Angiotensin-(1-9) prevents cardiomyocyte hypertrophy via miR-129-3p/PKIA/PKA signaling pathway

Angiotensin-(1-9) is a peptide from the non-canonical renin-angiotensin system with anti-hypertrophic effects in cardiomyocytes via an unknown mechanism. Our previous work proved that this peptide induces mitochondrial fusion through Drp1 phosphorylation and prevented norepinephrine-elicited mitochondrial fission. In the present work, we aimed to elucidate the underlying mechanism by which angiotensin-(1-9) could prevent cardiomyocyte hypertrophy together with its effects over mitochondrial dynamics evaluating the possible link between them and the signaling pathways activated during hypertrophy. Here we show, for the first time, that angiotensin-(1-9) prevents intracellular calcium dysregulation and the activation of Calcineurin/NFAT signaling pathway at a transcription and protein level in a model of norepinephrine-induced cardiomyocyte hypertrophy. To further investigate the anti-hypertrophic mechanism of angiotensin-(1- 9), we performed RNA-seq studies, identifying the upregulation of miR-129 under angiotensin-(1-9) treatment. miR-129 decreased the transcript levels of the protein kinase A inhibitor (PKIA), resulting in the activation of the protein kinase A (PKA) signaling pathway. Finally, we showed that the mere activation of PKA by angiotensin- (1-9) accounted for its effects on calcium handling and cardiomyocyte hypertrophy

Gestión de los fosfatos y del guano y su contribución a la economía nacional del Perú durante el periodo 2010 – 2019

El Perú es un país con enormes reservas de recursos naturales, como es el caso de los fosfatos y el guano, los cuales se producen en distintos contextos geográficos, ya que los fosfatos se extraen de minas en el norte del país; mientras que el guano se extrae de un conjunto de 22 islas e islotes y 11 puntas, en todo el litoral costero. El propósito de la presente investigación fue conocer la situación actual de la gestión de los fosfatos y el guano en el Perú, así como describir su contribución a la economía nacional durante el período 2010 – 2019; para lograrlo, se definieron indicadores que sustentan cada variable de estudio. Se diseñó un estudio descriptivo, con enfoque cuali-cuantitativo, por lo que se reunieron estadísticas publicadas por distintos entes como el Ministerio de Energía y Minas, el Ministerio de Desarrollo Agrario y Riego, Osinergmin, y la Superintendencia de Administración Tributaria, entre otros; los cuales se combinaron con información recopilada a través de entrevistas a profundidad con expertos en la gestión de estos recursos, conducidas con una guía de preguntas semiestructuradas. Los datos se analizaron combinando las series estadísticas con la información cualitativa, entre los resultados más relevantes destaca que la gestión de los fosfatos está a cargo del MINEM que controla las concesiones otorgadas a empresas privadas; mientras que la gestión del guano la hace Agro Rural, una entidad del Minagri. En ambos casos se extrae el máximo posible, que está limitado en el caso del fosfato por la inversión y en el caso del guano por la población de aves guaneras y la protección del ecosistema. Los fosfatos se destinan, casi en su totalidad a la exportación, mientras que el guano se distribuye a cinco segmentos, que incluye el mercado extranjero, pero dándole prioridad al pequeño agricultor peruano. El impacto directo del fosfato en la economía nacional se limita al impuesto a la renta, el Derecho de Vigencia y el canon minero; mientras que la actividad relacionada con el guano no está sujeta al pago de impuestos.Peru is a country with large natural resource reserves, as it is the case of phosphates and guano, which are produced in different geographical contexts, since phosphates are extracted from mines in the north of the country; while guano is extracted from a set of 22 islands and 11 points, mainly located in the Ica region. The purpose of this research was to know the current situation of the management of phosphates and guano in Peru, as well as to describe its contribution to national economy during the 2010 – 2019 period, to achieve this, indicators were defined that support each study variable. A descriptive study was designed, with a focus quali-quantitative, for which statistics published by different entities such as the Ministry of Energy and Mines, the Ministry of Agricultural Development and Irrigation, Osinergmin, and the Superintendence of Tax Administration, among others; which were combined with information collected through in-depth interviews with experts in the management of these resources, conducted with a guide of semi-structured questions. The data was analyzed by combining the statistical series with the qualitative information, among the most relevant results it is worth highlighting that the management of phosphates is in charge of the MINEM, which controls the concessions granted to private companies; while the management of guano is done by Agro Rural, an entity of the Minagri. In both cases, the maximum possible is extracted, which is limited in the case of phosphate by investment and in the case of guano by the population of guano birds and the protection of the ecosystem. The phosphates are almost entirely destined for export, while the guano is distributed to five segments, which includes the foreign market, but giving priority to the small Peruvian farmer. The direct impact of phosphate on the national economy is limited to income tax, the right of force and the mining canon; while the activity related to guano extraction is not subject to tax payment

Angiotensin-(1-9) prevents cardiomyocyte hypertrophy via miR-129-3p/PKIA/PKA signaling pathway

