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Identification and characteristics of microRNAs in rat abdominal aortic aneurysms

ABSTRACT: Abdominal aortic aneurysm (AAA) is a lethal disease, occurring mostly in men more than 65 years of age. Until recently, the pathogenesis of AAA remains poorly understood. MicroRNAs (miRNAs) are a novel class of endogenous small noncoding RNAs that play important roles in diverse biological and pathological processes and was more recently investigated in cardiovascular physiology and pathology. In this study, we employed microarray to detect and compare miRNA expressions of AAAs in rats. Four miRNAs were validated using real time RT-PCR. Functional annotations of putative targets of deregulated miRNAs via bioinformatics approaches revealed that predicted targets were highly enriched and involved in several signaling pathways important for AAA formation. Our results indicate that miRNAs are extensively involved in rat AAA formation and provide a global view of AAA miRNA profiles, which is expected to provide new clues to develop targeted therapies against this calamitous disease.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE24194 | GEO | 2010/09/18

SECONDARY ACCESSION(S): PRJNA130165

REPOSITORIES: GEO

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Project description:Tumor necrosis factor (TNF) is elevated in human abdominal aortic aneurysms (AAA). Non-selective TNF inhibition has been linked to several severe side effects. Compounds that target the proinflammatory soluble TNF (solTNF) while preserving the immunomodulatory capabilities of transmembrane TNF (tmTNF) may prevent such side effects. We hypothesize that inhibition of solTNF signaling by XPro1595 is just as effective as non-selective TNF inhibition by etanercept (ETN) in preventing AAA expansion. The effect of XPro1595 and ETN was examined in porcine pancreatic elastase (PPE) induced AAA mice and findings of XPro1595 was confirmed in Angiotensin II (AngII) induced AAA in hyperlipidemic apolipoprotein E (Apoe) -/- mice. XPro1595 treatment significantly reduced AAA expansion in both models, while a similar trend (p=0.06) was observed in ETN-treated mice using the PPE model. In the PPE aneurysm wall, elastin integrity scores were significantly improved in the XPro1595 group. In the aneurysms, mean TNFR1wasreduced no-significantly (p=0.07) by 50% non-significant after TNF inhibition, but the cellular location in murine AAAs were unaffected and like the localization in human AAAs. Systemic TNF levels were elevated in XPro1595-treated mice, while systemic IL-10 levels were significantly increased after ETN-treatment, while in AngII induced AAA mice systemic TNF and IL5 levels were elevated after XPro1595 treatment. In early AAA development, proteomic analyses revealed that components of the fibrinogen complex were elevated while prostaglandin E2 synthase was down regulated by Xpro1595 (unadjusted p-values). David’s ontology analyses revealed that several pathways including cell matrix adhesion, extracellular space, fibrinogen complex, blood microparticles and glycoproteins were elevated by XPro1595 treatment. In conclusion, selective inhibition of solTNF reduces aneurysm expansion. This supports targeting solTNF as an attractive treatment option for AAA patients.

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Identification and characteristics of microRNAs in rat abdominal aortic aneurysms

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