Molecular mechanism vascular remodeling and blood pressure regulation by orphan receptor, and theraputic

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Renin, an enzyme important in cardiovascular homeostasis, is regulated by cAMP. Our previous studies suggested that renin gene expression is regulated, at least partly, by a novel as acting DNA element (CNRE) in the gene's 5'-flanking region. We demonstrate here that a CNRE binding protein is the mouse homologue of human LXRa using a yeast one-hybrid cloning system. LXRα is a member of the superfamily of nuclear receptor regulators of transcription and functions as a heterodimer with RXRα, another member of this family. To examine the function of LXRα on the expression of renin gene, we transfected the renin-producing renal As4.1 cells with LXRα expression plasmid. Transient overexpression of LXRα in As4.1 cells confers cAMP inducibility to reporter constructs containing the CNRE. Moreover, following stable transfection of LXRα, As4.1 cells show a cAMP-inducible upregulation of renin mRNA expression with a significant increase in nuclear binding activity to CNRE, which is antagonized b … More y an anti-LXRα antibody. Interestingly, LXRα can also bind to the homologous CNRE in the c-myc promoter and mediate cAMP-inducible c-myc expression. The identification of LXRα as a novel cAMP responsive nuclear modulator of renin and c-myc gene expression should provide new insights not only into its role in nuclear receptor-signaling pathway, but also in the understanding of cardiovascular pathophysiology. To examine the pathophysiological roles of LXRα in cardiovascular remodeling, we employed polyethylene cuff-induced vascular injury model in me femoral artery mouse model. We found that LXRα was transactivated associated with the increase in the expression of c-myc and renin, and neointimal hyperplasia. We also observed that LXRα was upregulated in pressure-overload-induced cardiac hypertrophy in mice. Moreover, we demonstrated that activation of renin-angiotensin system is important in the cardiovascular remodeling in these mouse models. These results suggest the pathophysiological importance of LXRα in cardiovascular remodeling and LXRα can be a future target for gene therapy for cardiovascular diseases. Less