RESUMEN

Posttranslational modifications can enhance immunogenicity of self-proteins. In several conditions, including hypertension, systemic lupus erythematosus, and heart failure, isolevuglandins (IsoLGs) are formed by lipid peroxidation and covalently bond with protein lysine residues. Here, we show that the murine class I major histocompatibility complex (MHC-I) variant H-2Db uniquely presents isoLG-modified peptides and developed a computational pipeline that identifies structural features for MHC-I accommodation of such peptides. We identified isoLG-adducted peptides from renal proteins, including sodium glucose transporter 2, cadherin 16, Kelch domain-containing protein 7A, and solute carrier family 23, that are recognized by CD8+ T cells in tissues of hypertensive mice, induce T cell proliferation in vitro, and prime hypertension after adoptive transfer. Finally, we find patterns of isoLG-adducted antigen restriction in class I human leukocyte antigens that are similar to those in murine analogs. Thus, we have used a combined computational and experimental approach to define likely antigenic peptides in hypertension.

Asunto(s)

Modelos Animales de Enfermedad , Hipertensión , Procesamiento Proteico-Postraduccional , Animales , Hipertensión/inmunología , Hipertensión/metabolismo , Hipertensión/patología , Ratones , Humanos , Linfocitos T CD8-positivos/inmunología , Autoantígenos/inmunología , Autoantígenos/metabolismo , Antígenos H-2/inmunología , Antígenos H-2/genética , Antígenos H-2/metabolismo , Péptidos/inmunología , Péptidos/metabolismo

RESUMEN

Atrial Natriuretic Peptide (ANP) plays an important role in blood pressure regulation. Low levels of ANP correlate with the development of salt-sensitive hypertension (SS-HTN). Our previous studies indicated that ANP deficiency exacerbated renal function decline in SS-HTN. In the heart and fat tissue, ANP was reported to affect lipid peroxidation and mitochondrial bioenergetics but the effects of ANP on mitochondrial function in the kidney are unexplored. We hypothesized that ANP deficiency in SS-HTN causes renal bioenergetic shift, leading to disruption of mitochondrial network and oxidative stress. To address the hypothesis, we placed Dahl SS wild-type (SSWT) and ANP knockout (SSNPPA-/-) rats on 4% NaCl high salt (HS) diet to induce HTN or maintained them on 0.4% NaCl normal salt (NS) diet and assessed mitochondrial bioenergetics and dynamics using spectrofluorimetry, Seahorse assay, electron paramagnetic resonance (EPR) spectroscopy, Western blotting, electron microscopy, PCR and cytokine assays. We report that under high salt conditions, associated with hypertension and renal damage, the SSNPPA-/- rats exhibit a decrease in mitochondrial membrane potential and elevation in mitochondrial ROS levels compared to SSWT. The redox shift is also evident by the presence of more pronounced medullar lipid peroxidation in the SSNPPA-/- strain. We also revealed fragmented, more damaged mitochondria in the SSNPPA-/- rats, accompanied by increased turnover and biogenesis. Overall, our data indicate that ANP deficiency causes disruptions in mitochondrial bioenergetics and dynamics which likely contributes to aggravation of the renal damage and hypertension in the Dahl SS rat; the major pathological effects are evident in the groups subjected to a combined salt and ANP deficiency-induced mitochondrial stress.

Asunto(s)

Factor Natriurético Atrial , Metabolismo Energético , Hipertensión , Mitocondrias , Ratas Endogámicas Dahl , Animales , Factor Natriurético Atrial/metabolismo , Mitocondrias/metabolismo , Ratas , Hipertensión/metabolismo , Hipertensión/etiología , Hipertensión/patología , Masculino , Estrés Oxidativo , Corteza Renal/metabolismo , Corteza Renal/patología , Cloruro de Sodio Dietético/efectos adversos

RESUMEN

Hypertension affects one-third of the adult population worldwide, with primary aldosteronism (PA) accounting for at least 5-10% of these cases. The aldosterone synthase enzyme (CYP11B2) plays a pivotal role in PA manifestation, as increased expression of CYP11B2 leads to excess aldosterone synthesis. Physiological expression of CYP11B2 in humans is normally limited to cells of the adrenal zona glomerulosa under tight homeostatic regulation. In PA, however, there are CYP11B2-positive lesions in the adrenal cortex that autonomously secrete aldosterone, highlighting the dysregulation of adrenal cortex zonation and function as a key aspect of PA pathogenesis. Thus, this review aims to summarize the development of the adrenal glands, the key regulators of adrenal cortex homeostasis, and the dysregulation of this homeostasis. It also discusses the development of CYP11B2 inhibitors for therapeutic use in patients with hypertension, as well as the current knowledge of the effects of CYP11B2 inhibition on adrenal cortex homeostasis and cell fate. Understanding the control of adrenal cell fate may offer valuable insights into both the pathogenesis of PA and the development of alternative treatment approaches for PA.

