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1.
Bratisl Lek Listy ; 121(1): 73-78, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31950843

RESUMEN

AIM: The aim of the present study was to investigate the immunohistochemical expression of selected collagen types, namely collagen types I and V and procollagen type III in the renal parenchyma and interstitium and in the myocardium of spontaneously hypertensive rats. MATERIAL AND METHODS: For the present study, we used two age groups of 6- and 12-month-old spontaneously hypertensive rats. An immunohistochemical analysis was conducted with monoclonal antibodies against collagen types I and V and procollagen type III. A semi-quantitative analysis of immunostaining intensity was conducted with the Image J software. RESULTS: In the kidney, all three molecules showed higher expression at the age of 12 months, which was particularly notable for procollagen type III and collagen type V, which stained as highly-positive. In the myocardium, the immunoreactivity of collagen types I and V was stronger in 12-month-old animals, while that of procollagen type III did not change substantially. CONCLUSION: The present study suggests a role of collagen types III and V in hypertensive kidney disease, while also establishing the role of increased expression of collagen types I and V in adverse myocardial remodeling (Tab. 1, Fig. 2, Ref. 48).


Asunto(s)
Hipertensión , Riñón , Miocardio , Animales , Colágeno/metabolismo , Corazón , Hipertensión/metabolismo , Hipertensión/fisiopatología , Riñón/metabolismo , Miocardio/metabolismo , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Remodelación Vascular
2.
Life Sci ; 242: 117211, 2020 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-31891720

RESUMEN

Ventricular hypertrophy is a risk factors for arrhythmias, ischemia and sudden death. It involves cellular modifications leading to a pathological remodeling and is associated with heart failure. The activation of the G protein-coupled estrogen receptor (GPER) mediates beneficial actions in the cardiovascular system. Our goal was to prevent and regress the hypertrophy by the activation of GPER in neonatal cardiac myocytes (NRCM) and SHR male rats. Aldosterone increased the neonatal cardiomyocytes cell surface area after 48 h of incubation. The aldo-induced hypertrophy was blocked by the mineralocorticoid receptor (MR) inhibitor Eplererone or the reduction of MR expression by siRNA. The activation of GPER by the agonist G-1 totally prevented the increase surface area by Ald. The transfection of neonatal rat cardiac myocytes with a siRNA against GPER or the incubation with GPER blockers G-15 and G-36 inhibited the protection of G-1. The significant increase of cell surface area after 48 h of incubation with Ald was totally regressed in 24 h by the presence of G-1, indicating that the activation of GPER not only prevent the hypertrophy but also regress the hypertrophy when it is already established. In the in vivo model, G-1 or Vehicle was constantly infused via the minipump to SHR. The reduction of the hypertrophy by G-1 was evident by the cross-sectional area, BNP and ANP markers and by echocardiography. In this studied we demonstrated that the activation of GPER prevented and regressed the hypertrophy induced by Ald in NRCM and regressed hypertrophy in SHR rats.


Asunto(s)
Cardiomegalia/prevención & control , Receptores Acoplados a Proteínas G/metabolismo , Animales , Animales Recién Nacidos , Western Blotting , Cardiomegalia/diagnóstico por imagen , Células Cultivadas , Ciclopentanos/farmacología , Ecocardiografía , Eplerenona/farmacología , Masculino , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Quinolinas/farmacología , Ratas , Ratas Endogámicas SHR , Ratas Wistar , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Receptores Acoplados a Proteínas G/fisiología
3.
Int Heart J ; 61(1): 128-137, 2020 Jan 31.
Artículo en Inglés | MEDLINE | ID: mdl-31956144

RESUMEN

Sleep and estrogen levels have an impact on neural regulation and are associated with cardiovascular (CV) events. We investigated the effects of estrogen on heart rate variability (HRV) and circadian cycle in spontaneously hypertensive rats (SHRs). Polysomnographic recording was performed in seven male and seven female SHRs during sleep. The electroencephalogram (EEG) and electromyogram (EMG) were evaluated to define active waking (AW), quiet sleep (QS), and paradoxical sleep (PS) stages. Cardiac activities were measured by RR interval of the electrocardiogram (ECG), mean arterial pressure (MAP), and power spectrum of HRV.In ECG, estrogen prolonged the RR interval in total sleep when compared with that at baseline in male SHRs (203.74 ± 6.61 versus 181.30 ± 8.06 ms, P < 0.001) and in female SHRs (169.21 ± 6.43 versus 160.76 ± 10.66 ms, P < 0.05). In HRV, the estrogen increased the high frequency (HF) in total sleep when compared with that at baseline in male SHRs (1.03 ± 0.28 versus 0.60 ± 0.43 ln (ms2), P < 0.001) and in female SHRs (0.71 ± 0.26 versus 0.42 ± 0.19 ln (ms2), P < 0.05).In male SHRs, estrogen increased the frequency of QS (26.50 ± 4.85 versus 20.79 ± 5.07, P < 0.01) and PS (25.64 ± 5.18 versus 20.14 ± 4.75, P < 0.05) stages when compared with baseline. In female SHRs, estrogen increased the percentage of delta waves in total sleep (79.87% ± 3.10% versus 76.71% ± 2.74%, P < 0.05) when compared with that at baseline.In HRV, estrogen leads to neuromodulation by increased parasympathetic tone in all SHRs, suggesting a lower risk to CV events. In sleep analyses, estrogen in male SHRs caused poor sleep quality. In contrast, estrogen in female SHRs demonstrated improved quality of sleep and decreased risk of hypertension.