Doctorado en bioquímicaAngiotensin-(1-9) is a peptide from the non-canonical renin-angiotensin system with anti-hypertrophic effects in cardiomyocytes via an unknown mechanism. Our previous work proved that this peptide induces mitochondrial fusion through Drp1 phosphorylation and prevented norepinephrine-elicited mitochondrial fission. In the present work, we aimed to elucidate the underlying mechanism by which angiotensin-(1-9) could prevent cardiomyocyte hypertrophy together with its effects over mitochondrial dynamics evaluating the possible link between them and the signaling pathways activated during hypertrophy. Here we show, for the first time, that angiotensin-(1-9) prevents intracellular calcium dysregulation and the activation of Calcineurin/NFAT signaling pathway at a transcription and protein level in a model of norepinephrine-induced cardiomyocyte hypertrophy. To further investigate the anti-hypertrophic mechanism of angiotensin-(1-9), we performed RNA-seq studies, identifying the upregulation of miR-129 under angiotensin-(1-9) treatment. miR-129 decreased the transcript levels of the protein kinase A inhibitor (PKIA), resulting in the activation of the protein kinase A (PKA) signaling pathway. Finally, we showed that the mere activation of PKA by angiotensin-(1-9) accounted for its effects on calcium handling and cardiomyocyte hypertrophyCONICYT Doctorado 21140671; International Ph.D. program at Universität Regensburg (iPUR) scholarship (Alemania); FONDAP 15130011; FONDECYT 1161156; FONDECYT 120049

GLP-1 promotes mitochondrial metabolism in vascular smooth muscle cells by enhancing endoplasmic reticulum-mitochondria coupling

Incretin GLP-1 has important metabolic effects on several tissues, mainly through the regulation of glucose uptake and usage. One mechanism for increasing cell metabolism is modulating endoplasmic reticulum (ER)-mitochondria communication, as it allows for a more efficient transfer of Ca2+ into the mitochondria, thereby increasing activity. Control of glucose metabolism is essential for proper vascular smooth muscle cell (VSMC) function. GLP-1 has been shown to produce varied metabolic actions, but whether it regulates glucose metabolism in VSMC remains unknown. In this report, we show that GLP-1 increases mitochondrial activity in the aortic cell line A7r5 by increasing ER-mitochondria coupling. GLP-1 increases intracellular glucose and diminishes glucose uptake without altering glycogen content. ATP, mitochondrial potential and oxygen consumption increase at 3 h of GLP-1 treatment, paralleled by increased Ca2+ transfer from the ER to the mitochondria. Furthermore, GLP-1 increases le

Role of heterotrimeric G protein and calcium in cardiomyocyte hypertrophy induced by IGF-1

In the heart, insulin‐like growth factor‐1 (IGF‐1) is a peptide with pro‐hypertrophic and anti‐apoptotic actions. The pro‐hypertrophic properties of IGF‐1 have been attributed to the extracellular regulated kinase (ERK) pathway. Recently, we reported that IGF‐1 also increases intracellular Ca2þ levels through a pertussis toxin (PTX)‐sensitive G protein. Here we investigate whether this Ca2þ signal is involved in IGF‐1‐induced cardiomyocyte hypertrophy. Our results show that the IGF‐1‐induced increase in Ca2þ level is abolished by the IGF‐1 receptor tyrosine kinase inhibitor AG538, PTX and the peptide inhibitor of Gbg signaling, bARKct. Increases in the activities of Ca2þ‐dependent enzymes calcineurin, calmodulin kinase II (CaMKII), and protein kinase Ca (PKCa) were observed at 5 min after IGF‐1 exposure. AG538, PTX, bARKct, and the dominant negative PKCa prevented the IGF‐1‐dependent phosphorylation of ERK1/2. Participation of calcineurin and CaMKII in ERK phosphorylation was discounted. IGF‐1‐induced cardiomyocyte hypertrophy, determined by cell size and b‐myosin heavy chain (b‐MHC), was prevented by AG538, PTX, bARKct, dominant negative PKCa, and the MEK1/2 inhibitor PD98059. Inhibition of calcineurin with CAIN did not abolish IGF‐1‐induced cardiac hypertrophy. We conclude that IGF‐1 induces hypertrophy in cultured cardiomyocytes by activation of the receptor tyrosine kinase activity/bg‐subunits of a PTX‐sensitive G protein/Ca2þ/PKCa/ERK pathway without the participation of calcineurin

Alteration in mitochondrial Ca2+ uptake disrupts insulin signaling in hypertrophic cardiomyocytes

© 2014 Gutierrez et al.; licensee BioMed Central Ltd. Background: Cardiac hypertrophy is characterized by alterations in both cardiac bioenergetics and insulin sensitivity. Insulin promotes glucose uptake by cardiomyocytes and its use as a substrate for glycolysis and mitochondrial oxidation in order to maintain the high cardiac energy demands. Insulin stimulates Ca2+ release from the endoplasmic reticulum, however, how this translates to changes in mitochondrial metabolism in either healthy or hypertrophic cardiomyocytes is not fully understood. Results: In the present study we investigated insulin-dependent mitochondrial Ca2+ signaling in normal and norepinephrine or insulin like growth factor-1-induced hypertrophic cardiomyocytes. Using mitochondrion-selective Ca2+-fluorescent probes we showed that insulin increases mitochondrial Ca2+ levels. This signal was inhibited by the pharmacological blockade of either the inositol 1,4,5-triphosphate receptor or the mitochondrial Ca2+ unipor