Asunto(s)

Glándulas Suprarrenales , Aldosterona , Citocromo P-450 CYP11B2 , Hiperaldosteronismo , Humanos , Aldosterona/metabolismo , Aldosterona/biosíntesis , Citocromo P-450 CYP11B2/metabolismo , Hiperaldosteronismo/metabolismo , Hiperaldosteronismo/patología , Glándulas Suprarrenales/metabolismo , Animales , Corteza Suprarrenal/metabolismo , Corteza Suprarrenal/citología , Hipertensión/metabolismo , Hipertensión/patología , Zona Glomerular/metabolismo , Diferenciación Celular , Homeostasis

RESUMEN

INTRODUCTION: Hypertension (HTN) is a major cardiovascular disease that can cause and be worsened by renal damage and inflammation. We previously reported that renal lymphatic endothelial cells (LECs) increase in response to HTN and that augmenting lymphangiogenesis in the kidneys reduces blood pressure and renal pro-inflammatory immune cells in mice with various forms of HTN. Our aim was to evaluate the specific changes that renal LECs undergo in HTN. METHODS: We performed single-cell RNA sequencing. Using the angiotensin II-induced and salt-sensitive mouse models of HTN, we isolated renal CD31+ and podoplanin+ cells. RESULTS: Sequencing of these cells revealed three distinct cell types with unique expression profiles, including LECs. The number and transcriptional diversity of LECs increased in samples from mice with HTN, as demonstrated by 597 differentially expressed genes (p < 0.01), 274 significantly enriched pathways (p < 0.01), and 331 regulons with specific enrichment in HTN LECs. These changes demonstrate a profound inflammatory response in renal LECs in HTN, leading to an increase in genes and pathways associated with inflammation-driven growth and immune checkpoint activity in LECs. CONCLUSION: These results reinforce and help to further explain the benefits of renal LECs and lymphangiogenesis in HTN.

Asunto(s)

Modelos Animales de Enfermedad , Células Endoteliales , Hipertensión , Inflamación , Riñón , Animales , Ratones , Hipertensión/genética , Hipertensión/patología , Células Endoteliales/metabolismo , Células Endoteliales/patología , Riñón/patología , Riñón/metabolismo , Expresión Génica , Linfangiogénesis/genética

RESUMEN

Hyperproliferation of vascular smooth muscle cells (VSMCs) is a driver of hypertensive vascular remodeling. This study aimed to uncover the mechanism of BTB and CNC homology 1 (BACH1) and microRNAs (miRNAs) in VSMC growth and hypertensive vascular remodeling. With the help of TargetScan, miRWalk, miRDB, and miRTarBase online database, we identified that BACH1 might be targeted by miR-196a-5p, and overexpressed in VSMCs and aortic tissues from spontaneously hypertensive rats (SHRs). Gain- and loss-of-function experiments demonstrated that miR-196a-5p suppressed VSMC proliferation, oxidative stress and hypertensive vascular remodeling. Double luciferase reporter gene assay and functional verification showed that miR-196a-5p cracked down the transcription and translation of BACH1 in both Wistar Kyoto rats (WKYs) and SHRs. Silencing BACH1 mimicked the actions of miR-196a-5p overexpression on attenuating the proliferation and oxidative damage of VSMCs derived from SHRs. Importantly, miR-196a-5p overexpression and BACH1 knockdown cooperatively inhibited VSMC proliferation and oxidative stress in SHRs. Furthermore, miR-196a-5p, if knocked down in SHRs, aggravated hypertension, upregulated BACH1 and promoted VSMC proliferation, all contributing to vascular remodeling. Taken together, targeting miR-196a-5p to downregulate BACH1 may be a promising strategy for retarding VSMC proliferation and hypertensive vascular remodeling.

Asunto(s)

Factores de Transcripción con Cremalleras de Leucina de Carácter Básico , Proliferación Celular , MicroARNs , Músculo Liso Vascular , Miocitos del Músculo Liso , Estrés Oxidativo , Ratas Endogámicas SHR , Remodelación Vascular , Animales , Humanos , Masculino , Ratas , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Proliferación Celular/genética , Regulación de la Expresión Génica , Hipertensión/metabolismo , Hipertensión/genética , Hipertensión/patología , MicroARNs/genética , MicroARNs/metabolismo , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Ratas Endogámicas WKY , Remodelación Vascular/genética

