Person:
Lavín Plaza, Begoña

First Name

Begoña

Last Name

Lavín Plaza

URI

https://hdl.handle.net/20.500.14352/76244

Affiliation

Universidad Complutense de Madrid

Faculty / Institute

Ciencias Químicas

Department

Bioquímica y Biología Molecular

Area

Bioquímica y Biología Molecular

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Now showing 1 - 10 of 21

Nitric Oxide Prevents Aortic Neointimal Hyperplasia by Controlling Macrophage Polarization
(Arteriosclerosis, Thrombosis and Vascular Biology, 2014) Lavín Plaza, Begoña; Gómez, Monica; Pello, Oscar ; Castejon, Borja; Piedras, Maria ; Saura, Marta; Zaragoza, Carlos
Nitric oxide synthase 3 (NOS3) prevents neointima hyperplasia by still unknown mechanisms. To demonstrate the significance of endothelial nitric oxide in the polarization of infiltrated macrophages through the expression of matrix metalloproteinase (MMP)-13 in neointima formation.After aortic endothelial denudation, NOS3 null mice show elevated neointima formation, detecting increased mobilization of LSK (lineage-negative [Lin]-stem-cell antigen 1 [SCA1]+KIT+) progenitor cells, and high ratios of M1 (proinflammatory) to M2 (resolving) macrophages, accompanied by high expression of interleukin-5, interleukin-6, MCP-1 (monocyte chemoattractant protein), VEGF (vascular endothelial growth factor), GM-CSF (granulocyte-macrophage colony stimulating factor), interleukin-1β, and interferon-γ. In conditional c-Myc knockout mice, in which M2 polarization is defective, denuded aortas showed extensive wall thickening as well. Conditioned medium from NOS3-deficient endothelium induced extensive repolarization of M2 macrophages to an M1 phenotype, and vascular smooth muscle cells proliferated and migrated faster in conditioned medium from M1 macrophages. Among the different proteins participating in cell migration, MMP-13 was preferentially expressed by M1 macrophages. M1-mediated vascular smooth muscle cell migration was inhibited when macrophages were isolated from MMP-13–deficient mice, whereas exogenous administration of MMP-13 to vascular smooth muscle cell fully restored migration. Excess vessel wall thickening in mice lacking NOS3 was partially reversed by simultaneous deletion of MMP-13, indicating that NOS3 prevents neointimal hyperplasia by preventing MMP-13 activity. An excess of M1-polarized macrophages that coexpress MMP-13 was also detected in human carotid samples from endarterectomized patients.These findings indicate that at least M1 macrophage-mediated expression of MMP-13 in NOS3 null mice induces neointima formation after vascular injury, suggesting that MMP-13 may represent a new promising target in vascular disease.
Tropoelastin: an in vivo imaging marker of dysfunctional matrix turnover during abdominal aortic dilation
(Cardiovascular Research, 2019) Lavín Plaza, Begoña; Lacerda, Sara; Andia, Marcelo ; Lorrio, Silvia; Bakewell, Robert; Smith, Alberto; Rashid, Imran; Botnar, René M.; Phinikaridou, Alkystis
Aims Dysfunctional matrix turnover is present at sites of abdominal aortic aneurysm (AAA) and leads to the accumulation of monomeric tropoelastin rather than cross-linked elastin. We used a gadolinium-based tropoelastin-specific magnetic resonance contrast agent (Gd-TESMA) to test whether quantifying regional tropoelastin turnover correlates with aortic expansion in a murine model. The binding of Gd-TESMA to excised human AAA was also assessed. Methods and results We utilized the angiotensin II (Ang II)-infused apolipoprotein E gene knockout (ApoE−/−) murine model of aortic dilation and performed in vivo imaging of tropoelastin by administering Gd-TESMA followed by late gadolinium enhancement (LGE) magnetic resonance imaging (MRI) and T1 mapping at 3 T, with subsequent ex vivo validation. In a cross-sectional study (n = 66; control = 11, infused = 55) we found that Gd-TESMA enhanced MRI was elevated and confined to dilated aortic segments (control: LGE=0.13 ± 0.04 mm2, control R1= 1.1 ± 0.05 s−1 vs. dilated LGE =1.0 ± 0.4 mm2, dilated R1 =2.4 ± 0.9 s−1) and was greater in segments with medium (8.0 ± 3.8 mm3) and large (10.4 ± 4.1 mm3) compared to small (3.6 ± 2.1 mm3) vessel volume. Furthermore, a proof-of-principle longitudinal study (n = 19) using Gd-TESMA enhanced MRI demonstrated a greater proportion of tropoelastin: elastin expression in dilating compared to non-dilating aortas, which correlated with the rate of aortic expansion. Treatment with pravastatin and aspirin (n = 10) did not reduce tropoelastin turnover (0.87 ± 0.3 mm2 vs. 1.0 ± 0.44 mm2) or aortic dilation (4.86 ± 2.44 mm3 vs. 4.0 ± 3.6 mm3). Importantly, Gd-TESMA-enhanced MRI identified accumulation of tropoelastin in excised human aneurysmal tissue (n = 4), which was confirmed histologically. Conclusion Tropoelastin MRI identifies dysfunctional matrix remodelling that is specifically expressed in regions of aortic aneurysm or dissection and correlates with the development and rate of aortic expansion. Thus, it may provide an additive imaging marker to the serial assessment of luminal diameter for surveillance of patients at risk of or with established aortopathy.
