The long noncoding RNA H19 is a novel regulator of SMC survival in abdominal aortic aneurysm development and progression. Inhibition of H19 expression might serve as a novel molecular therapeutic target for aortic aneurysm disease.

Stroke is the second most common cause of death 2 and major cause of disability worldwide, 2 with survivors often depending on lifelong care. Carotid stenosis is the second most common predecessor of ischemic stroke, 3 and carotid endarterectomy (CEA; and to a lesser extent carotid artery stenting) are accepted as secondary, but also primary preventive therapy. 2,4,5 With new imaging techniques, vulnerable plaques at risk of rupture can be identified with increasing accuracy, 6 but in the majority of cases, the perioperative surgical risk of ≈3% still outweighs the risk of plaque rupture in asymptomatic carotid stenosis carriers.7 As a result, CEA and carotid artery stenting are currently unfavorable for most of these individuals.8 Detection and stabilization of a vulnerable plaque by influencing the local disease process biologically would provide a sophisticated solution for asymptomatic plaque carriers at risk of stroke. Molecular Medicine© 2016 American Heart Association, Inc. Conclusions: An unstable carotid plaque at risk of stroke is characterized by low expression of miR-210. miR-210 contributes to stabilizing carotid plaques through inhibition of APC, ensuring smooth muscle cell survival. We present local delivery of miR-210 as a therapeutic approach for prevention of atherothrombotic vascular events.

Objectives. A common nonsynonymous single nucleotide polymorphism (SNP) in the CD93 gene (rs3746731, Pro541Ser) has been associated with risk of coronary artery disease (CAD). CD93 is a transmembrane glycoprotein, which is detectable in soluble form in human plasma. We investigated whether the concentration of soluble CD93 in plasma is related to risk of myocardial infarction (MI) and CAD, using a case-control study of premature MI (n = 764) and a nested case-control analysis of a longitudinal cohort study of 60-year-old subjects (analysis comprising 844 of 4232 subjects enrolled at baseline). In addition, SNPs in the CD93 gene were studied in relation to plasma CD93 concentration and CD93 mRNA expression. Methods and Results.A sensitive and specific enzymelinked immunosorbent assay was established for determination of the plasma CD93 concentration. Subjects were divided into three groups according to tertiles of the distribution of CD93 concentration. Lower odds ratios for risk of MI and incidence of CAD were observed in the middle CD93 tertile (142-173 lg L )1 ): odds ratio (95% confidence interval), 0.69 (0.49-0.97) and 0.61 (0.40-0.94), respectively. These associations were independent of traditional CAD risk factors. The minor allele of a SNP in the 3¢ untranslated region of CD93 (rs2749812) was associated with increased plasma CD93 concentrations (P = 0.03) and increased CD93 mRNA expression levels (P = 0.02). Conclusion.The results of the present study suggest that the concentration of soluble CD93 in plasma is a potential novel biomarker for CAD, including MI.

Background: Long noncoding RNAs (lncRNAs) are important regulators of biological processes involved in vascular tissue homeostasis and disease development. The current study assessed the functional contribution of the lncRNA Myocardial Infarction Associated Transcript ( MIAT ) to atherosclerosis and carotid artery disease. Methods: We profiled differences in RNA transcript expression in patients with advanced carotid artery atherosclerotic lesions from the Biobank of Karolinska Endarterectomies (BiKE). The lncRNA MIAT was identified as the most upregulated non-coding RNA transcript in carotid plaques compared to non-atherosclerotic control arteries, which was confirmed by quantitative real time PCR (qRT-PCR) and in situ hybridization. Results: Experimental knockdown of MIAT , utilizing site-specific antisense oligonucleotides (LNA-GapmeRs) not only markedly decreased proliferation and migration rates of cultured human carotid artery smooth muscle cells (SMCs), but also increased their apoptosis. Mechanistically, MIAT regulated SMC proliferation via the EGR1-ELK1-ERK pathway. MIAT is further involved in SMC phenotypic transition to proinflammatory macrophage-like cells through binding to the promoter region of KLF4 and enhancing its transcription. Studies using Miat −/− and Miat −/− ApoE −/− mice as well as Yucatan LDLR −/− mini-pigs confirmed the regulatory role of this lncRNA in SMC de- and trans-differentiation and advanced atherosclerotic lesion formation. Conclusions: The lncRNA MIAT is a novel regulator of cellular processes in advanced atherosclerosis that controls proliferation, apoptosis, and phenotypic transition of SMCs as well as the pro-inflammatory properties of macrophages.

Extracellular vesicles (EVs) have recently emerged as a highly promising cell-free biotherapeutics. While a range of engineering strategies have been developed to functionalize the EV surface, current approaches fail to address the limitations associated with endogenous surface display, pertaining to the heterogeneous display of commonly used EV-loading moieties among different EV subpopulations. Here we present a novel engineering platform to display multiple protein therapeutics simultaneously on the EV surface. As proof-of-concept, we screened multiple endogenous display strategies for decorating the EV surface with cytokine binding domains derived from tumor necrosis factor receptor 1 (TNFR1) and interleukin 6 signal transducer (IL6ST), which can act as decoys for the pro-inflammatory cytokines TNFα and IL6, respectively. Combining synthetic biology and systematic screening of loading moieties, resulted in a three-component system which increased the display and decoy activity of TNFR1 and IL6ST, respectively. Further, this system allowed for .