RESUMEN

Hypertension, a disease with known sexual dimorphism, accelerates aging-associated arterial stiffening, partly because of the activation of matrix remodeling caused by increased biomechanical load. In this study, we tested the effect of biological sex and the role of the matrix remodeling enzyme lysyl oxidase-like 2 (LOXL2) in hypertension-induced arterial stiffening. Hypertension was induced by angiotensin II (ANG II) infusion via osmotic minipumps in 12- to 14-wk-old male and female mice. Blood pressure and pulse wave velocity (PWV) were measured noninvasively. Wire myography and uniaxial tensile testing were used to test aortic vasoreactivity and mechanical properties. Aortic wall composition was examined by histology and Western blotting. Uniaxial stretch of cultured cells was used to evaluate the effect of biomechanical strain. LOXL2's catalytic function was examined using knockout and inhibition. ANG II infusion-induced hypertension in both genotypes and sexes. Wild-type (WT) males exhibited arterial stiffening in vivo and ex vivo. Aortic remodeling with increased wall thickness, intralamellar distance, higher LOXL2, and collagen I and IV content was noted in WT males. Female mice did not exhibit increased PWV despite the onset of hypertension. LOXL2 depletion improved vascular reactivity and mechanics in hypertensive males. LOXL2 depletion improved aortic mechanics but worsened hypercontractility in females. Hypertensive cyclic strain contributed to LOXL2 upregulation in the cell-derived matrix in vascular smooth muscle cells (VSMCs) but not endothelial cells. LOXL2's catalytic function facilitated VSMC alignment in response to biomechanical strain. In conclusion, in males, arterial stiffening in hypertension is driven both by VSMC response and matrix remodeling. Females are protected from PWV elevation in hypertension. LOXL2 depletion is protective in males with improved mechanical and functional aortic properties. VSMCs are the primary source of LOXL2 in the aorta, and hypertension increases LOXL2 processing and shifts to collagen I accumulation. Overall, LOXL2 depletion offers protection in young hypertensive males and females.NEW & NOTEWORTHY We examined the effect of sex on the evolution of angiotensin II (ANG II)-induced hypertension and the role of lysyl oxidase-like 2 (LOXL2), an enzyme that catalyzes matrix cross linking. While ANG II led to hypertension and worsening vascular reactivity in both sexes, aortic remodeling and stiffening occurred only in males. LOXL2 depletion improved outcomes in males but not females. Thus males and females exhibit a distinct etiology of hypertension and LOXL2 is an effective target in males.

Asunto(s)

Aminoácido Oxidorreductasas , Angiotensina II , Hipertensión , Remodelación Vascular , Rigidez Vascular , Animales , Femenino , Masculino , Ratones , Aminoácido Oxidorreductasas/metabolismo , Aminoácido Oxidorreductasas/genética , Aorta/fisiopatología , Aorta/patología , Aorta/enzimología , Aorta/efectos de los fármacos , Aorta/metabolismo , Células Cultivadas , Modelos Animales de Enfermedad , Hipertensión/inducido químicamente , Hipertensión/fisiopatología , Hipertensión/enzimología , Hipertensión/metabolismo , Hipertensión/patología , Ratones Endogámicos C57BL , Ratones Noqueados , Músculo Liso Vascular/fisiopatología , Músculo Liso Vascular/enzimología , Músculo Liso Vascular/patología , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/efectos de los fármacos , Miocitos del Músculo Liso/enzimología , Miocitos del Músculo Liso/patología , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/efectos de los fármacos , Factores Sexuales

RESUMEN

Hypertension affects a large number of individuals globally and is a common cause of nephropathy, stroke, ischaemic heart disease and other vascular diseases. While many anti-hypertensive medications are used safely and effectively in clinic practice, controlling hypertensive complications solely by reducing blood pressure (BP) can be challenging. α-Mangostin, a xanthone molecule extracted from the pericarp of Garcinia mangostana L., has shown various beneficial effects such as anti-tumor, anti-hyperuricemia, and anti-inflammatory properties. However, the effects of α-Mangostin on hypertension remain unknown. In this study, we observed that α-Mangostin significantly decreased systolic and diastolic blood pressure in spontaneously hypertensive rats (SHR), possibly through the down-regulation of angiotensin II (Ang II). We also identified early markers of hypertensive nephropathy, including urinary N-acetyl-ß-D-glucosaminidase (NAG) and ß2-microglobulin (ß2-MG), which were reduced by α-Mangostin treatment. Mechanistic studies suggested that α-Mangostin may inhibit renal tubular epithelial-to-mesenchymal transformation (EMT) by down-regulating the TGF-ß signaling pathway, thus potentially offering a new therapeutic approach for hypertension and hypertensive nephropathy.

Asunto(s)

Angiotensina II , Presión Sanguínea , Transición Epitelial-Mesenquimal , Hipertensión , Xantonas , Animales , Humanos , Masculino , Ratas , Angiotensina II/metabolismo , Antihipertensivos/farmacología , Antihipertensivos/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Línea Celular , Transición Epitelial-Mesenquimal/efectos de los fármacos , Fibrosis/tratamiento farmacológico , Garcinia mangostana/química , Hipertensión/tratamiento farmacológico , Hipertensión/patología , Hipertensión Renal/tratamiento farmacológico , Hipertensión Renal/patología , Nefritis , Ratas Endogámicas SHR , Transducción de Señal/efectos de los fármacos , Xantonas/farmacología , Xantonas/uso terapéutico