Targeted molecular iron oxide contrast agents for imaging atherosclerotic plaque
(Nanotheranostics, 2020) Evans, Rhiannon ; Lavín Plaza, Begoña; Phinikaridou, Alkystis; Chooi, Kok Yean; Mohri, Zahra; Wong, Eunice; Boyle, Joseph ; Krams, Rob; Botnar, René; Long, Nicholas
Cardiovascular disease remains a leading cause of death worldwide, with vulnerable plaque rupture the underlying cause of many heart attacks and strokes. Much research is focused on identifying an imaging biomarker to differentiate stable and vulnerable plaque. Magnetic Resonance Imaging (MRI) is a non-ionising and non-invasive imaging modality with excellent soft tissue contrast. However, MRI has relatively low sensitivity (micromolar) for contrast agent detection compared to nuclear imaging techniques. There is also an increasing emphasis on developing MRI probes that are not based on gadolinium chelates because of increasing concerns over associated systemic toxicity and deposits1. To address the sensitivity and safety concerns of gadolinium this project focused on the development of a high relaxivity probe based on superparamagnetic iron oxide nanoparticles for the imaging of atherosclerotic plaque with MRI. With development, this may facilitate differentiating stable and vulnerable plaque in vivo.
Increased vascular permeability measured with an albumin-binding magnetic resonance contrast agent is a surrogate marker of rupture-prone atherosclerotic plaque
(Circulation: Cardiovascular Imaging, 2016) Phinikaridou, Alkystis; Andia, Marcelo ; Lavín Plaza, Begoña; Smith, Alberto; Saha, Prakash; Botnar. René
Background: Compromised structural integrity of the endothelium and higher microvessel density increase vascular permeability. We investigated whether vascular permeability measured in vivo by magnetic resonance imaging using the albumin-binding contrast agent, gadofosveset, is a surrogate marker of rupture-prone atherosclerotic plaque in a rabbit model. Methods and results: New Zealand white rabbits (n=10) were rendered atherosclerotic by cholesterol-diet and endothelial denudation. Plaque rupture was triggered with Russell's viper venom and histamine. Animals were imaged pre-triggering, at 3 and 12 weeks, to quantify plaque area, vascular permeability, vasodilation, and stiffness and post-triggering to identify thrombus. Plaques identified on the pretrigger scans were classified as stable or rupture-prone based on the absence or presence of thrombus on the corresponding post-trigger magnetic resonance imaging, respectively. All rabbits had developed atherosclerosis, and 60% had ruptured plaques. Rupture-prone plaques had higher vessel wall relaxation rate (R1; 2.30±0.5 versus 1.86±0.3 s-1; P<0.001), measured 30 minutes after gadofosveset administration, and higher R1/plaque area ratio (0.70±0.06 versus 0.47±0.02, P= 0.01) compared with stable plaque at 12 weeks. Rupture-prone plaques had higher percent change in R1 between the 3 and 12 weeks compared with stable plaque (50.80±7.2% versus 14.22±2.2%; P<0.001). Immunohistochemistry revealed increased vessel wall albumin and microvessel density in diseased aortas and especially in ruptured plaque. Electron microscopy showed lack of structural integrity in both luminal and microvascular endothelium in diseased vessels. Functionally, the intrinsic vasodilation of the vessel wall decreased at 12 weeks compared with 3 weeks (18.60±1.0% versus 23.43±0.8%; P<0.001) and in rupture-prone compared with stable lesions (16.40±2.0% versus 21.63±1.2%; P<0.001). Arterial stiffness increased at 12 weeks compared with 3 weeks (5.00±0.1 versus 2.53±0.2 m/s; P<0.001) both in animals with stable and rupture-prone lesions. Conclusions: T1 mapping using an albumin-binding contrast agent (gadofosveset) could quantify the changes in vascular permeability associated with atherosclerosis progression and rupture-prone plaques.
Current Development of Molecular Coronary Plaque Imaging using Magnetic Resonance Imaging towards Clinical Application
(Current Cardiovascular Imaging Reports, 2014) Lavín Plaza, Begoña; Phinikaridou, Alkystis; Henningsson, Markus; Botnar, René
