Browsing by Author "Ocaranza Jeraldino, María Paz"

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    Angiotensin I-converting enzyme gene polymorphism influences chronic hypertensive response in the rat Goldblatt model
    (LIPPINCOTT WILLIAMS & WILKINS, 2002) Ocaranza Jeraldino, María Paz; Piddo, Ana M.; Faundez, Perla; Lavandero, Sergio; Jalil Milad, Jorge Emilio
    Background and objective In humans, the insertion/ deletion polymorphism in the anglotensin (Ang) I converting enzyme (ACE) gene significantly determines ACE activity. The deletion allele induces higher ACE levels and is associated with hypertension in men. In the rat, a microsatellite marker in the ACE gene allows differentiation of the ACE alleles among strains with different ACE levels. We evaluated the effect of genetically determined ACE expression on the development of renovascular hypertension in the rat.
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    Angiotensin I-converting enzyme gene polymorphism influences chronic hypertensive response in the rat Goldblatt model
    (LIPPINCOTT WILLIAMS & WILKINS, 2002) Ocaranza Jeraldino, María Paz; Piddo, Ana M.; Faundez, Perla; Lavandero, Sergio; Jalil Milad, Jorge Emilio
    Background and objective In humans, the insertion/ deletion polymorphism in the anglotensin (Ang) I converting enzyme (ACE) gene significantly determines ACE activity. The deletion allele induces higher ACE levels and is associated with hypertension in men. In the rat, a microsatellite marker in the ACE gene allows differentiation of the ACE alleles among strains with different ACE levels. We evaluated the effect of genetically determined ACE expression on the development of renovascular hypertension in the rat.
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    Angiotensin I-converting enzyme insertion/deletion polymorphism and adrenergic response to exercise in hypertensive patients.
    (2002) Braun Jones, Vivian Sandra; Chamorro Spikin, Gastón Alberto; Cordova Alvestegui, Samuel Edmundo; Fardella Bello, Carlos Enrique; Jalil Milad, Jorge Emilio; Lavandero, Sergio; Ocaranza Jeraldino, María Paz; Schumacher, Erwin
    BackgroundThe insertion/deletion ACE polymorphism (ACE I/D) regulates different levels of circulating and tissue ACE activities, which may induce diverse adrenergic responses to physiological stimuli. The aim of this study was to evaluate the influence of
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    AT2 Receptor Mediated Activation of the Tyrosine Phosphatase PTP1B Blocks Caveolin-1 Enhanced Migration, Invasion and Metastasis of Cancer Cells
    (2019) Martínez-Meza, Samuel; Díaz, Jorge; Sandoval-Bórquez, Alejandra; Valenzuela-Valderrama, Manuel; Díaz-Valdivia, Natalia; Rojas-Celis, Victoria; Contreras, Pamela; Huilcaman, Ricardo; Ocaranza Jeraldino, María Paz; Chiong, Mario; Leyton, Lissette; Lavandero, Sergio; Quest, Andrew F. G.
    The renin-angiotensin receptor AT2R controls systemic blood pressure and is also suggested to modulate metastasis of cancer cells. However, in the latter case, the mechanisms involved downstream of AT2R remain to be defined. We recently described a novel Caveolin-1(CAV1)/Ras-related protein 5A (Rab5)/Ras-related C3 botulinum toxin substrate 1 (Rac1) signaling axis that promotes metastasis in melanoma, colon, and breast cancer cells. Here, we evaluated whether the anti-metastatic effect of AT2R is connected to inhibition of this pathway. We found that murine melanoma B16F10 cells expressed AT2R, while MDA-MB-231 human breast cancer cells did not. AT2R activation blocked migration, transendothelial migration, and metastasis of B16F10(cav-1) cells, and this effect was lost when AT2R was silenced. Additionally, AT2R activation reduced transendothelial migration of A375 human melanoma cells expressing CAV1. The relevance of AT2R was further underscored by showing that overexpression of the AT2R in MDA-MB-231 cells decreased migration. Moreover, AT2R activation increased non-receptor protein tyrosine phosphatase 1B (PTP1B) activity, decreased phosphorylation of CAV1 on tyrosine-14 as well as Rab5/Rac1 activity, and reduced lung metastasis of B16F10(cav-1) cells in C57BL/6 mice. Thus, AT2R activation reduces migration, invasion, and metastasis of cancer cells by PTP1B-mediated CAV1 dephosphorylation and inhibition of the CAV1/Rab5/Rac-1 pathway. In doing so, these observations open up interesting, novel therapeutic opportunities to treat metastatic cancer disease.
