Browsing by Author "Pedrozo, Zully"

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    Dexmedetomidine preconditioning activates pro-survival kinases and attenuates regional ischemia/reperfusion injury in rat heart
    (ELSEVIER, 2012) Ibacache, Mauricio; Sanchez, Gina; Pedrozo, Zully; Galvez, Felipe; Humeres, Claudio; Echevarria, Ghislaine; Duaso, Juan; Hassi, Mario; Garcia, Lorena; Diaz Araya, Guillermo; Lavandero, Sergio
    Pharmacological preconditioning limits myocardial infarct size after ischemia/reperfusion. Dexmedetomidine is an alpha(2)-adrenergic receptor agonist used in anesthesia that may have cardioprotective properties against ischemia/reperfusion injury. We investigate whether dexmedetomidine administration activates cardiac survival kinases and induces cardioprotection against regional ischemia/reperfusion injury. In in vivo and ex vivo models, rat hearts were subjected to 30 min of regional ischemia followed by 120 min of reperfusion with dexmedetomidine before ischemia. The alpha(2)-adrenergic receptor antagonist yohimbine was also given before ischemia, alone or with dexmedetomidine. Erk1/2, Akt and eNOS phosphorylations were determined before ischemia/reperfusion. Cardioprotection after regional ischemia/reperfusion was assessed from infarct size measurement and ventricular function recovery. Localization of alpha(2)-adrenergic receptors in cardiac tissue was also assessed. Dexmedetomidine preconditioning increased levels of phosphorylated Erk1/2, Akt and eNOS forms before ischemia/reperfusion; being significantly reversed by yohimbine in both models. Dexmedetomidine preconditioning (in vivo model) and pen-insult protection (ex vivo model) significantly reduced myocardial infarction size, improved functional recovery and yohimbine abolished dexmedetomidine-induced cardioprotection in both models. The phosphatidylinositol 3-kinase inhibitor LY-294002 reversed myocardial infarction size reduction induced by dexmedetomidine preconditioning. The three isotypes of alpha(2)-adrenergic receptors were detected in the whole cardiac tissue whereas only the subtypes 2A and 2C were observed in isolated rat adult cardiomyocytes. These results show that dexmedetomidine preconditioning and dexmedetomidine pen-insult administration produce cardioprotection against regional ischemia/reperfusion injury, which is mediated by the activation of pro-survival kinases after cardiac alpha(2)-adrenergic receptor stimulation. (C) 2011 Elsevier B.V. All rights reserved.
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    Down syndrome critical region 1 gene, rcan1, helps maintain a more fused mitochondrial network
    (2018) Parra, Valentina; Altamirano, Francisco; Hernández Fuentes, Carolina P.; Tong, Dan; Kyrychenko, Victoriia; Rotter, David; Pedrozo, Zully; Hill, Joséph A.| Eisner Sagüés, Verónica Raquel; Lavandero, Sergio; Schneider, Jay W.; Rothermel, Beverly A.
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    Mitochondria, Myocardial Remodeling, and Cardiovascular Disease
    (2012) Verdejo, Hugo E.; del Campo, Andrea; Troncoso, Rodrigo; Gutierrez, Tomas; Toro, Barbra; Quiroga, Clara; Pedrozo, Zully; Pablo Munoz, Juan; Garcia, Lorena; Castro, Pablo F.; Lavandero, Sergio
    The process of muscle remodeling lies at the core of most cardiovascular diseases. Cardiac adaptation to pressure or volume overload is associated with a complex molecular change in cardiomyocytes which leads to anatomic remodeling of the heart muscle. Although adaptive at its beginnings, the sustained cardiac hypertrophic remodeling almost unavoidably ends in progressive muscle dysfunction, heart failure and ultimately death. One of the features of cardiac remodeling is a progressive impairment in mitochondrial function. The heart has the highest oxygen uptake in the human body and accordingly it has a large number of mitochondria, which form a complex network under constant remodeling in order to sustain the high metabolic rate of cardiac cells and serve as Ca2+ buffers acting together with the endoplasmic reticulum (ER). However, this high dependence on mitochondrial metabolism has its costs: when oxygen supply is threatened, high leak of electrons from the electron transport chain leads to oxidative stress and mitochondrial failure. These three aspects of mitochondrial function (Reactive oxygen species signaling, Ca2+ handling and mitochondrial dynamics) are critical for normal muscle homeostasis. In this article, we will review the latest evidence linking mitochondrial morphology and function with the process of myocardial remodeling and cardiovascular disease.
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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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    Polycystin-1 regulates cardiomyocyte mitophagy
    (2021) Ramirez-Sagredo, Andrea; Quiroga, Clara; Garrido-Moreno, Valeria; Lopez-Crisosto, Camila; Leiva-Navarrete, Sebastian; Norambuena-Soto, Ignacio; Ortiz-Quintero, Jafet; Diaz-Vesga, Magda C.; Perez, William; Hendrickson, Troy; Parra, Valentina; Pedrozo, Zully; Altamirano, Francisco; Chiong, Mario; Lavandero, Sergio
    Polycystin-1 (PC1) is a transmembrane protein found in different cell types, including cardiomyocytes. Alterations in PC1 expression have been linked to mitochondrial damage in renal tubule cells and in patients with autosomal dominant polycystic kidney disease. However, to date, the regulatory role of PC1 in cardiomyocyte mitochondria is not well understood. The analysis of mitochondrial morphology from cardiomyocytes of heterozygous PC1 mice (PDK1(+/-)) using transmission electron microscopy showed that cardiomyocyte mitochondria were smaller with increased mitochondria density and circularity. These parameters were consistent with mitochondrial fission. We knocked-down PC1 in cultured rat cardiomyocytes and human-induced pluripotent stem cells (iPSC)-derived cardiomyocytes to evaluate mitochondrial function and morphology. The results showed that downregulation of PC1 expression results in reduced protein levels of sub-units of the OXPHOS complexes and less functional mitochondria (reduction of mitochondrial membrane potential, mitochondrial respiration, and ATP production). This mitochondrial dysfunction activates the elimination of defective mitochondria by mitophagy, assessed by an increase of autophagosome adapter protein LC3B and the recruitment of the Parkin protein to the mitochondria. siRNA-mediated PC1 knockdown leads to a loss of the connectivity of the mitochondrial network and a greater number of mitochondria per cell, but of smaller sizes, which characterizes mitochondrial fission. PC1 silencing also deregulates the AKT-FoxO1 signaling pathway, which is involved in the regulation of mitochondrial metabolism, mitochondrial morphology, and processes that are part of cell quality control, such as mitophagy. Together, these data provide new insights about the controls that PC1 exerts on mitochondrial morphology and function in cultured cardiomyocytes dependent on the AKT-FoxO1 signaling pathway.