Cardiovascular disease (CVD) remains the leading cause of death in Western countries despite improvements in prevention, diagnosis and treatment. Atherosclerosis is a chronic inflammatory disease that remains clinically silent for many decades. Sudden rupture of “high-risk/vulnerable” plaques has been shown to be responsible for the majority of acute cardiovascular events, including myocardial infarction and stroke. Therefore, early detection of biological processes associated with atherosclerosis progression and plaque instability may improve diagnosis and treatment and help to better monitor the effectiveness of therapeutic interventions. Molecular magnetic resonance imaging (MRI) is a promising tool to detect molecular and cellular changes in the carotid, aortic and coronary vessel wall including endothelial dysfunction, inflammation, vascular remodelling, enzymatic activity, intraplaque haemorrhage and fibrin deposition and thus may allow early detection of unstable lesions and improve the prediction of future coronary events. Evaluation of atherosclerosis at both, the preclinical and clinical level includes non-contrast-enhanced (NCE) and contrast-enhanced (CE) MRI with and without the use of MR contrast agents. To increase the biological information obtained by MRI a variety of targeted-specific molecular probes have been developed for the non-invasive visualization of particular biological processes at the molecular and cellular level. This review will discuss the recent advances in molecular MRI of atherosclerosis, covering both pulse sequence development and also the design of novel contrast agents, for imaging atherosclerotic disease in vivo.
Nitric Oxide Induces the Progression of Abdominal Aortic Aneurysms through the Matrix Metalloproteinase Inducer EMMPRIN
(The American Journal of Pathology, 2009) Lizarbe, Tania ; Tarín, Carlos; Gómez, Mónica; Lavín Plaza, Begoña; Aracil Ávila, Enrique; Orte, Luis ; Zaragoza, Carlos
Nitric Oxide (NO) is involved in the development and progression of abdominal aortic aneurysms (AAA). We found that inhibition of inducible NO synthase (iNOS) protects mice in an elastase-induced AAA model, significantly inhibiting the production of matrix metalloproteinase-13 (MMP-13). The extracellular MMP inducer (EMMPRIN; CD147) was increased in human AAA biopsies and in wild-type murine AAA but not in AAA from iNOS null mice. In cells overexpressing ectopic EMMPRIN, MMP-13 secretion was stimulated, whereas silencing of EMMPRIN by RNA interference led to significant inhibition of MMP-13 expression. In addition, elastase infusion of MMP-13 null mouse aortas induced a significant increase of EMMPRIN but reduced aortic dilatation when compared with wild-type mice, suggesting that NO-mediated AAA may be mediated through EMMPRIN induction of MMP-13. These findings were further verified in elastase-infused iNOS null mice, in which daily administration of NO caused a significant aortic dilatation and the expression of EMMPRIN and MMP-13. By contrast, in iNOS wild-type mice, pharmacological inhibition of iNOS by administration of 1400 W induced a reduction of aortic diameter and inhibition of MMP-13 and EMMPRIN expression when compared with control mice. Our results suggest that NO may regulate the development of AAA in part by inducing the expression of EMMPRIN and modulating the activity of MMP-13 in murine and human aneurysms.
Inhibition of MYC in macrophages: tumor vs inflammation-related diseases
(OncoImmunology, 2014) Cano-Ramos, Emilio; Lavín Plaza, Begoña; Pello, Oscar
Inhibition of MYC has been postulated as one of the most promising anti-tumoral therapies. However, if some anti-inflammatory cells express MYC, would an anti-tumoral treatment targeting MYC facilitate subsequent inflammation-related disorders?
Simultaneous Assessment of Cardiac Inflammation and Extracellular Matrix Remodeling After Myocardial Infarction
(Circulation: Cardiovascular Imaging, 2018) Ramos, Isabel ; Henningsson, Markus; Nezafat, Maryam; Lavín Plaza, Begoña; Lorrio, Silvia; Gebhardt, Pierre; Protti, Andrea; Eykyn, Thomas ; Andia, Marcelo ; Floögel, Ulrich; Phinikaridou, Alkystis; Shah, Ajay ; Botnar, Reneé