RESUMEN

BACKGROUND: Salt-sensitive hypertension is often more prone to induce damage to target organs such as the heart and kidneys. Abundant recent studies have demonstrated a close association between ferroptosis and cardiovascular diseases. Therefore, we hypothesize that ferroptosis may be closely associated with organ damage in salt-sensitive hypertension. This study aimed to investigate whether ferroptosis is involved in the occurrence and development of myocardial fibrosis and renal fibrosis in salt-sensitive hypertensive rats. METHODS: Ten 7-week-old male Dahl salt-sensitive (Dahl-SS) rats were adaptively fed for 1 week, then randomly divided into two groups and fed either a normal diet (0.3% NaCl, normal diet group) or a high-salt diet (8% NaCl, high-salt diet group) for 8 weeks. Blood pressure of the rats was observed, and analysis of the hearts and kidneys of Dahl-SS rats was conducted via hematoxylin-eosin (HE) staining, Masson staining, Prussian blue staining, transmission electron microscopy, tissue iron content detection, malondialdehyde content detection, immunofluorescence, and Western blot. RESULTS: Compared to the normal diet group, rats in the high-salt diet group had increases in systolic blood pressure and diastolic blood pressure (P < 0.05); collagen fiber accumulation was observed in the heart and kidney tissues (P < 0.01), accompanied by alterations in mitochondrial ultrastructure, reduced mitochondrial volume, and increased density of the mitochondrial double membrane. Additionally, there were significant increases in both iron content and malondialdehyde levels (P < 0.05). Immunofluorescence and Western blot results both indicated significant downregulation (P < 0.05) of xCT and GPX4 proteins associated with ferroptosis in the high-salt diet group. CONCLUSIONS: Ferroptosis is involved in the damage and fibrosis of the heart and kidney tissues in salt-sensitive hypertensive rats.

Asunto(s)

Presión Sanguínea , Ferroptosis , Fibrosis , Hipertensión , Riñón , Miocardio , Ratas Endogámicas Dahl , Cloruro de Sodio Dietético , Animales , Masculino , Riñón/patología , Riñón/metabolismo , Riñón/fisiopatología , Hipertensión/fisiopatología , Hipertensión/patología , Hipertensión/metabolismo , Miocardio/patología , Miocardio/metabolismo , Miocardio/ultraestructura , Cloruro de Sodio Dietético/efectos adversos , Modelos Animales de Enfermedad , Ratas , Enfermedades Renales/patología , Enfermedades Renales/etiología , Enfermedades Renales/metabolismo , Enfermedades Renales/fisiopatología

RESUMEN

AIM: Methamphetamine (METH) chronic exposure is an important risk factor for hypertension development. However, the mechanisms behind METH-induced hypertension remain unclear. Therefore, we aimed to reveal the potential mechanisms underlying METH-induced hypertension. METHODS AND RESULTS: We structured the mouse hypertension model by METH, and observed that METH-treated mice have presented vascular remodeling (large-and small-size arteries) with collagen deposit around the vessel and increasing blood pressure (BP) and Sigma1 receptor (Sigmar1) in vascular tissue. We hypothesized that Sigmar1 is crucial in METH-induced hypertension and vascular remodeling. Sigmar1 knockout (KO) mice and antagonist (BD1047) pretreated mice exposed to METH for six-week showed higher BP and more collagen deposited around vessels than wild-type (WT) mice exposed to METH for six-week, in contrast, mice pretreated with Sigmar1 agonist (PRE-084) had unchanged BP and perivascular collagen despite the six-week METH exposure. Furthermore, we found that METH exposure induced vascular smooth muscle cells (VSMCs) and mesenchymal stem cells to differentiate into the myofibroblast-like cell and secrete collagen into surrounding vessels. Mechanically, Sigmar1 can suppress the COL1A1 expression by blocking the classical fibrotic TGF-ß/Smad2/3 signaling pathway in METH-exposed VSMCs and mesenchymal stem cells. CONCLUSION: Our results suggest that Sigmar1 is involved in METH-induced hypertension and vascular fibrosis by blocking the activation of the TGF-ß/Smad2/3 signaling pathway. Accordingly, Sigmar1 may be a novel therapeutic target for METH-induced hypertension and vascular fibrosis.

Asunto(s)

Hipertensión , Metanfetamina , Músculo Liso Vascular , Receptores sigma , Receptor Sigma-1 , Animales , Masculino , Ratones , Presión Sanguínea/efectos de los fármacos , Colágeno/metabolismo , Modelos Animales de Enfermedad , Hipertensión/inducido químicamente , Hipertensión/metabolismo , Hipertensión/patología , Hipertensión/genética , Células Madre Mesenquimatosas/metabolismo , Metanfetamina/efectos adversos , Metanfetamina/toxicidad , Ratones Endogámicos C57BL , Ratones Noqueados , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Músculo Liso Vascular/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Miocitos del Músculo Liso/efectos de los fármacos , Receptores sigma/metabolismo , Receptores sigma/genética , Transducción de Señal/efectos de los fármacos , Remodelación Vascular/efectos de los fármacos

