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BackgroundOne strategy to reduce the burden of cardiovascular disease is the early detection and treatment of atherosclerosis. This has led to significant interest in studies of subclinical atherosclerosis, using different phenotypes, not all of which are accurate reflections of the presence of asymptomatic atherosclerotic plaques. The aim of part 2 of this series is to provide a review of the existing literature on purported measures of subclinical disease and recommendations concerning which tests may be appropriate in the prevention of incident cardiovascular disease.MethodsWe conducted a critical review of measurements used to infer the presence of subclinical atherosclerosis in the major conduit arteries and focused on the predictive value of these tests for future cardiovascular events, independent of conventional cardiovascular risk factors, in asymptomatic people. The emphasis was on studies with >10 000 person-years of follow-up, with meta-analysis of results reporting adjusted hazard ratios (HRs) with 95% CIs. The arterial territories were limited to carotid, coronary, aorta, and lower limb arteries.ResultsIn the carotid arteries, the presence of plaque (8 studies) was independently associated with future stroke (pooled HR, 1.89 [1.04-3.44]) and cardiac events (7 studies), with a pooled HR, 1.77 (1.19-2.62). Increased coronary artery calcium (5 studies) was associated with the risk of coronary heart disease events, pooled HR, 1.54 (1.07-2.07) and increasing severity of calcification (by Agaston score) was associated with escalation of risk (13 studies). An ankle/brachial index (ABI) of

Simple Summary: Atherosclerosis, the leading cause of heart disease, involves cholesterol buildup within the artery wall. Current treatments are ineffective in removing excess cholesterol from the diseased arteries. Accordingly, increasing expression of cholesterol export proteins such as ATP-binding cassette subfamily A, member 1 (ABCA1), may enhance cholesterol efflux and impede atherosclerosis development. We previously showed that endothelial cells (ECs) transduced with a viral vector can release small delivery vehicles (exosomes) loaded with a therapeutic molecule (antagomir) targeting miR-33a-5p, which inhibits ABCA1. The addition of a short 'X-motif' sequence enhanced antagomir packaging into exosomes and delivery into artery wall cell types in vitro. In the present study, we explored whether this EC-based exosome-mediated strategy can deliver the anti-miR-33a-5p into the medial cells of the rabbit artery in vivo. The X-motif antagomir was found in the medial cells of the transduced arteries; however, this strategy still requires further refinement to enhance antagomir expression and delivery within the artery wall. In future studies, this strategy could help reduce plaque buildup in arteries, offering a new avenue for atherosclerosis treatment. Atherosclerosis is caused by the accumulation of cholesterol within intimal smooth muscle cells (SMCs) and macrophages. However, the transporter ATP-binding cassette subfamily A, member 1 (ABCA1), can remove cholesterol from these intimal, cells reducing atherosclerosis. Antagomir-mediated inhibition of miR-33a-5p, a microRNA that represses ABCA1 translation, promotes ABCA1-dependent cholesterol efflux and may impede atherosclerosis development. In our previous work, transducing cultured endothelial cells (ECs) with a helper-dependent adenoviral vector (HDAd) that expresses X-motif-tagged anti-miR-33a-5p enhanced antagomir packaging into EC-derived exosomes, which delivered the antagomir to cultured SMCs and macrophages. In this present study, we tested whether in vivo transduction of rabbit carotid artery endothelium can deliver an X-motif-tagged anti-miR-33a-5p to subendothelial cells. Rabbit carotid endothelial cells were transduced in vivo with an HDAd expressing anti-miR-33a-5p either with or without the X-motif (n = 11 arteries per vector). Contralateral carotids received HDAd that express scrambled oligonucleotides. Three days after transduction, the antagomir—without the X-motif—was detected in the intima but not in the media of transduced carotids (p = 0.062). The X-motif antagomir was detected in 82% of the intimal extracts (9 out of 11 carotids) and 27% of medial samples (3 out of 11 carotids, p = 0.031). However, the X-motif did not significantly enhance antagomir delivery to the media (p = 0.214 vs. non-X-motif antagomir). Expression of the antagomirs—with and without the X-motif—was sub-stoichiometric in ECs and SMCs. No antagomir-related changes in miR-33a-5p or ABCA1 expressions were detected. Despite its potential as a therapeutic strategy, our exosome-targeted gene transfer system requires further improvements to enhance antagomir expression and delivery to the subendothelial cells. [ABSTRACT FROM AUTHOR]

Uninjured rat arteries transduced with an adenoviral vector expressing an active form of transforming growth factor [Beta]1 (TGF-[Beta]1) developed a cellular and matrix-rich neointima, with cartilaginous metaplasia of the vascular media. Explant cultures of transduced arteries showed that secretion of active TGF-[Beta]1 ceased by 4 weeks, the time of maximal intimal thickening. Between 4 and 8 weeks, the cartilaginous metaplasia resolved and the intimal lesions regressed almost completely, in large part because of massive apoptosis. Thus, locally expressed TGF-[Beta]1 promotes intimal growth and appears to cause transdifferentiation of vascular smooth muscle cells into chondrocytes. Moreover, TGF-[Beta]1 withdrawal is associated with regression of vascular lesions. These data suggest an unexpected plasticity of the adult vascular smooth muscle cell phenotype and provide an etiology for cartilaginous metaplasia of the arterial wall. Our observations may help to reconcile divergent views of the role of TGF-[Beta]1 in vascular disease.

Oleic acid and other long chain fatty acids inhibit the binding of single chain urokinase (scuPA) with cultured trophoplasts, endothelial cells, and soluble urokinase receptor at physiological plasma concentrations. Such inhibitory effect is dose-dependent and saturable, consistent with the involvement of specific binding sites. Inhibition is maximal at the oleic acid concentration of 150 muM. The results suggests that unsaturated long chain fatty acids may act as physiological regulators of proteolytic events and intracellular signalling.