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    Circulating Vascular Cell Adhesion Molecule-1 (sVCAM-1) Is Associated With Left Atrial Remodeling in Long-Distance Runners
    (FRONTIERS MEDIA SA, 2021) Contreras Briceño, Felipe; Herrera, Sebastián; Vega Adauy, Julián; Salinas, Manuel; Ocaranza Jeraldino, María Paz; Jalil Milad, Jorge; Mandiola Ovalle, Jorge; García, Lorena; Chiong, Mario; Castro Galvez, Pablo Federico; Lavandero, Sergio; Gabrielli Nervi, Luigi Arnaldo
    Introduction: An increased risk of atrial fibrillation (AF) has been demonstrated in high-performance athletes. Soluble vascular adhesion molecule-1 (sVCAM-1), a biomarker involved in inflammation and cardiac remodeling, is associated with the development of AF in the general population. However, the relationship between sVCAM-1 and left atrial (LA) remodeling has been poorly investigated in long-distance runners (LDR).Aim: To determine the association between LA remodeling and sVCAM-1 levels in LDR during the training period before a marathon race.Methods: Thirty-six healthy male LDR (37.0 +/- 5.3 years; 174.0 +/- 7.0 height; BMI: 23.8 +/- 2.8; V degrees O-2-peak: 56.5 +/- 7.3 mL center dot kg(-1)center dot min(-1)) were evaluated in this single-blind and cross-sectional study. The LDR were separated into two groups according to previous training levels: high-training (HT) (n = 18) >= 100 km center dot week(-1) and low-training (LT) (n = 18) >= 70 and <100 km center dot week(-1). Also, 18 healthy non-active subjects were included as a control group (CTR). In all participants, transthoracic echocardiography was performed. sVCAM-1 blood levels were measured baseline and immediately finished the marathon race in LDR.Results: HT showed increased basal levels of sVCAM-1 (651 +/- 350 vs. 440 +/- 98 ng center dot mL(-1) CTR, p = 0.002; and vs. 533 +/- 133 ng center dot mL(-1) LT; p = 0.003) and a post-marathon increase (Delta sVCAM-1) (651 +/- 350 to 905 +/- 373 ng center dot mL(-1); p = 0.002), that did not occur in LT (533 +/- 133 to 651 +/- 138 ng center dot mL(-1); p = 0.117). In LDR was a moderate correlation between LA volume and sVCAM-1 level (rho = 0.510; p = 0.001).Conclusions: In male long-distance runners, sVCAM-1 levels are directly associated with LA remodeling. Also, the training level is associated with basal sVCAM-1 levels and changes after an intense and prolonged exercise (42.2 km). Whether sVCAM-1 levels predict the risk of AF in runners remains to be established.