RESUMEN

BACKGROUND: Vascular smooth muscle cells (VSMCs) are highly plastic. Vessel injury induces a phenotypic transformation from differentiated to dedifferentiated VSMCs, which involves reduced expression of contractile proteins and increased production of extracellular matrix and inflammatory cytokines. This transition plays an important role in several cardiovascular diseases such as atherosclerosis, hypertension, and aortic aneurysm. TGF-ß (transforming growth factor-ß) is critical for VSMC differentiation and to counterbalance the effect of dedifferentiating factors. However, the mechanisms controlling TGF-ß activity and VSMC phenotypic regulation under in vivo conditions are poorly understood. The extracellular matrix protein TN-X (tenascin-X) has recently been shown to bind TGF-ß and to prevent it from activating its receptor. METHODS: We studied the role of TN-X in VSMCs in various murine disease models using tamoxifen-inducible SMC-specific knockout and adeno-associated virus-mediated knockdown. RESULTS: In hypertensive and high-fat diet-fed mice, after carotid artery ligation as well as in human aneurysmal aortae, expression of Tnxb, the gene encoding TN-X, was increased in VSMCs. Mice with smooth muscle cell-specific loss of TN-X (SMC-Tnxb-KO) showed increased TGF-ß signaling in VSMCs, as well as upregulated expression of VSMC differentiation marker genes during vascular remodeling compared with controls. SMC-specific TN-X deficiency decreased neointima formation after carotid artery ligation and reduced vessel wall thickening during Ang II (angiotensin II)-induced hypertension. SMC-Tnxb-KO mice lacking ApoE showed reduced atherosclerosis and Ang II-induced aneurysm formation under high-fat diet. Adeno-associated virus-mediated SMC-specific expression of short hairpin RNA against Tnxb showed similar beneficial effects. Treatment with an anti-TGF-ß antibody or additional SMC-specific loss of the TGF-ß receptor reverted the effects of SMC-specific TN-X deficiency. CONCLUSIONS: In summary, TN-X critically regulates VSMC plasticity during vascular injury by inhibiting TGF-ß signaling. Our data indicate that inhibition of vascular smooth muscle TN-X may represent a strategy to prevent and treat pathological vascular remodeling.

Asunto(s)

Músculo Liso Vascular , Miocitos del Músculo Liso , Transducción de Señal , Tenascina , Remodelación Vascular , Animales , Humanos , Masculino , Ratones , Angiotensina II , Aneurisma de la Aorta/metabolismo , Aneurisma de la Aorta/patología , Aneurisma de la Aorta/genética , Aneurisma de la Aorta/prevención & control , Traumatismos de las Arterias Carótidas/patología , Traumatismos de las Arterias Carótidas/metabolismo , Traumatismos de las Arterias Carótidas/genética , Células Cultivadas , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Hipertensión/metabolismo , Hipertensión/patología , Hipertensión/fisiopatología , Hipertensión/genética , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Noqueados para ApoE , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Neointima , Fenotipo , Tenascina/metabolismo , Tenascina/genética , Tenascina/deficiencia , Factor de Crecimiento Transformador beta/metabolismo

RESUMEN

Aim of this study was to analyse the associations of cardiovascular health and adrenal gland volume as a rather new imaging biomarker of chronic hypothalamic-pituitary-adrenal (HPA) axis activation. The study population originates from the KORA population-based cross-sectional prospective cohort. 400 participants without known cardiovascular disease underwent a whole-body MRI. Manual segmentation of adrenal glands was performed on VIBE-Dixon gradient-echo sequence. MRI based evaluation of cardiac parameters was achieved semi-automatically. Cardiometabolic risk factors were obtained through standardized interviews and medical examination. Univariate and multivariate associations were derived. Bi-directional causal mediation analysis was performed. 351 participants were eligible for analysis (56 ± 9.1 years, male 58.7%). In multivariate analysis, significant associations were observed between adrenal gland volume and hypertension (outcome hypertension: Odds Ratio = 1.11, 95% CI [1.01, 1.21], p = 0.028), left ventricular remodelling index (LVRI) (outcome LVRI: ß = 0.01, 95% CI [0.00, 0.02], p = 0.011), and left ventricular (LV) wall thickness (outcome LV wall thickness: ß = 0.06, 95% CI [0.02, 0.09], p = 0.005). In bi-directional causal mediation analysis adrenal gland volume had a borderline significant mediating effect on the association between hypertension and LVRI (p = 0.052) as well as wall thickness (p = 0.054). MRI-based assessment of adrenal gland enlargement is associated with hypertension and LV remodelling. Adrenal gland volume may serve as an indirect cardiovascular imaging biomarker.

Asunto(s)

Glándulas Suprarrenales , Enfermedades Cardiovasculares , Imagen por Resonancia Magnética , Humanos , Masculino , Persona de Mediana Edad , Glándulas Suprarrenales/diagnóstico por imagen , Glándulas Suprarrenales/patología , Imagen por Resonancia Magnética/métodos , Femenino , Enfermedades Cardiovasculares/diagnóstico por imagen , Estudios Transversales , Anciano , Estudios Prospectivos , Hipertensión/diagnóstico por imagen , Hipertensión/patología , Remodelación Ventricular , Tamaño de los Órganos , Sistema Hipotálamo-Hipofisario/diagnóstico por imagen , Sistema Hipófiso-Suprarrenal/diagnóstico por imagen

