular function, oxidative stress, ET-1 and prostanoid levels and kidney damage during angiogenesis-inhibitor therapy in rodents. To this end, Wistar Kyoto rats were treated with vehicle, angiogenesis inhibitor (sunitinib) alone or in combination with low- or high-dose aspirin for 8 days (n=5-7/group). Our results demonstrated that prostacyclin (PGI2) and ET-1 were increased during angiogenesis-inhibitor therapy, while thromboxane (TXA2) was unchanged. Both low- and high-dose aspirin blunted angiogenesis inhibitor-induced hypertension and vascular superoxide production to a similar extent, whereas only high-dose aspirin prevented albuminuria. While circulating TXA2 and prostaglandin F2α levels were reduced by both low- and high-dose aspirin, circulating and urinary levels PGI2 were only reduced by high-dose aspirin. Lastly, treatment with aspirin did not significantly affect ET-1 or vascular function. Collectively our findings suggest that prostanoids contribute to the development of angiogenesis inhibitor-induced hypertension and renal damage and that targeting the prostanoid pathway could be an effective strategy to mitigate the unwanted cardiovascular and renal toxicities associated with angiogenesis inhibitors.
Assuntos
Hipertensão , Pré-Eclâmpsia , Inibidores da Angiogênese/uso terapêutico , Animais , Aspirina/farmacologia , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Endotelina-1/metabolismo , Epoprostenol/metabolismo , Epoprostenol/farmacologia , Epoprostenol/uso terapêutico , Feminino , Humanos , Hipertensão/induzido quimicamente , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Rim/metabolismo , Pré-Eclâmpsia/induzido quimicamente , Pré-Eclâmpsia/tratamento farmacológico , Pré-Eclâmpsia/metabolismo , Gravidez , Prostaglandina-Endoperóxido Sintases/metabolismo , Ratos , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
RESEARCH QUESTION: Does first-trimester maternal renin-angiotensin-aldosterone system (RAAS) activity determine early and late fetal growth and birthweight? DESIGN: A total of 201 ongoing pregnancies, of which 104 were conceived naturally, seven following single intrauterine insemination (IUI), eight after IUI with ovulation induction and 82 after IVF or intracytoplasmic sperm injection treatment were selected from the Rotterdam Periconceptional Cohort. Renin, prorenin and aldosterone concentrations were determined in blood plasma at 9 and 11 weeks of gestational age. Serial crown-rump length and embryonic volume at 7, 9 and 11 weeks of gestational age were measured using virtual reality software to assess early fetal growth. Estimated fetal weight at 22 and 32 weeks of gestational age and birthweight were measured to assess late fetal growth trajectories. Pregnancy outcomes, small for gestational age (SGA) (
Assuntos
Sistema Renina-Angiotensina , Renina , Aldosterona , Peso ao Nascer , Feminino , Desenvolvimento Fetal , Humanos , Gravidez , Primeiro Trimestre da Gravidez , Estudos Prospectivos , Sistema Renina-Angiotensina/fisiologia , Ultrassonografia Pré-NatalRESUMO
AIM: To determine the effect of the dipeptidyl peptidase-4 inhibitor linagliptin on postprandial glomerular hyperfiltration compared with the sulphonylurea glimepiride in adults with type 2 diabetes (T2D). MATERIALS AND METHODS: In this predefined substudy within a randomized, double-blind, parallel-group, intervention trial, overweight people with T2D without renal impairment were treated with once-daily linagliptin 5 mg (N = 10) or glimepiride 1 mg (N = 13) as an add-on to metformin for 8 weeks. After a standardized liquid protein-rich meal, the glomerular filtration rate (GFR) and effective renal plasma flow were determined by inulin and para-aminohippuric acid clearance, respectively, based on timed urine sampling. Intrarenal haemodynamics were estimated using the Gomez equations. Glucoregulatory/vasoactive hormones, urinary pH and fractional excretions (FE) of sodium, potassium and urea were measured. RESULTS: Compared with glimepiride, linagliptin increased the postprandial filtration fraction (FF; mean difference 2.1%-point; P = .016) and estimated glomerular hydraulic pressure (mean difference 3.0 mmHg; P = .050), and tended to increase GFR (P = .08) and estimated efferent renal arteriolar resistance (RE ; P = .08) from baseline to week 8. No differences in FE were noted. Glimepiride reduced HbA1c more than linagliptin (mean difference -0.40%; P = .004), without between-group differences in time-averaged postprandial glucose levels. In the linagliptin group, change in FF correlated with change in mean arterial pressure (R = 0.807; P = .009) and time-averaged mean glucagon (R = 0.782; P = .008), but not with changes in glucose, insulin, intact glucagon-like peptide-1, renin or FENa . Change in glucagon was associated with change in RE (R = 0.830; P = .003). CONCLUSIONS: In contrast to our hypothesis, compared with glimepiride, linagliptin does not reduce postprandial hyperfiltration, yet appears to increase FF after meal ingestion by increasing blood pressure or RE .
Assuntos
Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Adulto , Glicemia , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Dipeptidil Peptidases e Tripeptidil Peptidases , Método Duplo-Cego , Hemoglobinas Glicadas , Hemodinâmica , Humanos , Hipoglicemiantes/uso terapêutico , Linagliptina/uso terapêutico , Compostos de Sulfonilureia , Resultado do TratamentoRESUMO
[Figure: see text].