Polycystin-2-dependent control of cardiomyocyte autophagy

Considerable evidence points to critical roles of intracellular Cahomeostasis in the modulation and control of autophagic activity. Yet, underlying molecular mechanisms remain unknown. Mutations in the gene (pkd2) encoding polycystin-2 (PC2) are associated with autosomal dominant polycystic kidney disease (ADPKD), the most common inherited nephropathy. PC2 has been associated with impaired Cahandling in cardiomyocytes and indirect evidence suggests that this protein may be involved in autophagic control. Here, we investigated the role for PC2 as an essential regulator of Cahomeostasis and autophagy.status: publishe

Polycystin-2-dependent control of cardiomyocyte autophagy

Aims: Considerable evidence points to critical roles of intracellular Ca2+ homeostasis in the modulation and control of autophagic activity. Yet, underlying molecular mechanisms remain unknown. Mutations in the gene (pkd2) encoding polycystin-2 (PC2) are associated with autosomal dominant polycystic kidney disease (ADPKD), the most common inherited nephropathy. PC2 has been associated with impaired Ca2+ handling in cardiomyocytes and indirect evidence suggests that this protein may be involved in autophagic control. Here, we investigated the role for PC2 as an essential regulator of Ca2+ homeostasis and autophagy. Methods and results: Activation of autophagic flux triggered by mTOR inhibition either pharmacologically (rapamycin) or by means of nutrient depletion was suppressed in cells depleted of PC2. Moreover, cardiomyocytespecific PC2 knockout mice (alpha Mhc-cre;Pkd2(FIF) mice) manifested impaired autophagic flux in the setting of nutrient deprivation. Stress-induced autophagy was blunted by intracellular Ca2+ chelation using BAPTA-AM, whereas removal of extracellular Ca2+ had no effect, pointing to a role of intracellular Ca2+ homeostasis in stress-induced cardiomyocyte autophagy. To determine the link between stress-induced autophagy and PC2-induced Ca2+ mobilization, we over-expressed either wild-type PC2 (WT) or a Ca2+-channel deficient PC2 mutant (PC2-D509V). PC2 over-expression increased autophagic flux, whereas PC2-D509V expression did not. Importantly, autophagy induction triggered by PC2 over-expression was attenuated by BAPTA-AM, supporting a model of PC2-dependent control of autophagy through intracellular Ca2+. Furthermore, PC2 ablation was associated with impaired Ca2+ handling in cardiomyocytes marked by partial depletion of sarcoplasmic reticulum Ca2+ stores. Finally, we provide evidence that Ca2+-mediated autophagy elicited by PC2 is a mechanism conserved across multiple cell types. Conclusion: Together, this study unveils PC2 as a novel regulator of autophagy acting through control of intracellular Ca2+ homeostasis.National Institutes of Health HL-120732 HL-128215 HL-126012 American Heart Association 14SFRN20510023 14SFRN20670003 16POST30680016 13POST16520009 Fondation Leducq 11CVD04 Cancer Prevention and Research Institute of Texas RP110486P3 PEW Latin American Fellows Program in the Biomedical Science 00002991 Yale O'Brien Kidney Center P30 DK079310 Fondo Nacional de Desarrollo Cientifico y Tecnologico, FONDECYT 1171075 11150282 1161156 FONDAP 15130011 PAI Insertion Program from the Comision Nacional de Investigacion Cientifica y Tecnologica (CONICYT), Santiago, Chile 7915000

Proyecto De Tesis I - CI186 - 202101

Descripción: Curso de especialidad en la carrera de ingeniería civil de carácter teórico-práctico dirigido a los estudiantes del 9no ciclo. El curso Proyecto de Tesis I busca que los estudiantes de Ingeniería Civil apliquen sus capacidades adquiridas durante todos sus estudios, en completar una investigación, que plantea resolver una problemática en una de las líneas de la carrera. Con la ayuda de un docente asesor especialista en el tema lograran redactar el informe de tesis al 50%, este informe será revisado por otro docente especialista que proporciona sugerencias de mejoras a la investigación. Por último, los estudiantes exponen ante un jurado especialista sus resultados quienes evalúan y también hacen sugerencia de mejoras a la investigación. Propósito: En el Perú actualmente existe un gran número de estudiantes de Ingeniería Civil que no cuentan con el título profesional, por no realizar la tesis de investigación, lo cual disminuye significativamente su desarrollo profesional y sus oportunidades laborales. El curso de proyecto de Tesis 1 permite que los estudiantes puedan desarrollar el 50% de la Tesis de investigación, siendo la misma certificada por un asesor y un jurado evaluador. Contribuye con el desarrollo de las competencias generales de Pensamiento Crítico, Razonamiento Cuantitativo, Pensamiento Innovador y las competencias específicas 1, 4 y 7 de ABET, todas a nivel de logro 3