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RhoBTB1 protects against hypertension and arterial stiffness by restraining phosphodiesterase 5 activity. J Clin Invest 2019 03 21;129(6):2318-2332

Date

03/22/2019

Pubmed ID

30896450

Pubmed Central ID

PMC6546477

DOI

10.1172/JCI123462

Scopus ID

2-s2.0-85063644288   20 Citations

Abstract

Mice selectively expressing PPARĪ³ dominant negative mutation in vascular smooth muscle exhibit RhoBTB1-deficiency and hypertension. Our rationale was to employ genetic complementation to uncover the mechanism of action of RhoBTB1 in vascular smooth muscle. Inducible smooth muscle-specific restoration of RhoBTB1 fully corrected the hypertension and arterial stiffness by improving vasodilator function. Notably, the cardiovascular protection occurred despite preservation of increased agonist-mediated contraction and RhoA/Rho kinase activity, suggesting RhoBTB1 selectively controls vasodilation. RhoBTB1 augmented the cGMP response to nitric oxide by restraining the activity of phosphodiesterase 5 (PDE5) by acting as a substrate adaptor delivering PDE5 to the Cullin-3 E3 Ring ubiquitin ligase complex for ubiquitination inhibiting PDE5. Angiotensin-II infusion also caused RhoBTB1-deficiency and hypertension which was prevented by smooth muscle specific RhoBTB1 restoration. We conclude that RhoBTB1 protected from hypertension, vascular smooth muscle dysfunction, and arterial stiffness in at least two models of hypertension.

Author List

Mukohda M, Fang S, Wu J, Agbor LN, Nair AR, Ibeawuchi SC, Hu C, Liu X, Lu KT, Guo DF, Davis DR, Keen HL, Quelle FW, 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

Angiotensin II
Animals
Cullin Proteins
Cyclic Nucleotide Phosphodiesterases, Type 5
Disease Models, Animal
HEK293 Cells
Humans
Hypertension
Mice
Mice, Transgenic
Muscle, Smooth, Vascular
Nitric Oxide
Vascular Stiffness
Vasodilation
rho GTP-Binding Proteins
rho-Associated Kinases