PPARγ and RhoBTB1 in hypertension

Abstract

Purpose of review: This review provides an up-to-date understanding of how peroxisome proliferator activated receptor γ (PPARγ) exerts its cardioprotective effect in the vasculature through its activation of novel PPARγ target genes in endothelium and vascular smooth muscle.

Recent findings: In vascular endothelial cells, PPARγ plays a protective role by increasing nitric oxide bioavailability and preventing oxidative stress. RBP7 is a PPARγ target gene enriched in vascular endothelial cells, which is likely to form a positive feedback loop with PPARγ. In vascular smooth muscle cells, PPARγ antagonizes the renin-angiotensin system, maintains vascular integrity, suppresses vasoconstriction, and promotes vasodilation through distinct pathways. Rho-related BTB domain containing protein 1 (RhoBTB1) is a novel PPARγ gene target in vascular smooth muscle cells that mediates the protective effect of PPARγ by serving as a substrate adaptor between the Cullin-3 RING ubiquitin ligase and phosphodiesterase 5, thus restraining its activity through ubiquitination and proteasomal degradation.

Summary: In the vasculature, PPARγ exerts its cardioprotective effect through its transcriptional activity in endothelium and vascular smooth muscle. From the understanding of PPARγ's transcription targets in those pathways, novel hypertension therapy target(s) will emerge.

Figure 1.. Protective Role of PPARγ in the Vasculature.

In vascular endothelial cells, PPARγ increases the bioavailability of NO and reduces ROS derived from the endothelium. RBP7, a PPARγ target gene, likely forms a positive feedback loop with PPARγ. We have hypothesized this may occur through a mechanisms by which RBP7 delivers PPARγ ligands to the PPARγ transcriptional complex in the nucleus. This interaction between PPARγ and RBP7 promotes transcription of antioxidant genes which maintains appropriate redox balance in favor of an anti-oxidant environment which promotes NO bioavailibility. In vascular smooth muscle cells, PPARγ sensitizes the vascular muscle to the effects of endothelium-derived NO. Here the effects of PPARγ are multifaceted. PPARγ promotes expression of RGS5 which controls the activity of AT1 receptor. PPARγ also prevents remodeling, prevents calcification, and maintains the cellular circadian rhythm, thorugh its targets TIMP4, Klotho and Bmal, respectively. PPARγ also engages the Cullin-3 E3 ubiquitin ligase to influence both vasodilation and vasoconstriction. Loss of PPARγ decreases Cullin-3 activity which promotes vasoconstriction through increased RhoA and ROCK activity. The mechanism is a loss of RhoA ubiquitination through the Cullin-3 complex. PPARγ promotes vasodilation by increasing expression of RhoBTB1 which acts as an adaptor to deliver PDE5 to the Cullin-3 complex for ubiquitination and proteasomal degradation. This tightly controls PDE5 activity and consequenctly the levels of cGMP in the cell.

Figure 2.. The structure and molecular function of RhoBTB1.

A) RhoBTB1 is composed of a GTPase domain, a Proline-rich domain, two BTB domains and a C-terminal. B) RhoBTB1 serves as a substrate adaptor for Cullin-3-RING ubiquitin ligase and promotes PDE5 ubiquitination. The BTB domains are involved in the RhoBTB1:Cullin-3 interaction as well as the formation of the dimeric complex required to mediate its activity. PDE5 presumably interacts with the C terminal of RhoBTB1 but this has not been tested experimentally. The formation of the productive complex results in transfer of ubiquitin from the E2 enzyme to PDE5 which targets PDE5 for proteasonal degradation.