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    Genotipos del sistema renina-angiotensina-aldosterona: a la búsqueda de enfermedades cardiovasculares
    (2002) Jalil Milad, Jorge Emilio; Ocaranza Jeraldino, María Paz
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    Hydrochlorothiazide Reduces Cardiac Hypertrophy, Fibrosis and Rho-Kinase Activation in DOCA-Salt Induced Hypertension
    (2021) Mondaca Ruff, David Gonzalo; Araos Valdebenito, Fernando Patricio; Yañez, Cristián; Novoa, Ulises F.; Mora, Ítalo G.; Ocaranza Jeraldino, María Paz; Jalil Milad, Jorge Emilio
    Background: Thiazides are one of the most common antihypertensive drugs used for hypertension treatment and hydrochlorothiazide (HCTZ) is the most frequently used diuretic for hypertension treatment. The Rho/Rho-kinase (ROCK) path plays a key function in cardiovascular remodeling. We hypothesized that in preclinical hypertension HCTZ reduces myocardial ROCK activation and consequent myocardial remodeling. Methods: The preclinical model of deoxycorticosterone (DOCA)-salt hypertension was used (Sprague–Dawley male rats). After 3 weeks, in 3 different groups: HCTZ, the ROCK inhibitor fasudil or spironolactone was added (3 weeks). After 6 weeks myocardial hypertrophy and fibrosis, cardiac levels of profibrotic proteins, mRNA levels (RT PCR) of pro remodeling and pro oxidative molecules and ROCK activity were determined. Results: Blood pressure, myocardial hypertrophy and fibrosis were reduced significantly by HCTZ, fasudil and spironolactone. In the heart, increased levels of the pro-fibrotic proteins Col-I, Col-III and TGF-β1 and gene expression of pro-remodeling molecules TGF-β1, CTGF, MCP-1 and PAI-1 and the pro-oxidative molecules gp91phox and p22phox were significantly reduced by HCTZ, fasudil and spironolactone. ROCK activity in the myocardium was increased by 54% (P < 0.05) as related to the sham group and HCTZ, spironolactone and fasudil, reduced ROCK activation to control levels. Conclusions: HCTZ reduced pathologic LVH by controlling blood pressure, hypertrophy and myocardial fibrosis and by decreasing myocardial ROCK activation, expression of pro remodeling, pro fibrotic and pro oxidative genes. In hypertension, the observed effects of HCTZ on the myocardium might explain preventive outcomes of thiazides in hypertension, specifically on LVH regression and incident heart failure.
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    La vía de señalización Rho/Rho-cinasa en la enfermedad y el remodelado cardiovascular
    (EDICIONES DOYMA S/L, 2005) Jalil Milad, Jorge Emilio; Lavandero, Sergio; Chiong, Mario; Ocaranza Jeraldino, María Paz
    The small guanosine triphosphatase Rho and its target, Rho kinase, play important roles in both blood pressure regulation and vascular smooth muscle contraction. Rho is activated by agonists of receptors coupled to cell membrane G protein, such as angiotensin II and phenylephrine. Once Rho is activated, it translocates to the cell membrane where it, in turn, activates Rho kinase. Activated Rho kinase phosphorylates myosin light chain phosphatase, which is then inhibited. This sequence stimulates vascular smooth muscle contraction, stress fiber formation, and cell migration. In this way, Rho and Rho kinase activation have important effects on several cardiovascular diseases. Currently available substances that specifically inhibit this signaling pathway could offer clinical benefits in several cardiovascular, as well as non-cardiovascular, diseases, such as arterial hypertension, pulmonary hypertension, cerebral or coronary spasm, post-angioplasty restenosis, and erectile dysfunction.