Asunto(s)
Sistema Nervioso Autónomo/efectos de los fármacos , Estrógenos/administración & dosificación , Sueño/efectos de los fármacos , Animales , Relojes Circadianos/efectos de los fármacos , Electrocardiografía , Electroencefalografía , Estrógenos/farmacología , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Masculino , Polisomnografía , Ratas , Ratas Endogámicas SHR
4.
Biomed Chromatogr ; 34(1): e4714, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31633806

RESUMEN

Eucommia ulmoides Oliv. (E. ulmoides) is a valuable and nourishing medicinal herb in China that has been used in the treatment of hypertension. Given the fact that most traditional Chinese medicine is mainly used to treat disease, investigating the pharmacokinetics of traditional Chinese medicines in the pathological state is more useful than that in the normal state. However, the differences in the absorption kinetics of active ingredients of E. ulmoides extract between pathological and physiological conditions have not been reported. Therefore, in this study, the rat intestinal in situ circulatory perfusion model was used to investigate the differences in absorption kinetics of seven active ingredients of E. ulmoides extract in normal and spontaneously hypertensive rats, namely, genipinic acid, protocatechuic acid, neochlorogenic acid, chlorogenic acid, cryptochlorogenic acid, (+)-pinoresinol di-O-ß-D-glucopyranoside and (+)-pinoresinol 4'-O-ß-D-glucopyranoside. Our results indicate that the pathological state of spontaneous hypertension may change the absorption of active components of E. ulmoides extracts, and these findings may provide a reference for improving the rational use of E. ulmoides in the clinic.


Asunto(s)
Eucommiaceae , Absorción Intestinal , Extractos Vegetales , Animales , Antihipertensivos/análisis , Antihipertensivos/farmacocinética , Líquidos Corporales/química , Ácido Clorogénico/análogos & derivados , Ácido Clorogénico/análisis , Ácido Clorogénico/farmacocinética , Furanos/análisis , Furanos/farmacocinética , Hidroxibenzoatos/análisis , Hidroxibenzoatos/farmacocinética , Lignanos/análisis , Lignanos/farmacocinética , Extractos Vegetales/análisis , Extractos Vegetales/farmacocinética , Ratas , Ratas Endogámicas SHR , Ratas Wistar
5.
Life Sci ; 242: 117209, 2020 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-31870776

RESUMEN

AIMS: Hypertension is an independent risk factor for atrial fibrillation (AF). However, the direct effect of hydrostatic pressure on atrial electrical remodeling is unclear. The present study investigated whether hydrostatic pressure is responsible for atrial electrical remodeling and addressed a potential role of inflammation in this pathology. MAIN METHODS: Whole-cell patch-clamp recordings and biochemical assays were used to study the regulation and expression of ion channels in left atrial appendages in patients with AF, spontaneously hypertensive rats (SHRs), and atrium-derived cells (HL-1 cells) exposed to standard (0 mmHg) and elevated (20, 40 mmHg) hydrostatic pressure. KEY FINDINGS: Both TNF-α and MIF were highly expressed in patients with AF and SHRs. AF inducibility in SHRs was higher after atrial burst pacing, accompanied by a decrease in the L-type calcium current (ICa,L), an increase in the transient outward K+ current (Ito) and ultra-rapid delayed rectifier K+ current (IKur), and a shortened action potential duration (APD), which could be inhibited by atorvastatin. Furthermore, exposure to elevated pressure was associated with electrical remodeling of the HL-1 cells. The peak current density of ICa,L was reduced, while Ito and IKur were increased. Moreover, the expression levels of Kv4.3, Kv1.5, TNF-α, and MIF were upregulated, while the expression of Cav1.2 was downregulated in HL-1 cells after treatment with high hydrostatic pressure (40 mmHg). Atorvastatin alleviated the electrical remodeling and increased inflammatory markers in HL-1 cells induced by high hydrostatic pressure. SIGNIFICANCE: Elevated hydrostatic pressure led to atrial electrical remodeling and increased AF susceptibility by upregulating inflammation.


Asunto(s)
Remodelación Atrial , Citocinas/metabolismo , Presión Hidrostática/efectos adversos , Adulto , Animales , Western Blotting , Femenino , Atrios Cardíacos/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Miocitos Cardíacos/metabolismo , Técnicas de Placa-Clamp , Ratas Endogámicas SHR , Ratas Wistar , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Regulación hacia Arriba
6.
J Agric Food Chem ; 68(3): 759-768, 2020 Jan 22.
Artículo en Inglés | MEDLINE | ID: mdl-31841328

RESUMEN

In this study, we investigated the antihypertensive effects in vitro and in vivo of novel angiotensin-converting enzyme inhibitory (ACEI) peptides purified and identified from bovine bone gelatin hydrolysate (BGH). Thirteen ACEI peptides were identified from BGH, and among which, RGL-(Hyp)-GL and RGM-(Hyp)-GF exhibited high ACE inhibition with IC50 values of 1.44 and 10.23 µM. Molecular docking predicted that RGM-(Hyp)-GF and ACE residues of Glu384, His513, and Lys511 formed hydrogen-bonding interactions at distances of 2.57, 2.99, and 2.42 + 3.0 Å. RGL-(Hyp)-GL formed hydrogen bonds with Lys511 and Tyr523 and generated hydrogen-bonding interactions with His387 and Glu411 in the zinc(II) complexation motif at distances of 2.74 and 3.03 + 1.93 Å. The maximal decrements in systolic blood pressure in spontaneously hypertensive rats induced by one-time gavage of RGL-(Hyp)-GL and RGM-(Hyp)-GF at 30 mg/kg were 31.3 and 38.6 mmHg. RGL-(Hyp)-GL had higher enzyme degradation resistance than that of RGM-(Hyp)-GF in vitro incubation in rat plasma, and they were sequentially degraded into pentapeptides and tetrapeptides within 2 h. Our results indicate that BGH can serve as a nutritional candidate to control blood pressure.


Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/química , Antihipertensivos/química , Huesos/química , Gelatina/química , Péptidos/química , Inhibidores de la Enzima Convertidora de Angiotensina/administración & dosificación , Inhibidores de la Enzima Convertidora de Angiotensina/aislamiento & purificación , Animales , Antihipertensivos/administración & dosificación , Antihipertensivos/aislamiento & purificación , Presión Sanguínea/efectos de los fármacos , Bovinos , Humanos , Hipertensión/tratamiento farmacológico , Hipertensión/fisiopatología , Masculino , Simulación del Acoplamiento Molecular , Péptidos/administración & dosificación , Péptidos/aislamiento & purificación , Peptidil-Dipeptidasa A/química , Hidrolisados de Proteína/química , Ratas , Ratas Endogámicas SHR
7.
Food Chem ; 308: 125601, 2020 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-31670190

RESUMEN

The aim of this work was to analyse the hypotensive effect of amaranth protein/peptides on spontaneously hypertensive rats (SHR). The mechanism of action of these peptides was studied in vivo and ex vivo. We also tested the effect of protection against gastrointestinal digestion (GID) exerted by an O:W emulsion on the integrity of the antihypertensive peptides. All samples tested produced a decrease in blood pressure (SBP). The animals treated with emulsion (GE) and emulsion + peptide (GE+VIKP) showed the most significant reduction in the SBP (42 ±â€¯2 mmHg and 35 ±â€¯2 mmHg, respectively). The results presented suggest that after GID, a variety of peptides with biological activities were released or were resistant to this process. These peptides play a role in the regulation of the SBP by acting on plasma ACE, plasma renin and the vascular system. These results support the use of amaranth protein/peptides in the elaboration of functional foods for hypertensive individuals.


Asunto(s)
Amaranthus/química , Antihipertensivos/farmacología , Hipertensión/tratamiento farmacológico , Péptidos/farmacología , Sistema Renina-Angiotensina/efectos de los fármacos , Animales , Antihipertensivos/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Masculino , Péptidos/uso terapéutico , Proteínas de Plantas/farmacología , Proteínas de Plantas/uso terapéutico , Ratas , Ratas Endogámicas SHR
8.
J Sci Food Agric ; 100(1): 315-324, 2020 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-31525262

RESUMEN

BACKGROUND: In order to utilize tilapia skin gelatin hydrolysate protein, which is normally discarded as industrial waste in the process of fish manufacture, we study the in vivo and in vitro angiotensin-I-converting enzyme (ACE) inhibitory activity of the peptide Leu-Ser-Gly-Tyr-Gly-Pro (LSGYGP). The aim was to provide a pharmacological basis of the development of minimal side effects of ACE inhibitors by comparative analysis with captopril in molecular docking. RESULTS: This peptide from protein-rich wastes showed excellent ACE inhibitory activity (IC50  = 2.577 µmol L-1 ) and exhibited a mixed noncompetitive inhibitory pattern with Lineweaver-Burk plots. Furthermore, LSGYGP and captopril groups both showed significant decreases in blood pressure after 6 h and maintained good digestive stability over 4 h. Molecular bond interactions differentiate competitive captopril upon hydrogen bond interactions and Zn(II) interaction. The C-terminal Pro generates three interactions (hydrogen bonds, hydrophilic interactions and Van der Waals interactions) in the peptide and effectively interacts with the S1 and S2 pockets of ACE. CONCLUSION: LSGYGP, with an IC50 value of 2.577 µmol L-1 , has an antihypertensive effect in spontaneously hypertensive rats. Through comparison with captopril, this study revealed that LSGYGP may be a potential food-derived ACE inhibitory peptide and could act as a functional food ingredient to prevent hypertension. © 2019 Society of Chemical Industry.


Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/química , Antihipertensivos/química , Captopril/química , Hipertensión/tratamiento farmacológico , Péptidos/química , Secuencia de Aminoácidos , Inhibidores de la Enzima Convertidora de Angiotensina/administración & dosificación , Inhibidores de la Enzima Convertidora de Angiotensina/metabolismo , Animales , Antihipertensivos/administración & dosificación , Antihipertensivos/metabolismo , Presión Sanguínea/efectos de los fármacos , Captopril/administración & dosificación , Cíclidos , Digestión , Proteínas de Peces/química , Tracto Gastrointestinal/metabolismo , Humanos , Enlaces de Hidrógeno , Interacciones Hidrofóbicas e Hidrofílicas , Hipertensión/metabolismo , Hipertensión/fisiopatología , Cinética , Masculino , Simulación del Acoplamiento Molecular , Péptidos/metabolismo , Péptidos/farmacología , Peptidil-Dipeptidasa A/química , Peptidil-Dipeptidasa A/metabolismo , Hidrolisados de Proteína/química , Hidrolisados de Proteína/metabolismo , Ratas , Ratas Endogámicas SHR
9.
Zhen Ci Yan Jiu ; 44(12): 911-5, 2019 Dec 25.
Artículo en Chino | MEDLINE | ID: mdl-31867912