RESUMEN

Wnt/ß-catenin signaling dysregulation is associated with the pathogenesis of many human diseases, including hypertension and heart disease. The aim of this study was to immunohistochemically evaluate and compare the expression of the Fzd8, WNT1, GSK-3ß, and ß-catenin genes in the hearts of rats with spontaneous hypertension (SHRs) and deoxycorticosterone acetate (DOCA)-salt-induced hypertension. The myocardial expression of Fzd8, WNT1, GSK-3ß, and ß-catenin was detected by immunohistochemistry, and the gene expression was assessed with a real-time PCR method. In SHRs, the immunoreactivity of Fzd8, WNT1, GSK-3ß, and ß-catenin was attenuated in comparison to that in normotensive animals. In DOCA-salt-induced hypertension, the immunoreactivity of Fzd8, WNT1, GSK-3ß, and ß-catenin was enhanced. In SHRs, decreases in the expression of the genes encoding Fzd8, WNT1, GSK-3ß, and ß-catenin were observed compared to the control group. Increased expression of the genes encoding Fzd8, WNT1, GSK-3ß, and ß-catenin was demonstrated in the hearts of rats with DOCA-salt-induced hypertension. Wnt signaling may play an essential role in the pathogenesis of arterial hypertension and the accompanying heart damage. The obtained results may constitute the basis for further research aimed at better understanding the role of the Wnt/ß-catenin pathway in the functioning of the heart.

Asunto(s)

Glucógeno Sintasa Quinasa 3 beta , Hipertensión , Miocardio , Vía de Señalización Wnt , beta Catenina , Animales , Hipertensión/metabolismo , Hipertensión/etiología , Hipertensión/inducido químicamente , Hipertensión/patología , Ratas , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Masculino , Miocardio/metabolismo , Miocardio/patología , beta Catenina/metabolismo , beta Catenina/genética , Proteína Wnt1/metabolismo , Proteína Wnt1/genética , Ratas Endogámicas SHR , Receptores Frizzled/metabolismo , Receptores Frizzled/genética , Acetato de Desoxicorticosterona

RESUMEN

Stress can play a significant role in arterial hypertension and many other complications of cardiovascular diseases. Considerable attention is paid to the study of the molecular mechanisms involved in the body response to stressful influences, but there are still many blank spots in understanding the details. ISIAH rats model the stress-sensitive form of arterial hypertension. ISIAH rats are characterized by genetically determined enhanced activities of the hypothalamic-pituitary-adrenocortical and sympathetic-adrenomedullary systems, suggesting a functional state of increased stress reactivity. For the first time, the temporal expression patterns of Fos and several related genes were studied in the hypothalamus of adult male hypertensive ISIAH rats after a single exposure to restraint stress for 30, 60, or 120 min. Fos transcription was activated and peaked 1 h after the start of restraint stress. The time course of Fos activation coincided with that of blood pressure increase after stress. Activation of hypothalamic neurons also alters the transcription levels of several transcription factor genes (Jun, Nr4a3, Jdp2, and Ppargc1a), which are associated with the development of cardiovascular diseases. Because Fos induction is a marker of brain neuron activation, activation of hypothalamic neurons and an increase in blood pressure were concluded to accompany increased stress reactivity of the hypothalamic-pituitary-adrenocortical and sympathoadrenal systems in hypertensive ISIAH rats during short-term restraint.

Asunto(s)

Regulación de la Expresión Génica , Hipertensión , Hipotálamo , Animales , Hipertensión/metabolismo , Hipertensión/genética , Hipertensión/patología , Ratas , Hipotálamo/metabolismo , Masculino , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Proteínas Proto-Oncogénicas c-fos/genética , Proteínas Proto-Oncogénicas c-fos/metabolismo , Proteínas Proto-Oncogénicas c-fos/biosíntesis , Restricción Física , Estrés Psicológico/metabolismo , Estrés Psicológico/genética , Estrés Psicológico/fisiopatología , Presión Sanguínea/genética , Estrés Fisiológico/genética , Neuronas/metabolismo , Neuronas/patología

RESUMEN

Purpose: Both hypertension and diabetes are known to increase the wall-to-lumen ratio (WLR) of retinal arterioles, but the differential effects are unknown. Here, we study the timing and relative impact of hypertension versus diabetes on the WLR in diabetic retinopathy (DR) to address this unresolved question. Methods: This prospective cross-sectional study compared the retinal arteriolar WLR in 17 healthy eyes, 15 with diabetes but no apparent DR (DM no DR), and 8 with diabetic macular edema (DME) and either nonproliferative or proliferative DR. We imaged each arteriole using adaptive optics scanning laser ophthalmoscopy and measured the WLR using ImageJ. Multiple linear regression (MLR) was performed to estimate the effects of hypertension, diabetes, and age on the WLR. Results: Both subjects with DM no DR and subjects with DME had significantly higher WLR than healthy subjects (0.36 ± 0.08 and 0.42 ± 0.08 vs. 0.29 ± 0.07, 1-way ANOVA P = 0.0009). MLR in healthy subjects and subjects with DM no DR showed hypertension had the strongest effect (regression coefficient = 0.08, P = 0.009), whereas age and diabetes were not significantly correlated with WLR. MLR in all three groups together (healthy, DM no DR, and DME) showed diabetes had the strongest effect (regression coefficient = 0.05, P = 0.02), whereas age and hypertension were not significantly correlated with WLR. Conclusions: Hypertension may be an early driver of retinal arteriolar wall thickening in preclinical DR, independent of age or diabetes, whereas changes specific to DR may drive wall thickening in DME and later DR stages. Translational Relevance: We offer a framework for understanding the relative contributions of hypertension and diabetes on the vascular wall, and emphasize the importance of hypertension control early in diabetes even before DR onset.

