PPARy is a ligand activated nuclear receptor and transcription factor targeted by the thiazoiidinedione (TZD) class of anti-diabetes drugs. There is increased appreciation for the importance of PPARy in the cardiovascular system. TZDs lower blood pressure (BP) and suppress atherosclerosis and human subjects carrying dominant negafive mutations in PPARy exhibit severe hypertension. The investigator provides convincing evidence for a protective role of PPARy in the blood vessel through direct activation of PPARy in the endothelium and vascular smooth muscle. The investigator will use unique transgenic models targeting dominant negative mutations In PPARy specifically to EC and SMC using cell-specific promoters to test the hypothesis that PPARy in EC and SMC acts to transcripfionally program the blood vessel to an anti-oxidant, anti-inflammatory, and pro-vasodilatory state, and is protecfive in atherosclerosis, effects which are markedly impaired by PPARy-interference. The investigative team will examine this hypothesis by interrogating novel mechanisms and transcriptional pathways by which PPARy in vascular SMC promotes a vasodilator state and regulates BP and the mechanisms by which EC and SMC PPARy are protective in atherosclerosis.
Two specific aims are proposed: 1) Examine the importance of the ROCK signaling pathway in SMC in S-P467L mice evaluating the molecular mechanisms by which PPARy interference increases ROCK signaling, and funcfionally validate the mechanism of PPARy-dependent regulation of 3 novel PPARy target genes which influence the contractile state of the blood vessel, and 2) examine the importance of EC and SMC PPARy in atherosclerosis by testing the hypothesis that EC and SMC-specific expression of a constitutively active mutant of PPARy attenuates atherosclerosis, whereas expression of dominant negative mutant accentuates atherosclerosis in ApoE-deficient mice. In future experiments the investigator will extend gene expression profiling and bioinformatics platform to identify addifional novel PPARy target genes that function outside the Rho/ROCK pathway but have functional significance in vasomotor funcfion (oxidant stress, inflammation, metabolism). These studies will significantly advance our understanding of the mechanisms in EC and SMC by which PPARy regulates vasomotor tone, BP, and protects against atherosclerosis. The studies are significant because PPARy ligands lower BP whereas mutations cause HT, and are innovative in the use of unique mouse models targeting PPARy interference to EC and SMC, and in identifying and examining novel PPARy target genes in SMC and EC that effect vasomotor acfivity and BP regulation.
Our novel concept is that the beneficial actions of thiazolidinediones in lowering blood pressure occur via acfivafion of PPARy in the vascular endothelial and smooth muscle cells. The aims of this proposal are significant in that they will identify the molecular mechanisms by which PPARy interference and activation regulate vascular tone and arterial pressure, and modulate atherosclerosis, and will test potential PPARy target genes as mediators of these effects.
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