Faculty Collaboration Database

The 2023 Walter B. Cannon Award Lecture: Mechanisms Regulating Vascular Function and Blood Pressure by the PPARγ-RhoBTB1-CUL3 Pathway. Function (Oxf) 2024;5(1):zqad071

Date

01/10/2024

Pubmed ID

38196837

Pubmed Central ID

PMC10775765

DOI

10.1093/function/zqad071

Scopus ID

2-s2.0-85182088208 (requires institutional sign-in at Scopus site)

Abstract

Human genetic and clinical trial data suggest that peroxisome proliferator activated receptor γ (PPARγ), a nuclear receptor transcription factor plays an important role in the regulation of arterial blood pressure. The examination of a series of novel animal models, coupled with transcriptomic and proteomic analysis, has revealed that PPARγ and its target genes employ diverse pathways to regulate vascular function and blood pressure. In endothelium, PPARγ target genes promote an antioxidant state, stimulating both nitric oxide (NO) synthesis and bioavailability, essential components of endothelial-smooth muscle communication. In vascular smooth muscle, PPARγ induces the expression of a number of genes that promote an antiinflammatory state and tightly control the level of cGMP, thus promoting responsiveness to endothelial-derived NO. One of the PPARγ targets in smooth muscle, Rho related BTB domain containing 1 (RhoBTB1) acts as a substrate adaptor for proteins to be ubiquitinated by the E3 ubiquitin ligase Cullin-3 and targeted for proteasomal degradation. One of these proteins, phosphodiesterase 5 (PDE5) is a target of the Cullin-3/RhoBTB1 pathway. Phosphodiesterase 5 degrades cGMP to GMP and thus regulates the smooth muscle response to NO. Moreover, expression of RhoBTB1 under condition of RhoBTB1 deficiency reverses established arterial stiffness. In conclusion, the coordinated action of PPARγ in endothelium and smooth muscle is needed to maintain NO bioavailability and activity, is an essential regulator of vasodilator/vasoconstrictor balance, and regulates blood vessel structure and stiffness.

Author List

Sigmund CD

Author

Curt Sigmund PhD Chair, Professor in the Physiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Blood Pressure
Cullin Proteins
Cyclic Nucleotide Phosphodiesterases, Type 5
Humans
PPAR gamma
Proteomics