Asunto(s)

Retinopatía Diabética , Hipertensión , Oftalmoscopía , Humanos , Estudios Transversales , Masculino , Retinopatía Diabética/patología , Femenino , Persona de Mediana Edad , Estudios Prospectivos , Arteriolas/patología , Arteriolas/diagnóstico por imagen , Hipertensión/complicaciones , Hipertensión/patología , Anciano , Adulto , Arteria Retiniana/patología , Arteria Retiniana/diagnóstico por imagen , Edema Macular/patología , Edema Macular/diagnóstico por imagen , Edema Macular/etiología

RESUMEN

Apelin receptor (APJ), a member of the class A family of G protein-coupled receptor (GPCR), plays a crucial role in regulating cardiovascular and central nervous systems function. APJ influences the onset and progression of various diseases such as hypertension, atherosclerosis, and cerebral stroke, making it an important target for drug development. Our preliminary findings indicate that APJ can form homodimers, heterodimers, or even higher-order oligomers, which participate in different signaling pathways and have distinct functions compared with monomers. APJ homodimers can serve as neuroprotectors against, and provide new pharmaceutical targets for vascular dementia (VD). This review article aims to summarize the structural characteristics of APJ dimers and their roles in physiology and pathology, as well as explore their potential pharmacological applications.

Asunto(s)

Receptores de Apelina , Multimerización de Proteína , Humanos , Receptores de Apelina/metabolismo , Receptores de Apelina/genética , Receptores de Apelina/química , Animales , Transducción de Señal , Aterosclerosis/metabolismo , Demencia Vascular/metabolismo , Demencia Vascular/patología , Hipertensión/metabolismo , Hipertensión/patología

Asunto(s)

Hipertensión , Animales , Ratones , Hipertensión/inmunología , Hipertensión/patología , Hipertensión/metabolismo , Remodelación Ventricular , Ratones Noqueados , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Humanos , Inmunomodulación

RESUMEN

Biological membranes are composed of a lipid bilayer with embedded proteins, including ion channels like the epithelial sodium channel (ENaC), which are critical for sodium homeostasis and implicated in arterial hypertension (HTN). Changes in the lipid composition of the plasma membrane can significantly impact cellular processes related to physiological functions. We hypothesized that the observed overexpression of ENaC in neutrophils from HTN patients might result from alterations in the structuring domains within the plasma membrane, disrupting the endocytic processes responsible for ENaC retrieval. This study assessed the structural lipid composition of neutrophil plasma membranes from HTN patients along with the expression patterns of key elements regulating ENaC at the plasma membrane. Our findings suggest alterations in microdomain structure and SGK1 kinase activity, which could prolong ENaC presence on the plasma membrane. Additionally, we propose that the proteasomal and lysosomal degradation pathways are insufficient to diminish ENaC presence at the plasma membrane in HTN. These results highlight the importance of understanding ENaC retrieval mechanisms and suggest that targeting these mechanisms could provide insights for developing drugs to prevent and treat HTN.

Asunto(s)

Membrana Celular , Endocitosis , Canales Epiteliales de Sodio , Hipertensión , Neutrófilos , Canales Epiteliales de Sodio/metabolismo , Humanos , Neutrófilos/metabolismo , Hipertensión/metabolismo , Hipertensión/patología , Membrana Celular/metabolismo , Lípidos de la Membrana/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Masculino , Femenino , Proteínas Inmediatas-Precoces/metabolismo , Persona de Mediana Edad , Microdominios de Membrana/metabolismo

RESUMEN

Chronic inflammation is a key element in the progression of essential hypertension (EH). Calcium plays a key role in inflammation, so its receptor, the calcium-sensing receptor (CaSR), is an essential mediator of the inflammatory process. Compelling evidence suggests that CaSR mediates inflammation in tissues and immune cells, where it mediates their activity and chemotaxis. Macrophages (Mφs) play a major role in the inflammatory response process. This study provided convincing evidence that R568, a positive regulator of CaSR, was effective in lowering blood pressure in spontaneously hypertensive rats (SHRs), improving cardiac function by alleviating cardiac hypertrophy and fibrosis. R568 can increase the content of CaSR and M2 macrophages (M2Mφs, exert an anti-inflammatory effect) in myocardial tissue, reduce M1 macrophages (M1Mφs), which have a pro-inflammatory effect in this process. In contrast, NPS2143, a negative state regulator of CaSR, exerted the opposite effect in all of the above experiments. Following this study, R568 increased CaSR content in SHR myocardial tissue, lowered blood pressure, promoted macrophages to M2Mφs and improved myocardial fibrosis, but interestingly, both M1Mφs and M2Mφs were increased in the peritoneal cavity of SHRs, the number of M2Mφs remained lower than M1Mφs. In vitro, R568 increased CaSR content in RAW264.7 cells (a macrophage cell line), regulating intracellular Ca2+ ([Ca2+]i) inhibited NOD-like receptor family protein 3 (NLRP3) inflammasome activation and ultimately prevented its conversion to M1Mφs. The results showed that a decrease in CaSR in hypertensive rats causes further development of hypertension and cardiac damage. EH myocardial remodeling can be improved by CaSR overexpression by suppressing NLRP3 inflammasome activation and macrophage polarization toward M1Mφs and increasing M2Mφs.