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    Levels of plasma angiotensin-(1-7) in patients with hypertension who have the angiotensin–I-converting enzyme deletion/deletion genotype
    (2003) Chiong, Mario; Godoy Jorquera, Iván Esteban; Jalil Milad, Jorge Emilio; Lavandero, Sergio; Ocaranza Jeraldino, María Paz; Palomera, Cristián; Román, Maritza
    In patients with hypertension who have the DD-ACE genotype (higher angiotensin-converting enzyme [ACE] activity), plasma levels of angiotensin-(1-7) are 4 times lower than in patients with the II-ACE genotype (lower ACE levels). Angiotensin II levels are
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    Nanoparticle-Mediated Angiotensin-(1-9) Drug Delivery for the Treatment of Cardiac Hypertrophy
    (2021) Sepúlveda-Rivas, Sabrina; Leal, Matías S.; Pedrozo, Zully; Kogan Alterman, Marcelo; Ocaranza Jeraldino, María Paz; Morales, Javier
    Ang-(1-9) peptide is a bioactive vasodilator peptide that prevents cardiomyocyte hypertrophy in vitro and in vivo as well as lowers blood pressure and pathological cardiovascular remodeling; however, it has a reduced half-life in circulation, requiring a suitable carrier for its delivery. In this work, hybrid nanoparticles composed of polymeric nanoparticles (pNPs) based on Eudragit® E/Alginate (EE/Alg), and gold nanospheres (AuNS), were developed to evaluate their encapsulation capacity and release of Ang-(1-9) under different experimental conditions. Hybrid pNPs were characterized by dynamic light scattering, zeta potential, transmission and scanning electron microscopy, size distribution, and concentration by nanoparticle tracking analysis. Nanometric pNPs, with good polydispersity index and colloidally stable, produced high association efficiency of Ang-(1-9) and controlled release. Finally, the treatment of neonatal cardiomyocytes in culture with EE/Alg/AuNS 2% + Ang-(1-9) 20% pNPs decreased the area and perimeter, demonstrating efficacy in preventing norepinephrine-induced cardiomyocyte hypertrophy. On the other hand, the incorporation of AuNS did not cause negative effects either on the cytotoxicity or on the association capacity of Ang-(1-9), suggesting that the hybrid carrier EE/Alg/AuNS pNPs could be used for the delivery of Ang-(1-9) in the treatment of cardiovascular hypertrophy.
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    Neutral endopeptidase and angiotensin I converting enzyme insertion/deletion gene polymorphism in humans
    (2004) Braun, S.; Chamorro, G.; Córdova, S.; Fardella, C.; Godoy, I.; Jalil, J.E.; Lavandero, S.; Michel, J-B.; Oliveri, C.; Ocaranza Jeraldino, María Paz
    Neutral endopeptidase (NEP) hydrolyses angiotensins (Ang) I and II and generates angiotensin-(1-7) [Ang-(17)]. In humans, the insertion/deletion (I/D) angiotensin- I converting enzyme ( ACE) gene polymorphism determined plasma ACE levels by 40%. In rats,
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    On endogenous Angiotensin II antagonism in hypertension
    (Lippincott Williams and Wilkins, 2016) Ocaranza Jeraldino, María Paz; Jalil Milad, Jorge Emilio
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    Polycystin-1 is required for insulin-like growth factor 1-induced cardiomyocyte hypertrophy
    (2021) Fernández, Carolina; Torrealba, Natalia; Altamirano, Francisco; Garrido-Moreno, Valeria; Vásquez-Trincado, César; Flores-Vergara, Raúl; López-Crisosto, Camila; Ocaranza Jeraldino, María Paz; Chiong, Mario; Z, Pedrozo; Lavandero, Sergio
    Cardiac hypertrophy is the result of responses to various physiological or pathological stimuli. Recently, we showed that polycystin-1 participates in cardiomyocyte hypertrophy elicited by pressure overload and mechanical stress. Interestingly, polycystin-1 knockdown does not affect phenylephrine-induced cardiomyocyte hypertrophy, suggesting that the effects of polycystin-1 are stimulus-dependent. In this study, we aimed to identify the role of polycystin-1 in insulin-like growth factor-1 (IGF-1) signaling in cardiomyocytes. Polycystin-1 knockdown completely blunted IGF-1-induced cardiomyocyte hypertrophy. We then investigated the molecular mechanism underlying this result. We found that polycystin-1 silencing impaired the activation of the IGF-1 receptor, Akt, and ERK1/2 elicited by IGF-1. Remarkably, IGF-1-induced IGF-1 receptor, Akt, and ERK1/2 phosphorylations were restored when protein tyrosine phosphatase 1B was inhibited, suggesting that polycystin-1 knockdown deregulates this phosphatase in cardiomyocytes. Moreover, protein tyrosine phosphatase 1B inhibition also restored IGF-1-dependent cardiomyocyte hypertrophy in polycystin-1-deficient cells. Our findings provide the first evidence that polycystin-1 regulates IGF-1-induced cardiomyocyte hypertrophy through a mechanism involving protein tyrosine phosphatase 1B.
