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INTRODUCTION: The vascular cell adhesion molecule (VCAM-1) is a transmembrane sialoglycoprotein detected in activated endothelial and vascular smooth muscle cells involved in the adhesion and transmigration of inflammatory cells into damaged tissue. Widely used as a pro-inflammatory marker, its potential role as a targeting molecule has not been thoroughly explored. AREAS COVERED: We discuss the current evidence supporting the potential targeting of VCAM-1 in atherosclerosis, diabetes, hypertension and ischemia/reperfusion injury. EXPERT OPINION: There is emerging evidence that VCAM-1 is more than a biomarker and may be a promising therapeutic target for vascular diseases. While there are neutralizing antibodies that allow preclinical research, the development of pharmacological tools to activate or inhibit this protein are required to thoroughly assess its therapeutic potential.

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Cardiomyopathy is commonly observed in patients with autosomal dominant polycystic kidney disease (ADPKD), even when they have normal renal function and arterial pressure. The role of cardiomyocyte polycystin-1 (PC1) in cardiovascular pathophysiology remains unknown. PC1 is a potential regulator of BIN1 that maintains T-tubule structure, and alterations in BIN1 expression induce cardiac pathologies. We used a cardiomyocyte-specific PC1-silenced (PC1-KO) mouse model to explore the relevance of cardiomyocyte PC1 in the development of heart failure (HF), considering reduced BIN1 expression induced T-tubule remodeling as a potential mechanism. PC1-KO mice exhibited an impairment of cardiac function, as measured by echocardiography, but no signs of HF until 7-9 months of age. Of the PC1-KO mice, 43% died suddenly at 7 months of age, and 100% died after 9 months with dilated cardiomyopathy. Total BIN1 mRNA, protein levels, and its localization in plasma membrane-enriched fractions decreased in PC1-KO mice. Moreover, the BIN1 + 13 isoform decreased while the BIN1 + 13 + 17 isoform was overexpressed in mice without signs of HF. However, BIN1 + 13 + 17 overexpression was not observed in mice with HF. T-tubule remodeling and BIN1 score measured in plasma samples were associated with decreased PC1-BIN1 expression and HF development. Our results show that decreased PC1 expression in cardiomyocytes induces dilated cardiomyopathy associated with diminished BIN1 expression and T-tubule remodeling. In conclusion, positive modulation of BIN1 expression by PC1 suggests a novel pathway that may be relevant to understanding the pathophysiological mechanisms leading to cardiomyopathy in ADPKD patients.

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Despite important advances in the treatment of myocardial infarction that have significantly reduced mortality, there is still an unmet need to limit the infarct size after reperfusion injury in order to prevent the onset and severity of heart failure. Multiple cardioprotective maneuvers, therapeutic targets, peptides and drugs have been developed to effectively protect the myocardium from reperfusion-induced cell death in preclinical studies. Nonetheless, the translation of these therapies from laboratory to clinical contexts has been quite challenging. Comorbidities, comedications or inadequate ischemia/reperfusion experimental models are clearly identified variables that need to be accounted for in order to achieve effective cardioprotection studies. The aging heart is characterized by altered proteostasis, DNA instability, epigenetic changes, among others. A vast number of studies has shown that multiple therapeutic strategies, such as ischemic conditioning phenomena and protective drugs are unable to protect the aged heart from myocardial infarction. In this Mini-Review, we will provide an updated state of the art concerning potential new cardioprotective strategies targeting the aging heart.

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Resumen: Introducción: Las células de la musculatura lisa vascular (CMLV) se caracterizan por mantener cierto grado de desdiferenciación, variando su fenotipo entre el contráctil y el secretor, de acuerdo con las necesidades del tejido, y el contráctil predominante en condiciones fisiológicas. Cualquier alteración del estímulo mecánico, ya sea en el flujo sanguíneo o la tensión mecánica ejercida sobre las CMLV, conducen a cambios de su fenotipo y remodelamiento de la vasculatura, lo que puede constituir el punto de inflexión de varias patologías relevantes en la salud pública como, por ejemplo, la hipertensión arterial. Objetivo: Realizar una revisión sobre los mecanosensores y las vías transduccionales conocidas e implicadas en el cambio de fenotipo de las CMLV. Metodología: Se realizó una búsqueda sistemática en las bases de datos PubMed, Scopus, Google Académico y Scielo sobre la mantención y cambio de fenotipo de las células de la musculatura lisa vascular asociado principalmente a el estrés mecánico, la participación de los mecanosensores más relevantes y las vías de señalización involucrados en este proceso. Conclusión: Los mecanosensores implicados en el cambio de fenotipo de las CMLV contemplan principalmente receptores acoplados a proteína G, moléculas de adhesión y canales iónicos activados por estiramiento. Los estudios se han concentrado en la activación o inhibición de vías como las proteínas quinasas activadas por mitógenos (MAPK), la vía AKT, mTOR y factores transcripcionales que regulan la expresión de genes de diferenciación y/o desdiferenciación, como las miocardinas. Existen además otros receptores involucrados en la respuesta al estrés mecánico, como los receptores tirosina quinasas. A pesar de la importancia que reviste el conocimiento de los mecanosensores y las vías implicadas en el cambio de fenotipo de las CMLV, así como el papel que cumplen en el establecimiento de patologías vasculares, es aún escaso el conocimiento que se tiene sobre los mismos.

