Light deficiency in Apoe-/-mice increases atheroma plaque size and vulnerability by modulating local immunity.

Previous research suggests a potential involvement of the cytokine LIGHT (TNFSF14) in atherosclerosis. In this study, the genetic inactivation of Light in Apolipoprotein E deficient mice (male and female C57BL) augmented plaque size and vulnerability while decreasing Treg cells. Human and mouse transcriptomic results demonstrated deranged immune pathways in human atheromas with low LIGHT expression levels and in Light-deficient murine atheromas. In agreement with this, in vitro LIGHT-treatment of human lymphocytes, induced an elevation of Treg cell prevalence while proteomic analysis showed a downregulation of apoptotic and leukocyte cytotoxic pathways. Consistently, Light-deficient mouse lesions displayed increased plaque apoptosis and detrimental adventitial T-lymphocyte aggregates. Altogether suggested that LIGHT could promote a Treg prevalence in the local immunity to prevent the generation of vulnerable plaques via decreased cytotoxic microenvironment and apoptosis. Light gene delivery in Apoe-/-Light-/- mice, through bone marrow transplantation approaches, consistently diminished lesion size and restored local plaque immunity. Altogether demonstrate that Light-deficiency promotes atheroma plaque progression, at least in part through local loss of immune homeostasis and increased apoptosis. This study suggest that therapies based on the local delivery of LIGHT within plaques might therefore prevent immune cell derangement and advanced atherosclerosis.

Vascular smooth muscle cell phenotype is modulated by ligands of the lymphotoxin beta receptor and the tumor necrosis factor receptor / El fenotipo de las células de músculo liso vascular es modulado por los ligandos del receptor de la linfotoxina beta y del receptor del factor de necrosis tumoral

Objective: Vascular smooth muscle cells (VSMCs) undergo a phenotypic-switching process during the generation of unstable atheroma plaques. In this investigation, the potential implication of the tumor necrosis factor superfamily (TNFSF) ligands, in the gene expression signature associated with VSMC plasticity was studied. Material and methods: Human aortic (ha)VSMCs were obtained commercially and treated with the cytokine TNFSF14, also called LIGHT, the lymphotoxin alpha (LTα), the heterotrimer LTα1β2 or with vehicle for 72h. The effect of the different treatments on gene expression was analyzed by quantitative PCR and included the study of genes associated with myofibroblast-like cell function, osteochondrogenesis, pluripotency, lymphorganogenesis and macrophage-like cell function. Results: HaVSMCs displayed a change in myofibroblast-like cell genes which consisted in reduced COL1A1 and TGFB1 mRNA levels when treated with LTα or LIGHT and with augmented MMP9 expression levels when treated with LTα. LTα and LIGHT treatments also diminished the expression of genes associated with osteochondrogenesis and pluripotency SOX9, CKIT, and KLF4. By contrary, all the above genes were no affected by the treatment with the trimer LTα1β2. In addition, haVSMC treatment with LTα, LTα1β2 and LIGHT altered lymphorganogenic cytokine gene expression which consisted of augmented CCL20 and CCL21 mRNA levels by LTα and a reduction in the gene expression of CCL21 and CXCL13 by LIGHT and LTα1β2 respectively. Neither, LTα or LIGHT or LTα1β2 treatments affected the expression of macrophage-like cell markers in haVSMC. Conclusions: Altogether, indicates that the TNFSF ligands through their interconnected network of signaling, are important in the preservation of VSMC identity against the acquisition of a genetic expression signature compatible with functional cellular plasticity.(AU)

Objetivo: La transición de placa de ateroma estable a placa inestable implica, entre otros procesos, un cambio fenotípico de las células del músculo liso vascular (CMLVs). En esta investigación, se estudió el posible papel de los ligandos de la superfamilia del factor de necrosis tumoral (TNFSF), en los cambios de expresión génica asociada a la plasticidad de las CMLVs. Materiales y métodos: Las CMLVs de aorta humana (CMLVah) se obtuvieron comercialmente y se trataron con la citoquina TNFSF14, también llamada LIGHT, la linfotoxina alfa (LTα), el heterotrímero LTα1β2 o con vehículo durante 72 horas. El efecto de los diferentes tratamientos se analizó mediante el estudio de la expresión génica por PCR cuantitativa e incluyó genes asociados con fenotipo miofibroblástico, osteocondrogénico, genes de pluripotencia, genes de linforganogénesis y genes característicos de macrófagos. Resultados: El estudio de genes asociados a fenotipo miofibroblástico en las CMLVah reveló una reducción de la expresión génica de COL1A1 y TGFB1 tras el tratamiento con LTα o LIGHT mientras que el tratamiento con LTα aumentó los niveles de mRNA de MMP9. LTα y LIGHT también disminuyeron la expresión de genes de osteocondrogénesis y pluripotencia como SOX9, CKIT y KLF4. Por el contrario, la expresión de los genes anteriores no se vio afectada por el tratamiento con el trímero LTα1β2. El tratamiento de las CMLVah con LTα, LTα1β2 y LIGHT alteró la expresión génica de citoquinas linforganogénicas con una expresión aumentada de los genes CCL20 y CCL21 por LTα y una reducción de los niveles de mRNA de CCL21 y CXCL13 por LIGHT y LTα1β2, respectivamente. Ninguno de los tres tratamientos alteró la expresión de genes típicos de macrófagos en las CMLVah. Conclusiones: La presente investigación indica que los ligandos de la familia de los TNFSF a través de su red de señalización...(AU)

Vascular smooth muscle cell phenotype is modulated by ligands of the lymphotoxin ß receptor and the tumor necrosis factor receptor.