RESUMEN

OBJECTIVE: To observe the effect of electroacupuncture (EA) on blood pressure, renal fibrosis and expression of tissue inhibitors of metalloproteinase-1 (TIMP-1), plasminogen activator inhibitor 1 (PAI-1), and alpha smooth muscle actin (α-SMA) in spontaneous hypertension rats (SHR), so as to explore its mechanisms underlying improving hypertensive renal damage. METHODS: Forty male SHR (15 weeks in age) were randomly divided into 5 groups: model, medication (Losartan), Shenshu, Geshu, and Shenshu+Geshu groups(n=8 rats in each group), and the same age-old male 8 Wistar-Kyoto (WKY) rats were used as the normal control group. Rats of the medication group were treated by gavage of Losartan potassium solution (3 mg/mL, 30 mg·kg-1·d-1, once a day for 12 weeks), and those of the 3 EA groups treated by EA stimulation of bilateral "Shenshu" (BL23), "Geshu"(BL17) or both BL23 and BL17 (2 Hz/100 Hz, 1 mA, 15 min each time, once every other day for 12 weeks). The systolic blood pressure of the tail artery was measured before, and 4, 8 and 12 weeks after the intervention. The expression of TIMP-1, PAI-1 and α-SMA proteins of the right kidney tissue was measured by immunohistochemistry. Histopathological changes of the right renal tissue were observed under light microscope after H.E. stain. RESULTS: The blood pressure was significantly higher in the mo-del group than those in the normal control group (P<0.01), and considerably decreased at the 4th , 8th, and 12th week of the interventions in the medication and 3 EA groups (P<0.01). The expression levels of renal TIMP-1, PAI-1 and α-SMA proteins were notably higher in the model group than those in the normal control group and considerably decreased at the 12th week of the interventions in the medication and 3 EA groups than in the model group (P<0.01). H.E. staining of the renal tissue showed disordered arrangement of the renal cells, congestion and dilation of capillaries with thickened vascular wall, renal tubule atrophy and lumen stenosis with some necrosis of renal tubules, protein tubule and cell tubules, increase of some glomerular mesangial matrix and hyperplasia of fibrous tissue in the model group, which was re-latively milder in the medication and 3 EA groups. CONCLUSION: EA of BL23 and BL17 can reduce the blood pressure in SHR, which may be related to its function in down-regulating expression of TIMP-1, PAI-1 and α-SMA proteins.


Asunto(s)
Electroacupuntura , Hipertensión , Animales , Fibrosis , Masculino , Ratas , Ratas Endogámicas SHR , Ratas Sprague-Dawley
10.
Nihon Yakurigaku Zasshi ; 154(5): 250-254, 2019.
Artículo en Japonés | MEDLINE | ID: mdl-31735753

RESUMEN

Benign prostatic hyperplasia/benign prostatic enlargement (BPH/BPE) is a common proliferative disease, and giving rise to associate with lower urinary tract symptoms (LUTS). However, the pathogenesis is not well clarified, and thought to be multifactorial. There are some lines of evidence that impairment in the blood supply of the lower urinary tract causes development of BPH/BPE. Clinical data showed an association between the development of BPH/BPE and atherosclerotic disease such as hypertension, diabetes and hyperlipidemia. The spontaneously hypertensive rat (SHR) has been used as model of genetic hypertension. SHR also shows decreased blood flow and hyperplastic morphological abnormalities in the ventral prostate. Our previous studies demonstrated that chronic treatment with vasodilative drugs nicorandil (ATP sensitive potassium channel opener) and silodosin (alpha1 adrenoceptor antagonist) increased blood flow and suppressed the growth factor and morphological abnormalities in the SHR ventral prostate. These data suggested that prostatic blood flow could be therapeutic targets for BPH/LUTS.


Asunto(s)
Próstata/irrigación sanguínea , Hiperplasia Prostática/tratamiento farmacológico , Vasodilatadores/uso terapéutico , Animales , Hipertensión/complicaciones , Indoles/uso terapéutico , Síntomas del Sistema Urinario Inferior/etiología , Masculino , Nicorandil/uso terapéutico , Próstata/fisiopatología , Hiperplasia Prostática/complicaciones , Ratas , Ratas Endogámicas SHR
11.
J Appl Oral Sci ; 27: e20180574, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31596365

RESUMEN

OBJECTIVES: Hypertension is one of the main causes of premature death in the world; also, it is associated with several bone alterations. Preclinical studies have demonstrated delayed alveolar bone healing in hypertensive rats. However, losartan has been favorable for consolidation of bone grafts and reduction in active periodontitis. Therefore, losartan is suggested to be effective in bone formation stages, as well as in the synthesis of matrix proteins and mineralization. To evaluate the alveolar bone dynamics in hypertensive rats treated with losartan by laser confocal microscopy and histological analysis. METHODOLOGY: Thirty-two rats, 16 spontaneously hypertensive rats (SHR) and 16 Wistar albinus rats, treated or not with losartan (30 mg/kg/day) were used. Calcein fluorochrome at 21 days and alizarin red fluorochrome at 49 days were injected in rats (both 20 mg/kg). The animals were submitted to euthanasia 67 days after treatment, and then the right maxilla was removed for laser confocal microscopy analysis and the left maxilla for histological analysis. RESULTS: This study showed a greater calcium marking in normotensive animals treated with losartan in relation to the other groups. Laser confocal microscopy parameters showed higher values of bone volume formed, mineralized surface, active surface of mineralization and bone formation rate in normotensive animals treated with losartan. However, a smaller mineralized surface was observed in all hypertensive animals. CONCLUSION: Losartan can improve bone mineralization parameters under normal physiological conditions, but the same anabolic effect does not occur under hypertension.