Abstract: Introduction: Vascular smooth muscle cells (VS- MCs) are characterized by maintaining a certain de- gree of dedifferentiation. VSMCs may vary their phenotype between contractile and secretory according to tissue needs. Under physiological conditions, the predominant phenotype is contractile. Any alteration of the mechanical stimulus, either in the blood flow or the mechanical stress exerted on the VSMCs, leads to changes in their phenotype and remodeling of the vasculature. These changes can constitute the turning point in several hypertension and other diseases relevant in public health. Objective: To review the main mechanosensor and transduction pathways involved changes in VSMCs phenotype. Methods: A systematic search of PubMed, Scopus, Google Scholar and Scielo databases was carried out to ascertain the state of the art regarding the maintenance and change of VSMCs phenotype mainly associated with mechanical stress. Additionally, the participation of the most relevant mechanosensors and the signaling pathways involved in this process are discussed. Conclusion: The mechanosensors involved in the change in VSMCs phenotype mainly contempla- te G-protein-coupled receptors, adhesion molecules, and stretch-activated ion channels. Studies have been focused on the activation or inhibition of MAPK, AKT, mTOR, pathways and transcriptional factors that regulate the expression of differentiation and/or des differentiation genes such as Myocardins. There are also other receptors involved in the response to mechanical stress such as the tyrosine kinases receptor. Although the importance of understanding mechanosensors, the signaling pathways involved in VSMC phenotype switching and their role in the establishment of vascular pathologies, knowledge about them is limited.

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The right and left ventricles have traditionally been studied as individual entities. Furthermore, modifications found in diseased left ventricles are assumed to influence on right ventricle alterations, but the connection is poorly understood. In this review, we describe the differences between ventricles under physiological and pathological conditions. Understanding the mechanisms that differentiate both ventricles would facilitate a more effective use of therapeutics and broaden our knowledge of right ventricle (RV) dysfunction. RV failure is the strongest predictor of mortality in pulmonary arterial hypertension, but at present, there are no definitive therapies directly targeting RV failure. We further explore the current state of drugs and molecules that improve RV failure in experimental therapeutics and clinical trials to treat pulmonary arterial hypertension and provide evidence of their potential benefits in heart failure.

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Cancer remains a leading cause of death worldwide despite decades of intense efforts to understand the molecular underpinnings of the disease. To date, much of the focus in research has been on the cancer cells themselves and how they acquire specific traits during disease development and progression. However, these cells are known to secrete large numbers of extracellular vesicles (EVs), which are now becoming recognized as key players in cancer. EVs contain a large number of different molecules, including but not limited to proteins, mRNAs, and miRNAs, and they are actively secreted by many different cell types. In the last two decades, a considerable body of evidence has become available indicating that EVs play a very active role in cell communication. Cancer cells are heterogeneous, and recent evidence reveals that cancer cell-derived EV cargos can change the behavior of target cells. For instance, more aggressive cancer cells can transfer their "traits" to less aggressive cancer cells and convert them into more malignant tumor cells or, alternatively, eliminate those cells in a process referred to as "cell competition". This review discusses how EVs participate in the multistep acquisition of specific traits developed by tumor cells, which are referred to as "the hallmarks of cancer" defined by Hanahan and Weinberg. Moreover, as will be discussed, EVs play an important role in drug resistance, and these more recent advances may explain, at least in part, why pharmacological therapies are often ineffective. Finally, we discuss literature proposing the use of EVs for therapeutic and prognostic purposes in cancer.

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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.

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