Our laboratory has developed a partial carotid ligation mouse model to investigate mechanisms involved in flow induced vascular remodeling. Phenotypic analysis of the effect of decreased blood flow in the left carotid arteries of C3HeB/FeJ (C3H/F) showed that these mice are resistant to intima formation when blood flow decreases while SJL/J are highly susceptible to intima-media thickening associated with increases in vascular smooth muscle cell (VSMC) proliferation and increased inflammation. Investigations of differences in these two strains showed that SJL/J had increased inflammatory cytokines (IL-18 and Mif1) endothelial dysfunction, decreased superoxide dismutase (SOD2) and increased nitortyrosine. Microarray analysis of carotids from sham-operated C3H/F and SJL/J mice generated a list of candidate genes that may contribute to the difference in intima phenotype seen in SJL/J compared to C3H/F. Two of the candidate genes identified were ribosomal proteins (Rpl), Rpl17 and Rpl7-like1. While several laboratories have suggested a role for Rpl's in VSMC proliferation, this topic has not been well studied. Importantly, two microarray studies of VSMC phenotypic modulation have demonstrated significant changes in Rpl's including one that also identified Rpl17. Furthermore, evidence suggests that Rpl's can act as tumor suppressors, decreasing cell proliferation. Based on our results and the supporting evidence in the literature, our major hypothesis is that Rpl function is critical in regulating strain dependent VSMC mediated intima formation.
Atherosclerotic cardiovascular disease is the leading cause of morbidity in the Western world with hypertension being a predominant risk factor. IMT has been well validated as an important predictor of cardiovascular disease. A clearer understanding of the pathways that regulate IMT should assist in the design of more effective therapeutic agents to reduce carotid, coronary and peripheral vascular disease. At a basic science level, investigation of the role of ribosomal protein function VSMC growth and inflammation will provide novel information regarding the molecular pathways in vascular homeostasis.
| Smolock, Elaine M; Korshunov, Vyacheslav A; Glazko, Galina et al. (2012) Ribosomal protein L17, RpL17, is an inhibitor of vascular smooth muscle growth and carotid intima formation. Circulation 126:2418-27 |
