RESUMEN
BACKGROUND AND AIMS: The platelet inhibitor aspirin reduces inflammation and atherosclerosis in both apolipoprotein E deficient (apoE-/-) mice and low-density lipoprotein receptor deficient (Ldlr-/-) mice. Similarly, the factor Xa inhibitor rivaroxaban reduces atherosclerosis in both apoE-/- and Ldlr-/- mice. We tested the hypothesis that the combination of aspirin and rivaroxaban reduces atherosclerosis in mice to a greater extent than either agent alone. METHODS: Male Ldlr-/- mice were fed a western-type diet for 12 weeks to induce atherosclerosis. Cohorts of mice received aspirin in the water and/or rivaroxaban in the diet. Atherosclerosis and lesion composition were measured in the aortic sinus and the aorta. Expression of 55 proteins in the aorta and plasma was determined using multiplex ELISA assays. RESULTS: Aspirin alone, rivaroxaban alone, and the combination of both agents significantly reduced atherosclerosis in the Ldlr-/- mice compared with control Ldlr-/- mice fed a western-type diet. However, there were no significant differences in atherosclerosis in the group receiving aspirin and rivaroxaban compared with the groups that received aspirin or rivaroxaban alone. Aspirin, rivaroxaban and the combination reduced macrophage content and apoptosis in the lesions compared with controls but there was no difference between the three treatment groups. We observed statistically significant changes in the expression of a small number of proteins in the aorta and plasma in mice treated with aspirin and/or rivaroxaban. CONCLUSIONS: Contrary to our expectation, the combination of aspirin and rivaroxaban did not further reduce atherosclerosis in Ldlr-/- mice beyond the level observed with each agent alone.
Asunto(s)
Aterosclerosis , Rivaroxabán , Animales , Aorta/patología , Apolipoproteínas E , Aspirina/farmacología , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/genética , Aterosclerosis/prevención & control , Modelos Animales de Enfermedad , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de LDL , Rivaroxabán/metabolismo , Rivaroxabán/farmacologíaRESUMEN
Adipose tissue homeostasis plays a central role in cardiovascular physiology, and the presence of thermogenically active brown adipose tissue (BAT) has recently been associated with cardiometabolic health. We have previously shown that adipose tissue-specific deletion of HuR (Adipo-HuR-/-) reduces BAT-mediated adaptive thermogenesis, and the goal of this work was to identify the cardiovascular impacts of Adipo-HuR-/-. We found that Adipo-HuR-/- mice exhibit a hypercontractile phenotype that is accompanied by increased left ventricle wall thickness and hypertrophic gene expression. Furthermore, hearts from Adipo-HuR-/- mice display increased fibrosis via picrosirius red staining and periostin expression. To identify underlying mechanisms, we applied both RNA-seq and weighted gene coexpression network analysis (WGCNA) across both cardiac and adipose tissue to define HuR-dependent changes in gene expression as well as significant relationships between adipose tissue gene expression and cardiac fibrosis. RNA-seq results demonstrated a significant increase in proinflammatory gene expression in both cardiac and subcutaneous white adipose tissue (scWAT) from Adipo-HuR-/- mice that is accompanied by an increase in serum levels of both TNF-α and IL-6. In addition to inflammation-related genes, WGCNA identified a significant enrichment in extracellular vesicle-mediated transport and exosome-associated genes in scWAT, whose expression most significantly associated with the degree of cardiac fibrosis observed in Adipo-HuR-/- mice, implicating these processes as a likely adipose-to-cardiac paracrine mechanism. These results are significant in that they demonstrate the spontaneous onset of cardiovascular pathology in an adipose tissue-specific gene deletion model and contribute to our understanding of how disruptions in adipose tissue homeostasis may mediate cardiovascular disease.NEW & NOTEWORTHY The presence of functional brown adipose tissue in humans is known to be associated with cardiovascular health. Here, we show that adipocyte-specific deletion of the RNA binding protein HuR, which we have previously shown to reduce BAT-mediated thermogenesis, is sufficient to mediate a spontaneous development of cardiac hypertrophy and fibrosis. These results may have implications on the mechanisms by which BAT function and adipose tissue homeostasis directly mediate cardiovascular disease.