OBJECTIVE: Vascular smooth muscle cells (VSMCs) undergo a phenotypic-switching process during the generation of unstable atheroma plaques. In this investigation, the potential implication of the tumor necrosis factor superfamily (TNFSF) ligands, in the gene expression signature associated with VSMC plasticity was studied. MATERIAL AND METHODS: Human aortic (ha)VSMCs were obtained commercially and treated with the cytokine TNFSF14, also called LIGHT, the lymphotoxin alpha (LTα), the heterotrimer LTα1ß2 or with vehicle for 72h. The effect of the different treatments on gene expression was analyzed by quantitative PCR and included the study of genes associated with myofibroblast-like cell function, osteochondrogenesis, pluripotency, lymphorganogenesis and macrophage-like cell function. RESULTS: HaVSMCs displayed a change in myofibroblast-like cell genes which consisted in reduced COL1A1 and TGFB1 mRNA levels when treated with LTα or LIGHT and with augmented MMP9 expression levels when treated with LTα. LTα and LIGHT treatments also diminished the expression of genes associated with osteochondrogenesis and pluripotency SOX9, CKIT, and KLF4. By contrary, all the above genes were no affected by the treatment with the trimer LTα1ß2. In addition, haVSMC treatment with LTα, LTα1ß2 and LIGHT altered lymphorganogenic cytokine gene expression which consisted of augmented CCL20 and CCL21 mRNA levels by LTα and a reduction in the gene expression of CCL21 and CXCL13 by LIGHT and LTα1ß2 respectively. Neither, LTα or LIGHT or LTα1ß2 treatments affected the expression of macrophage-like cell markers in haVSMC. CONCLUSIONS: Altogether, indicates that the TNFSF ligands through their interconnected network of signaling, are important in the preservation of VSMC identity against the acquisition of a genetic expression signature compatible with functional cellular plasticity.

Novel Therapies for Cardiometabolic Disease: Recent Findings in Studies with Hormone Peptide-Derived G Protein Coupled Receptor Agonists.

The increasing prevalence of obesity and type 2 diabetes (T2DM) is provoking an important socioeconomic burden mainly in the form of cardiovascular disease (CVD). One successful strategy is the so-called metabolic surgery whose beneficial effects are beyond dietary restrictions and weight loss. One key underlying mechanism behind this surgery is the cooperative improved action of the preproglucagon-derived hormones, glucagon, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP) which exert their functions through G protein-coupled receptors (GPCR). Great success has been reached with therapies based on the GLP-1 receptor monoagonism; therefore, a logical and rational approach is the use of the dual and triagonism of GCPC to achieve complete metabolic homeostasis. The present review describes novel findings regarding the complex biology of the preproglucagon-derived hormones, their signaling, and the drug development of their analogues, especially those acting as dual and triagonists. Moreover, the main investigations into animal models and ongoing clinical trials using these unimolecular dual and triagonists are included which have demonstrated their safety, efficacy, and beneficial effects on the CV system. These therapeutic strategies could greatly impact the treatment of CVD with unprecedented benefits which will be revealed in the next years.

Therapies for the Treatment of Cardiovascular Disease Associated with Type 2 Diabetes and Dyslipidemia.

Cardiovascular disease (CVD) is the leading cause of death worldwide and is the clinical manifestation of the atherosclerosis. Elevated LDL-cholesterol levels are the first line of therapy but the increasing prevalence in type 2 diabetes mellitus (T2DM) has positioned the cardiometabolic risk as the most relevant parameter for treatment. Therefore, the control of this risk, characterized by dyslipidemia, hypertension, obesity, and insulin resistance, has become a major goal in many experimental and clinical studies in the context of CVD. In the present review, we summarized experimental studies and clinical trials of recent anti-diabetic and lipid-lowering therapies targeted to reduce CVD. Specifically, incretin-based therapies, sodium-glucose co-transporter 2 inhibitors, and proprotein convertase subtilisin kexin 9 inactivating therapies are described. Moreover, the novel molecular mechanisms explaining the CVD protection of the drugs reviewed here indicate major effects on vascular cells, inflammatory cells, and cardiomyocytes, beyond their expected anti-diabetic and lipid-lowering control. The revealed key mechanism is a prevention of acute cardiovascular events by restraining atherosclerosis at early stages, with decreased leukocyte adhesion, recruitment, and foam cell formation, and increased plaque stability and diminished necrotic core in advanced plaques. These emergent cardiometabolic therapies have a promising future to reduce CVD burden.