Asunto(s)
Proceso Alveolar/efectos de los fármacos , Proceso Alveolar/fisiopatología , Antihipertensivos/farmacología , Hipertensión/fisiopatología , Losartán/farmacología , Proceso Alveolar/patología , Animales , Presión Sanguínea/efectos de los fármacos , Regeneración Ósea/efectos de los fármacos , Calcificación Fisiológica/efectos de los fármacos , Fluoresceínas/análisis , Masculino , Microscopía Confocal , Osteogénesis/efectos de los fármacos , Ratas Endogámicas SHR , Ratas Wistar , Reproducibilidad de los Resultados , Factores de Tiempo
12.
Cell Physiol Biochem ; 53(4): 713-730, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31599538

RESUMEN

BACKGROUND/AIMS: Renal injury related to hypertension is characterized by glomerular and tubulointerstitial damage. The overactivation of the renin-angiotensin system mainly by angiotensin II (AII) seems to be a main contributor to progressive renal fibrosis. Epithelial to mesenchymal transition (EMT) is a mechanism that promotes renal fibrosis. Owing to heat shock protein 70 (Hsp70) cytoprotective properties, the chaperone exhibits an important potential as a therapeutic target. We investigate the role of Hsp70 on Angiotensin II induced epithelial mesenchymal transition within the Losartan effect in proximal tubule cells (PTCs) from a genetic model of hypertension in rats (SHR). METHODS: Primary cell culture of PTCs from SHR and Wistar Kyoto (WKY) rats were stimulated with AII, treated with Losartan (L), (L+AII) or untreated (Cc). The functional Hsp70 role in Losartan effect, after silencing its expression by cell transfection, was determined by Immunofluorescence; Western blotting; Gelatin Zymography assays; Scratch wound assays; flow cytometry; and Live Cell Time-lapse microscopy. RESULTS: (L) and (L+AII) treatments induced highly organized actin filaments and increased cortical actin in SHR PTCs. However, SHR PTCs (Cc) and (AII) treated cells showed disorganized actin. After Hsp72 knockdown in SHR PTCs, (L) was unable to stabilize the actin cytoskeleton. We demonstrated that (L) and (L+AII) increased E-cadherin levels and decreased vinculin, α-SMA, vimentin, pERK, p38 and Smad2-3 activation compared to (AII) and (Cc) SHR PTCs. Moreover, (L) inhibited MMP-2 and MMP-9 secretion, reduced migration and cellular displacement, stabilizing intercellular junctions. Notably, (L) treatment in shHsp72 knockdown SHR PTCs showed results similar to SHR PTCs (Cc). CONCLUSION: Our results demonstrate that Losartan through Hsp70 inhibits the EMT induced by AII in proximal tubule cells derived from SHR.


Asunto(s)
Angiotensina II/farmacología , Transición Epitelial-Mesenquimal/efectos de los fármacos , Proteínas HSP70 de Choque Térmico/metabolismo , Losartán/farmacología , Citoesqueleto de Actina/efectos de los fármacos , Animales , Cadherinas/metabolismo , Movimiento Celular/efectos de los fármacos , Células Cultivadas , Adhesiones Focales/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Proteínas HSP70 de Choque Térmico/antagonistas & inhibidores , Proteínas HSP70 de Choque Térmico/genética , Túbulos Renales Proximales/citología , Túbulos Renales Proximales/metabolismo , Masculino , Metaloproteinasa 2 de la Matriz/metabolismo , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Vinculina/metabolismo
13.
Life Sci ; 237: 116890, 2019 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-31606379

RESUMEN

AIMS: Telmisartan (TEL), an angiotensin II type I receptor blocker and PPARγ partial agonist, has been used for to treat hypertension. It is known that PPARγ activation induces bone loss. Therefore, we evaluate the effects of telmisartan on PPARγ protein expression, biomechanics, density and bone microarchitecture of femurs and lumbar vertebrae in SHR ovariectomized animals, a model of hypertension in which preexisting bone impairment has been demonstrated. MAIN METHODS: SHR females (3 months old) were distributed into four groups: sham (S), sham + TEL (ST), OVX (C) and OVX + TEL (CT). TEL (5 mg/kg/day) or vehicle were administered according to the groups. After the protocol, blood pressure was measured and density, microarchitecture and biomechanics of bone were analyzed. Western blotting analysis was performed to evaluate PPARγ protein expression in the bones. KEY FINDINGS: Castration induced a deleterious effect on mineral density and trabecular parameters, with telmisartan enhancing such effects. Telmisartan increased PPARγ levels, which were at their highest when the treatment was combined with castration. As to biomechanical properties, telmisartan reduced the stiffness in the castration group (CT vs. S or C group), as well as resilience and failure load in ST group (vs. all others groups). SIGNIFICANCE: These results demonstrated that telmisartan compromised bone density and microarchitecture in animals that shows preexisting osteoporotic bone disorders, probably via mechanisms associated with increased PPARγ. If this translates to humans, a need for greater caution in the use of telmisartan by patients that have preexisting bone problems, as in the postmenopausal period, may be in order.


Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Enfermedades Óseas/tratamiento farmacológico , Hueso Esponjoso/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Osteoporosis/tratamiento farmacológico , PPAR gamma/metabolismo , Telmisartán/farmacología , Animales , Densidad Ósea/efectos de los fármacos , Enfermedades Óseas/metabolismo , Enfermedades Óseas/fisiopatología , Hueso Esponjoso/diagnóstico por imagen , Hueso Esponjoso/patología , Femenino , Osteoporosis/metabolismo , Osteoporosis/fisiopatología , PPAR gamma/genética , Ratas , Ratas Endogámicas SHR , Tomografía Computarizada por Rayos X
14.
Life Sci ; 237: 116919, 2019 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-31610200

RESUMEN

AIMS: Stroke-prone spontaneously hypertensive rats (SHRSP) show significantly lower body weight than normotensive Wistar-Kyoto rats (WKY). Our hypotheses are as follows: weight loss of the skeletal muscle is related to hypertension-related diseases, and muscle hypotrophy is useful as a therapeutic target for hypertension and hypertension-related diseases. In this study, we aimed to investigate the pathophysiological characteristics of muscle hypotrophy in SHRSP to determine the therapeutic target molecule(s). MAIN METHODS: The difference in skeletal muscles in the lower leg between WKY and SHRSP was evaluated mainly through weight/tibial length, histological, gene expression, and protein expression analyses. KEY FINDINGS: SHRSP had a significantly lower weight/tibial length in soleus and gastrocnemius, but not in plantaris and tibialis anterior, indicating that muscles consisting of a relatively high amount of slow muscle fiber were affected. This result was confirmed by the histological analysis of soleus, showing that type I fiber mainly decreased the fiber size. Microarray and protein expression analyses showed that the muscle-specific ubiquitin ligase, muscle RING finger 1 (MuRF1), but not atrogin-1, was highly expressed in soleus, but not in plantaris, in SHRSP. TNF-like weak inducer of apoptosis receptor (TWEAKR) was predicted as a MuRF1 up-regulator by Ingenuity Pathway Analysis and immunostained only in type II fiber in WKY but in both type I and II fibers in SHRSP. SIGNIFICANCE: TWEAKR is a type II-specific receptor in the skeletal muscle. Ectopic TWEAKR expression in type I fiber of SHRSP is most likely involved in slow muscle-specific hypotrophy through MuRF1 overexpression.


Asunto(s)
Hipertensión/patología , Fibras Musculares Esqueléticas/patología , Músculo Esquelético/patología , Músculo Liso Vascular/patología , Atrofia Muscular/patología , Accidente Cerebrovascular/patología , Receptor de TWEAK/metabolismo , Animales , Hipertensión/complicaciones , Hipertensión/metabolismo , Masculino , Fibras Musculares Esqueléticas/metabolismo , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Músculo Esquelético/metabolismo , Músculo Liso Vascular/metabolismo , Atrofia Muscular/etiología , Atrofia Muscular/metabolismo , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/metabolismo , Receptor de TWEAK/genética , Proteínas de Motivos Tripartitos/genética , Proteínas de Motivos Tripartitos/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo
15.
Hypertension ; 74(5): 1200-1214, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31542964

RESUMEN

Endothelial cells line all blood vessels and are critical regulators of vascular tone. In hypertension, disruption of endothelial function alters the release of endothelial-derived vasoactive factors and results in increased vascular tone. Although the release of endothelial-derived vasodilators occurs in a Ca2+-dependent manner, little is known on how Ca2+ signaling is altered in hypertension. A key element to endothelial control of vascular tone is Ca2+ signals at specialized regions (myoendothelial projections) that connect endothelial cells and smooth muscle cells. This work describes disruption in the operation of this key Ca2+ signaling pathway in hypertension. We show that vascular reactivity to phenylephrine is increased in hypertensive (spontaneously hypertensive rat) when compared with normotensive (Wistar Kyoto) rats. Basal endothelial Ca2+ activity limits vascular contraction, but that Ca2+-dependent control is impaired in hypertension. When changes in endothelial Ca2+ levels are buffered, vascular contraction to phenylephrine increased, resulting in similar responses in normotension and hypertension. Local endothelial IP3(inositol trisphosphate)-mediated Ca2+ signals are smaller in amplitude, shorter in duration, occur less frequently, and arise from fewer sites in hypertension. Spatial control of endothelial Ca2+ signaling is also disrupted in hypertension: local Ca2+ signals occur further from myoendothelial projections in hypertension. The results demonstrate that the organization of local Ca2+ signaling circuits occurring at myoendothelial projections is disrupted in hypertension, giving rise to increased contractile responses.