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    Prevencion Precoz de Hipertrofia Ventricular Izquierda en la Hipertension Experimental y Concentraciones de Angiotensina II
    (2001) Gálvez, Anita; Ocaranza Jeraldino, María Paz; Lavandero, Sergio; Jalil Milad, Jorge Emilio
    Introducción.Las concentraciones de angiotensina IIpueden inhibirse parcialmente durante la administracióncrónica de inhibidores de la enzima conversiva de la an-giotensina (ECA), limitando desde el punto de vista clíni-co su eficacia en el tratamiento de la hipertensión arterial.Existen pocos estudios que relacionan directamente laactividad de la ECA y la prevención precoz de hipertrofiaventricular izquierda (HVI) secundaria a hipertensión arte-rial durante la administración de un inhibidor de la ECA(IECA). Objetivo.Evaluar los efectos de la inhibición precoz dela ECA con perindopril sobre el desarrollo de hiperten-sión, HVI y concentraciones de angiotensina II plasmáticay en el ventrículo izquierdo en el modelo Goldblatt en larata (Gb; 2 riñones-un pinzado) a las 2 semanas de la ci-rugía. Resultados.La presión arterial sistólica y la masa ven-tricular izquierda relativa aumentaron un 42 y un 20%,respectivamente, en el grupo Gb (p < 0,001). Las acti-vidades de ECA circulante y en el ventrículo izquierdofueron significativamente mayores en las ratas Gb com-paradas con los controles. Las concentraciones de angio-tensina II plasmática y en el ventrículo izquierdo tambiénaumentaron un 129 y un 800%, respectivamente. El pe-rindopril previno la aparición de hipertensión y el desarro-llo de HVI, ya que inhibió la ECA plasmática (y en el ven-trículo izquiedo), además de la angiotensina II circulantey en el ventrículo izquierdo.Conclusiones. En este modelo experimental de HVIhipertensiva existe una activación temprana de la ECAplasmática y cardíaca. La administración precoz de unIECA previene el desarrollo de hipertensión e HVI al inhi-bir el aumento de angiontensina II en el plasma y el ven-trículo izquierdo.
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    Protective Role of the ACE2/Ang-(1-9) Axis in Cardiovascular Remodeling
    (2012) Jalil Milad, Jorge Emilio; Ocaranza Jeraldino, María Paz
    Despite reduction in cardiovascular (CV) events and end-organ damage with the current pharmacologic strategies, CV disease remains the primary cause of death in the world. Pharmacological therapies based on the renin angiotensin system (RAS) blockade are used extensively for the treatment of hypertension, heart failure, and CV remodeling but in spite of their success the prevalence of end-organ damage and residual risk remain still high. Novel approaches must be discovered for a more effective treatment of residual CV remodeling and risk. The ACE2/Ang-(1–9) axis is a new and important target to counterbalance the vasoconstrictive/proliferative RAS axis. Ang-(1–9) is hydrolyzed slower than Ang-(1–7) and is able to bind the Ang II type 2 receptor. We review here the current experimental evidence suggesting that activation of the ACE2/Ang-(1–9) axis protects the heart and vessels (and possibly the kidney) from adverse cardiovascular remodeling in hypertension as well as in heart failure.