Background: Optimal healing of the myocardium after myocardial infarction (MI) requires a suitable degree of inflammation and its timely resolution, together with a well-orchestrated deposition and degradation of ECM (extracellular matrix) proteins. Methods and Results: MI and SHAM-operated animals were imaged at 3, 7, 14, and 21 days with 3T magnetic resonance imaging using a 19F/1H surface coil. Mice were injected with 19F-perfluorocarbon nanoparticles to study inflammatory cell recruitment, and with a gadolinium-based elastin-binding contrast agent to evaluate elastin content. 19F magnetic resonance imaging signal colocalized with infarction areas, as confirmed by late gadolinium enhancement, and was highest 7 days post-MI, correlating with macrophage content (MAC-3 immunohistochemistry; ρ=0.89, P<0.0001). 19F quantification with in vivo (magnetic resonance imaging) and ex vivo nuclear magnetic resonance spectroscopy correlated linearly (ρ=0.58, P=0.020). T1 mapping after gadolinium-based elastin-binding contrast agent injection showed increased relaxation rate (R1) in the infarcted regions and was significantly higher at 21 days compared with 7 days post-MI (R1 [s−1]: 21 days=2.8 [interquartile range, 2.69–3.30] versus 7 days=2.3 [interquartile range, 2.12–2.5], P<0.05), which agreed with an increased tropoelastin content (ρ=0.89, P<0.0001). The predictive value of each contrast agent for beneficial remodeling was evaluated in a longitudinal proof-of-principle study. Neither R1 nor 19F at day 7 were significant predictors for beneficial remodeling (P=0.68; P=0.062). However, the combination of both measurements (R1<2.34 Hz and 0.55≤19F≤1.85) resulted in an odds ratio of 30.0 (CI 95%, 1.41–638.15; P=0.029) for favorable post-MI remodeling. Conclusions: Multinuclear 1H/19F magnetic resonance imaging allows the simultaneous assessment of inflammation and elastin remodeling in a murine MI model. The interplay of these biological processes affects cardiac outcome and may have potential for improved diagnosis and personalized treatment.
NOD1 Activation Induces Cardiac Dysfunction and Modulates Cardiac Fibrosis and Cardiomyocyte Apoptosis
(Plos one, 2012) Fernández-Velasco, María; Prieto, Patricia; Terrón, Verónica; Benito, Gemma; Flores Landeira, Juana María; Delgado, Carmen; Zaragoza, Carlos; Lavín Plaza, Begoña; Gómez-Parrizas, Mónica; López-Collazo, Eduardo; Martín Sanz, Paloma; Bosca Gomar, Lisardo
The innate immune system is responsible for the initial response of an organism to potentially harmful stressors, pathogens or tissue injury, and accordingly plays an essential role in the pathogenesis of many inflammatory processes, including some cardiovascular diseases. Toll like receptors (TLR) and nucleotide-binding oligomerization domain-like receptors (NLRs) are pattern recognition receptors that play an important role in the induction of innate immune and inflammatory responses. There is a line of evidence supporting that activation of TLRs contributes to the development and progression of cardiovascular diseases but less is known regarding the role of NLRs. Here we demonstrate the presence of the NLR member NOD1 (nucleotide-binding oligomerization domain containing 1) in the murine heart. Activation of NOD1 with the specific agonist C12-iEDAP, but not with the inactive analogue iE-Lys, induces a time- and dose-dependent cardiac dysfunction that occurs concomitantly with cardiac fibrosis and apoptosis. The administration of iEDAP promotes the activation of the NF-κB and TGF-β pathways and induces apoptosis in whole hearts. At the cellular level, both native cardiomyocytes and cardiac fibroblasts expressed NOD1. The NLR activation in cardiomyocytes was associated with NF-κB activation and induction of apoptosis. NOD1 stimulation in fibroblasts was linked to NF-κB activation and to increased expression of pro-fibrotic mediators. The down-regulation of NOD1 by specific siRNAs blunted the effect of iEDAP on the pro-fibrotic TGF-β pathway and cell apoptosis. In conclusion, our report uncovers a new pro-inflammatory target that is expressed in the heart, NOD1. The specific activation of this NLR induces cardiac dysfunction and modulates cardiac fibrosis and cardiomyocyte apoptosis, pathological processes involved in several cardiac diseases such as heart failure.
Molecular Imaging in Ischemic Heart Disease
(Current Cardiovascular Imaging Reports, 2019) Lavín Plaza, Begoña; Theodoulou, Iakovos; Rashid, Imran; Hajhosseiny, Reza; Phinikaridou, Alkystis; Botnar, Rene
This review summarizes the state of art of non-invasive molecular imaging of the myocardium during ischemia and after myocardial infarction using PET and MRI. We also describe the different contrast agents that have been developed to image the different phases of cardiac healing and the biological processes associated with each of those phases. Importantly, here we focus on imaging of inflammation as it is the key biological process that orchestrates clearance of dead cells, tissue remodeling, cardiac repair, and future outcome. We also focus on clinical translation of some of the novel contrast agents that have been tested in patients and discuss the need for larger, multi-center patient studies to fully validate the applicability of new imaging probes.