Asunto(s)
Señalización del Calcio/efectos de los fármacos , Endotelio Vascular/metabolismo , Hipertensión/fisiopatología , Fenilefrina/farmacología , Receptores Sensibles al Calcio/metabolismo , Animales , Señalización del Calcio/fisiología , Modelos Animales de Enfermedad , Células Endoteliales/citología , Células Endoteliales/metabolismo , Endotelio Vascular/fisiopatología , Hipertensión/metabolismo , Masculino , Potenciales de la Membrana/efectos de los fármacos , Músculo Liso Vascular/metabolismo , Distribución Aleatoria , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Valores de Referencia , Sensibilidad y Especificidad , Vasoconstricción/efectos de los fármacos , Vasoconstricción/fisiología
16.
Life Sci ; 235: 116862, 2019 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-31513814

RESUMEN

Dysregulation of miR-29 has been revealed in multiple diseases, but its role in the development of hypertension and vascular endothelial dysfunction has not been defined. Here, we found that, compared with the wild-type (WT) Wistar rats, miR-29b was robustly upregulated in spontaneously hypertensive rats (SHRs), while CTRP6 was distinctly downregulated. There were two miRNA-responding-elements (MREs) for miR-29 in the 3'-UTR of CTRP6 mRNA, and the luciferase activity assay revealed that miR-29b directly targeted CTRP6 mRNA. Intraventricular injection was applied to deliver the miR-29b mimic or miR-29b inhibitor (4 mg/kg) into SHRs once two weeks from 10th week. Downregulation of miR-29b could increase serum CTRP6 content in SHRs, decrease the arterial systolic pressure, reduce serum concentrations of Ang II and ET-1, and enhance serum NO content. Meanwhile, we demonstrated that inhibition of miR-29b increased the phosphorylation of ERK1/2 to activate PPARγ, an inducer of Ang II. Finally, miR-29b expression was manipulated in, and CTRP6 recombinant protein was applied to incubate with the primary aortic endothelial cells. Inhibition of miR-29b increased CTRP6 expression, improved cell proliferation and migration, suppressed secretion of Ang II and ET-1, and decreased ROS accumulation and LDH release, displaying a similar effect to the CTRP6 recombinant protein. Moreover, the CTRP6 recombinant protein could antagonize the suppressive effect of miR-29b on activation of the ERK/PPARγ axis and function of aortic endothelial cells. In conclusion, miR-29b antagonism can alleviate Ang II-induced hypertension and vascular endothelial dysfunction through activating the CTRP6/ERK/PPARγ axis.


Asunto(s)
Angiotensina II/efectos adversos , Células Endoteliales/efectos de los fármacos , Hipertensión/genética , Hipertensión/prevención & control , MicroARNs/antagonistas & inhibidores , Adipoquinas/sangre , Angiotensina II/sangre , Animales , Presión Sanguínea/efectos de los fármacos , Movimiento Celular/fisiología , Proliferación Celular/fisiología , Regulación hacia Abajo/efectos de los fármacos , Endotelina-1/sangre , Hipertensión/inducido químicamente , Hipertensión/fisiopatología , L-Lactato Deshidrogenasa/metabolismo , Masculino , MicroARNs/agonistas , MicroARNs/biosíntesis , MicroARNs/genética , Óxido Nítrico/sangre , Fosforilación/efectos de los fármacos , Ratas , Ratas Endogámicas SHR , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacos
17.
J Agric Food Chem ; 67(37): 10313-10320, 2019 Sep 18.
Artículo en Inglés | MEDLINE | ID: mdl-31502448

RESUMEN

A peptide fraction with molecular masses below 3 kDa (PSH-3 kDa) from a peach seed hydrolysate demonstrated high angiotensin converting enzyme (ACE) inhibitory activity (concentration to inhibit 50% ACE (IC50) = 16.4 µg/mL) in our previous work. This work proposes a further study of this highly active fraction. RP-HPLC enabled two fractions (F3 and F4) with high inhibitory activity (IC50 = 2.0 ± 0.5 and 1.2 ± 0.2 µg/mL, respectively) to be isolated. Peptide analysis by LC-Q-TOF-MS/MS using reverse-phase and hydrophilic interaction chromatography enabled 33 peptides within both fractions to be identified. Among them, peptide isoleucine-tyrosine-serine-proline-histidine (IYSPH) showed the highest capacity. The lack of cytotoxicity of peptides was demonstrated in three different cell lines (HeLa, HT-29, and HK-2). Oral administration of PSH-3 kDa fraction or peptide IYSPH caused a significant systolic blood pressure reduction (-30 mmHg) on spontaneously hypertensive rats after 3-6 h treatment.


Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/administración & dosificación , Inhibidores de la Enzima Convertidora de Angiotensina/química , Antihipertensivos/administración & dosificación , Antihipertensivos/química , Hipertensión/tratamiento farmacológico , Extractos Vegetales/administración & dosificación , Extractos Vegetales/química , Prunus persica/química , Inhibidores de la Enzima Convertidora de Angiotensina/aislamiento & purificación , Animales , Antihipertensivos/aislamiento & purificación , Presión Sanguínea/efectos de los fármacos , Humanos , Hipertensión/enzimología , Hipertensión/fisiopatología , Masculino , Peptidil-Dipeptidasa A/metabolismo , Extractos Vegetales/aislamiento & purificación , Hidrolisados de Proteína/química , Ratas , Ratas Endogámicas SHR , Semillas/química
18.
Int J Mol Sci ; 20(17)2019 Sep 02.
Artículo en Inglés | MEDLINE | ID: mdl-31480672