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    Recent insights and therapeutic perspectives of angiotensin-(1-9) in the cardiovascular system
    (2014) Ocaranza Jeraldino, María Paz; Michea, Luis; Chiong, Mario; Lagos Arévalo, Carlos Fernando; Lavandero, Sergio; Jalil Milad, Jorge Emilio
    Chronic RAS (renin-angiotensin system) activation by both AngII (angiotensin II) and aldosterone leads to hypertension and perpetuates a cascade of pro-hypertrophic, pro-inflammatory, pro-thrombotic and atherogenic effects associated with cardiovascular damage. In 2000, a new pathway consisting of ACE2 (angiotensin-converting enzyme2), Ang-(1-9) [angiotensin-(1-9)], Ang-(1-7) [angiotensin-(1-7)] and the Mas receptor was discovered. Activation of this novel pathway stimulates vasodilation, anti-hypertrophy and anti-hyperplasia. For some time, studies have focused mainly on ACE2, Ang-(1-7) and the Mas receptor, and their biological properties that counterbalance the ACE/AngII/AT(1)R (angiotensin type 1 receptor) axis. No previous information about Ang-(1-9) suggested that this peptide had biological properties. However, recent data suggest that Ang-(1-9) protects the heart and blood vessels (and possibly the kidney) from adverse cardiovascular remodelling in patients with hypertension and/or heart failure. These beneficial effects are not modified by the Mas receptor antagonist A779 [an Ang-(1-7) receptor blocker], but they are abolished by-the AT(2)R (angiotensin type 2 receptor) antagonist PD123319. Current information suggests that the beneficial effects of Ang-(1-9) are mediated via the AT2R. In the present review, we summarize the biological effects of the novel vasoactive peptide Ang-(1-9), providing new evidence of its cardiovascular-protective activity. We also discuss the potential mechanism by which this peptide prevents and ameliorates the cardiovascular damage induced by RAS activation.
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    Reproducibility of plasma angiotensin-converting enzyme activity in human subjects determined by fluorimetry with Z-phenylalanine-histidyl-leucine as substrate
    (MOSBY-YEAR BOOK INC, 1999) Jalil Milad, Jorge Emilio; Ocaranza Jeraldino, María Paz; Piddo, Ana María
    Despite the major physiologic role of angiotensin-converting enzyme (ACE), few studies have evaluated the ideal conditions for measuring human plasma ACE activity, specifically when using Z-phenylalanine-histidyl-leucine as substrate. This study, performed in volunteer patients, assessed the reproducibility of human plasma ACE activity measured by fluorimetry with Z-phenyl-histidyl-leucine as the substrate. After blood centrifugation, plasma was stored under different conditions until processing. The following sources of variability were evaluated: (1) the interval to centrifugation of blood after collection, (2) the temperature and (3) safe time for storing the plasma after cold centrifugation, (4) the effect of fasting. Plasma ACE activity was 20.6 ± 7.7 U/mL, 20.9 ± 8 U/mL, and 20.5 ± 7.9 U/mL (n = 25) when samples were centrifuged immediately, after 1 hour of blood sampling, and after 3 hours of blood sampling, respectively (not significant). In plasma kept at –20°C, ACE activity was not different after 1 week (17.4 ± 4.3 U/mL) nor after 1 month (17.9 ± 4 U/mL), whereas baseline ACE was 16.7 ± 4.3 U/mL (n = 10). In plasma stored at –80°C, ACE activity was 15.5 ± 5.7 U/mL after 1 month (baseline 15 ± 5.3 U/mL; not significant; n = 12). No evidence for hydrolysis of the reaction product of ACE (his-leu dipeptide) was observed in plasma samples kept for 1 month at –20°C or at –80°C (by high-performance liquid chromatography analysis). In plasma obtained before breakfast, ACE activity was 12.8 ± 7.1 U/mL, and it was 12.3 ± 7.5 U/mL 2 hours afterwards (not significant; n = 12). Thus, to determine human plasma ACE activity by fluorimetry with reliability, with Z-phenylalanine-histidyl-leucine used as a substrate, there is a safe interval of at least 3 hours before blood centrifugation at –4°C. Plasma may be kept at –20°C or at –80°C for at least 4 weeks before final processing. Fasting does not influence its enzymatic activity. (J Lab Clin Med 1999;133:501-6)