Atherosclerosis is evoked by both lipid deposition and chronic vascular inflammation, in which monocytes/macrophages play critical roles. The recent identification of heterogeneity of circulating monocytes and lesional macrophages has provided new insights into the mechanism underlying the involvement of monocytes/macrophages in atherogenesis. An emerging notion is that in the presence of systemic pro-atherogenic stress (i.e., hyperlipidemia and inflammation), some circulating monocytes acquire distinct pro-inflammatory phenotypes that prime them to infiltrate the arterial wall and give rise to a pro-inflammatory macrophage subset within the plaque. MicroRNAs (miRs) are short non-coding RNA molecules capable of regulating gene expression by targeting mRNAs, resulting in translational repression or mRNA degradation. They play essential roles in multiple biological and pathological processes, thus emerging as new targets for diagnosis and therapy of several human diseases. One miR, miR155, has been demonstrated to play a crucial role in immune response regulation. Recent studies have shown that miR155 expression in monocytes and macrophages is up-regulated upon stimulation with various ligands for toll-like receptors (TLRs), and it may exaggerate monocyte and macrophage inflammation by targeting several negative regulators of TLR-mediated signaling. While TLRs and their ligands are fundamentally involved in atherogenesis, the contribution of monocyte/macrophage miR155 to atherosclerosis has not been investigated. Our preliminary studies suggest a potential role of monocyte/macrophage miR155 in atherosclerosis, and prompt us to hypothesize that up-regulation of miR155 expression is an integral feature of the pro-atherogenic phenotype of circulating monocytes.
Two specific aims are proposed to test this hypothesis. SA1. To test the hypothesis that miR155 expression is up-regulated in circulating monocytes of atherosclerotic mice. We will measure miR155 expression in circulating monocytes using two hypercholesterolemic mouse models, evaluate its correlation with lesion size, plasma lipids, and inflammatory markers, and examine whether miR155 is differentially expressed in circulating monocyte subsets. SA2. To test the hypothesis that increased miR155 expression represents a pro-atherogenic phenotype of monocytes. We will transduce monocytes isolated from mice with lentiviral vectors to introduce miR155 overexpression or inhibition, and test the effects of miR155 manipulation on monocyte adhesion to aortic endothelium, infiltration into intima and foam cell transformation. We will also explore the underlying molecular mechanism.
Atherosclerosis is the direct cause of heart attack and stroke, the No. 1 and No. 3 killers in the United States. There is an urgent call for more sensitive noninvasive diagnostic tools to detect patients at high risk of clinical events as well as for developing effective and safe anti-inflammation therapies to complement cholesterol-lowering therapy for atherosclerosis. The identification of miR155 as a pro- atherogenic feature of circulating monocytes holds the potential to significantly impact future clinical practice.