RESUMEN

Cardiovascular diseases have a high prevalence worldwide and constitute the leading causes of mortality. Recently, malfunctioning of ß-catenin signaling has been addressed in hypertensive heart condition. Ang-II is an important mediator of cardiovascular remodeling processes which not only regulates blood pressure but also leads to pathological cardiac changes. However, the contribution of Ang-II/ß-catenin axis in hypertrophied hearts is ill-defined. Employing in vitro H9c2 cells and in vivo spontaneously hypertensive rats (SHR) cardiac tissue samples, western blot analysis, luciferase assays, nuclear-cytosolic protein extracts, and immunoprecipitation assays, we found that under hypertensive condition ß-catenin gets abnormally induced that co-activated LEF1 and lead to cardiac hypertrophy changes by up-regulating the IGF-IIR signaling pathway. We identified putative LEF1 consensus binding site on IGF-IIR promoter that could be regulated by ß-catenin/LEF1 which in turn modulate the expression of cardiac hypertrophy agents. This study suggested that suppression of ß-catenin expression under hypertensive condition could be exploited as a clinical strategy for cardiac pathological remodeling processes.


Asunto(s)
Cardiomegalia/inducido químicamente , Cardiomegalia/metabolismo , Receptor IGF Tipo 2/metabolismo , Transducción de Señal , beta Catenina/metabolismo , Angiotensina II , Animales , Biomarcadores/metabolismo , Cardiomegalia/patología , Núcleo Celular/metabolismo , Factor de Transcripción GATA4/metabolismo , Subunidades alfa de la Proteína de Unión al GTP Gq-G11/metabolismo , Factor de Unión 1 al Potenciador Linfoide/metabolismo , Miocitos Cardíacos/metabolismo , Factores de Transcripción NFATC/metabolismo , Regiones Promotoras Genéticas/genética , Proteína Quinasa C-alfa/metabolismo , Ratas Endogámicas SHR
19.
Urology ; 133: 249.e1-249.e7, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31476348

RESUMEN

OBJECTIVE: To investigate the relationship between the upregulated expression of sphingosine-1-phosphate receptor 1 (S1P1) in the corpus cavernosum and erectile function in spontaneously hypertensive rats (SHRs). METHODS: Twelve-week-old healthy male Wistar-Kyoto rats (WKY) and SHR rats were randomly divided into 4 groups: WKY, SHR, WKY transfection, and SHR transfection (n = 5). A lentiviral vector carrying the S1P1 gene was injected into the corpus cavernosum penis of rats in the transfection groups (1 × 109 TU/mL, 20 µL). After 1 week, the maximum penile intracavernous pressure/mean arterial pressure (ICPmax/MAP), nitric oxide (NO) content, and the expression of eNOS, P-eNOS, ROCK1, ROCK2, and S1P1 in the corpus cavernosum penis of rats in each group were measured. RESULTS: The ICPmax/MAP value was significantly higher in the SHR transfection group than in the SHR group under 3-V and 5-V electrical stimulations (P <.01). The expression of S1P1 and P-eNOS proteins significantly increased (P <.01), while that of ROCK1 and ROCK2 proteins significantly decreased (P <.01) in the SHR transfected group compared with the SHR group. The NO content was significantly higher in the SHR transfection group than in the SHR group (P <.01). CONCLUSION: The upregulated expression of S1P1 in SHR corpus cavernosum penis may improve the SHR erectile function by upregulating the P-eNOS/eNOS ratio and inhibiting the RhoA/Rho kinase signaling pathway.


Asunto(s)
Erección Peniana/genética , /genética , Animales , Masculino , Distribución Aleatoria , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Transfección
20.
Biol Pharm Bull ; 42(9): 1482-1490, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31474709

RESUMEN

Zhengganxifeng decoction (ZGXFD) is a traditional Chinese medicinal formula, from "Medical Zhong parameter West recorded" by Xichun Zhang, which has been applied to the treatment of clinical essential hypertension. Besides its effect in blood pressure reduction, ZGXFD is also known to be a radical therapy with little or no side effects. Compared with western medicines, Chinese medicinal formulas have the advantage of simultaneously attacking multiple targets. However, such a property brings trouble to the pharmacological studies of Chinese medicines. This study investigated the composition of gut microbiota in spontaneously hypertensive rats (SHR) treated with ZGXFD. ZGXFD was shown to cause similar effects in the treatment group as benazepril: both were able to reduce in SHR the microbial diversity, Firmicutes to Bacteroidetes (F/B) ratio and coccus to bacillus (C/B) ratio. Meanwhile, ZGXFD can maintain the integrity of intestinal mechanistic barrier and elevate the percentage of bacteria producing short chain fatty acids (SCFA). By investigating renin-angiotensin system (RAS) system, we found that ZGXFD can decrease the expression of angiotensin-converting-enzyme (ACE) in lungs, which in turn causes a increase in AngI produces angiotensin1-7 (Ang1-7) and decrease in AngII. ZGXFD regulate blood pressure in SHR via RAS.


Asunto(s)
Antihipertensivos/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Medicamentos Herbarios Chinos/uso terapéutico , Microbioma Gastrointestinal/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Sistema Renina-Angiotensina/efectos de los fármacos , Animales , Ácidos Grasos Volátiles/metabolismo , Microbioma Gastrointestinal/fisiología , Hipertensión/microbiología , Ratas Endogámicas SHR , Ratas Endogámicas WKY
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