Asunto(s)

Macrófagos , Receptores Sensibles al Calcio , Remodelación Ventricular , Animales , Masculino , Ratones , Ratas , Presión Sanguínea , Fibrosis/metabolismo , Hipertensión/metabolismo , Hipertensión/patología , Macrófagos/metabolismo , Miocardio/patología , Miocardio/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Ratas Endogámicas SHR , Receptores Sensibles al Calcio/metabolismo , Remodelación Ventricular/fisiología

RESUMEN

The corpus callosum is composed of several subregions, distinct in cellular and functional organization. This organization scheme may render these subregions differentially vulnerable to the aging process. Callosal integrity may be further compromised by cardiovascular risk factors, which negatively influence white matter health. Here, we test for heterochronicity of aging, hypothesizing an anteroposterior gradient of vulnerability to aging that may be altered by the effects of cardiovascular health. In 174 healthy adults across the adult lifespan (mean age = 53.56 ± 18.90; range, 20-94 years old, 58.62% women), pulse pressure (calculated as participant's systolic minus diastolic blood pressure) was assessed to determine cardiovascular risk. A deterministic tractography approach via diffusion-weighted imaging was utilized to extract fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (AD) from each of five callosal subregions, serving as estimates of microstructural health. General linear models tested the effects of age, hypertension, and pulse pressure on these cross-sectional metrics. We observed no significant effect of hypertensive diagnosis on callosal microstructure. We found a significant main effect of age and an age-pulse pressure interaction whereby older age and elevated pulse pressure were associated with poorer FA, AD, and RD. Age effects revealed nonlinear components and occurred along an anteroposterior gradient of severity in the callosum. This gradient disappeared when pulse pressure was considered. These results indicate that age-related deterioration across the callosum is regionally variable and that pulse pressure, a proxy of arterial stiffness, exacerbates this aging pattern in a large lifespan cohort.

Asunto(s)

Envejecimiento , Presión Sanguínea , Cuerpo Calloso , Humanos , Cuerpo Calloso/diagnóstico por imagen , Cuerpo Calloso/fisiología , Femenino , Persona de Mediana Edad , Anciano , Adulto , Masculino , Envejecimiento/fisiología , Envejecimiento/patología , Anciano de 80 o más Años , Adulto Joven , Presión Sanguínea/fisiología , Imagen de Difusión Tensora , Hipertensión/fisiopatología , Hipertensión/patología , Estudios Transversales , Imagen de Difusión por Resonancia Magnética

RESUMEN

Currently, more and more people are suffering from chronic kidney disease (CKD). It is estimated that CKD affects over 10% of the population worldwide. This is a significant issue, as the kidneys largely contribute to maintaining homeostasis by, among other things, regulating blood pressure, the pH of blood, and the water-electrolyte balance and by eliminating unnecessary metabolic waste products from blood. What is more, this disease does not show any specific symptoms at the beginning. The development of CKD is predisposed by certain conditions, such as diabetes mellitus or hypertension. However, these disorders are not the only factors promoting the onset and progression of CKD. The primary purpose of this review is to examine renin-angiotensin-aldosterone system (RAAS) activity, transforming growth factor-ß1 (TGF-ß1), vascular calcification (VC), uremic toxins, and hypertension in the context of their impact on the occurrence and the course of CKD. We firmly believe that a deeper comprehension of the cellular and molecular mechanisms underlying CKD can lead to an enhanced understanding of the disease. In the future, this may result in the development of medications targeting specific mechanisms involved in the decline of kidney function. Our paper unveils the selected processes responsible for the deterioration of renal filtration abilities.

Asunto(s)

Progresión de la Enfermedad , Insuficiencia Renal Crónica , Sistema Renina-Angiotensina , Humanos , Insuficiencia Renal Crónica/patología , Insuficiencia Renal Crónica/metabolismo , Sistema Renina-Angiotensina/fisiología , Animales , Hipertensión/fisiopatología , Hipertensión/patología , Calcificación Vascular/metabolismo , Calcificación Vascular/patología , Calcificación Vascular/fisiopatología , Factor de Crecimiento Transformador beta1/metabolismo , Riñón/patología , Riñón/metabolismo , Riñón/fisiopatología