Summary Dominant negative mutations in the nuclear hormone receptor peroxisome proliferator-activated receptor-γ (PPARγ) cause hypertension by an unknown mechanism. Hypertension and vascular dysfunction are recapitulated by expression of dominant negative PPARγ specifically in vascular smooth muscle of transgenic mice. Dominant negative PPARγ increases RhoA and Rho-kinase activity, and inhibition of Rho-kinase restores normal reactivity and reduces arterial pressure. RhoBTB1, a component of the Cullin-3 RING E3 ubiquitin ligase complex, is a PPARγ target gene. Decreased RhoBTB1, Cullin-3 and neddylated Cullin-3 correlated with increased levels of the Cullin-3 substrate RhoA. Knockdown of Cullin-3 or inhibition of cullin-RING ligase activity in aortic smooth muscle cells increased RhoA. Cullin-RING ligase inhibition enhanced agonist-mediated contraction in aortic rings from normal mice by a Rho-kinase-dependent mechanism, and increased arterial pressure in vivo. We conclude that Cullin-3 regulates vascular function and arterial pressure thus providing a mechanistic link between mutations in Cullin-3 and hypertension in humans.

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Innate immune receptors represent important therapeutic targets for inflammatory disorders. In particular, the Toll-like receptor (TLR) family has emerged as a promoter of chronic inflammation that contributes to obesity, insulin resistance and atherosclerosis. Importantly, triggering receptor expressed on myeloid cells-1 (TREM-1) has been characterized as an 'amplifier' of TLR2 and TLR4 signaling. TREM-1- and TREM-2-dependent signaling, as opposed to TREM-like transcript-1 (TLT-1 or TREML1), are mediated through association with the transmembrane adaptor DNAX activation protein of 12 kDa (DAP12). Recessive inheritance of rare mutations in DAP12 or TREM-2 results in a disorder called polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, and surprisingly these subjects are not immunocompromised. Recent progress into the roles of TREM/DAP12 signaling is critically reviewed here with a focus on metabolic, cardiovascular and inflammatory diseases. The expanding repertoire of putative ligands for TREM receptors is also discussed.

Rationale Activation of peroxisome proliferator-activated receptor-γ (PPARγ) by thiazolidinediones lowers blood pressure, whereas PPARγ mutations cause hypertension. Previous studies suggest these effects may be mediated through the vasculature, but the underlying mechanisms remain unclear. Objective To identify PPARγ mechanisms and transcriptional targets in vascular smooth muscle and their role in regulating resistance artery tone. Methods and Results We studied mesenteric artery (MA) from transgenic mice expressing dominant negative (DN) mutant PPARγ driven by a smooth muscle cell (SMC)-specific promoter. MA from transgenic mice exhibited a robust increase in myogenic tone. Patch clamp analysis revealed a reduced large conductance Ca2+-activated K+ (BKCa) current in freshly dissociated SMC from transgenic MA. Inhibition of protein kinase C (PKC) corrected both enhanced myogenic constriction and impaired BKCa channel function. Gene expression profiling revealed a marked loss of the regulator of G protein signaling 5 (RGS5) mRNA in transgenic MA, which was accompanied by a substantial increase in angiotensin II-induced constriction in MA. RGS5 siRNA caused augmented myogenic tone in intact mesenteric arteries and increased activation of PKC in SMC cultures. PPARγ and PPARδ each bind to a PPAR response element close to the RGS5 promoter. RGS5 expression in non-transgenic MA was induced following activation of either PPARγ or PPARδ, an effect that was markedly blunted by DN PPARγ. Conclusions We conclude that RGS5 in smooth muscle is a PPARγ and PPARδ target, which when activated blunts angiotensin-II-mediated activation of PKC, preserves BKCa channel activity, thus providing tight control of myogenic tone in the microcirculation.