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RhoBTB1 protects against hypertension and arterial stiffness by restraining phosphodiesterase 5 activity
Masashi Mukohda, … , Frederick W. Quelle, Curt D. Sigmund
Masashi Mukohda, … , Frederick W. Quelle, Curt D. Sigmund
Published March 21, 2019
Citation Information: J Clin Invest. 2019;129(6):2318-2332. https://doi.org/10.1172/JCI123462.
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Research Article Vascular biology

RhoBTB1 protects against hypertension and arterial stiffness by restraining phosphodiesterase 5 activity

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Abstract

Mice selectively expressing a PPARγ dominant-negative mutation in vascular smooth muscle exhibit RhoBTB1 deficiency and hypertension. Our rationale was to use genetic complementation to uncover the mechanism of action of RhoBTB1 in vascular smooth muscle. Inducible smooth muscle–specific restoration of RhoBTB1 fully corrected hypertension and arterial stiffness by improving vasodilator function. Notably, the cardiovascular protection occurred despite the preservation of increased agonist-mediated contraction and RhoA and Rho kinase activity, suggesting that RhoBTB1 selectively controls vasodilation. RhoBTB1 augmented the cyclic 3′,5′-monophosphate (cGMP) response to NO by restraining the activity of phosphodiesterase 5 (PDE5) through its action as a substrate adaptor delivering PDE5 to the Cullin-3 E3 ring ubiquitin ligase complex for ubiquitination, thereby inhibiting PDE5. Angiotensin II infusion also caused RhoBTB1 deficiency and hypertension, which were prevented by smooth muscle–specific RhoBTB1 restoration. We conclude that RhoBTB1 protected against hypertension, vascular smooth muscle dysfunction, and arterial stiffness in at least 2 models of hypertension.

Authors

Masashi Mukohda, Shi Fang, Jing Wu, Larry N. Agbor, Anand R. Nair, Stella-Rita C. Ibeawuchi, Chunyan Hu, Xuebo Liu, Ko-Ting Lu, Deng-Fu Guo, Deborah R. Davis, Henry L. Keen, Frederick W. Quelle, Curt D. Sigmund

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Figure 7

Role of p-PDE5.

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Role of p-PDE5.
(A) Western blot of total aortic protein from Tx-treated...
(A) Western blot of total aortic protein from Tx-treated mice detecting p-PDE5 and total PDE5, PPARγ, tdTomato, and GAPDH. Size markers transferred from the original blots are shown. Shown are 3 representative blots from 10 samples assayed. The levels of p-PDE5 and total PDE5 from all 10 samples were quantified. Data were normalized to the average control value, set to 1.0. *P < 0.05 versus control; #P < 0.05 versus S-P467L; 1-way ANOVA. (B) Reciprocal co-IP of WT and Ser92A mutation in PDE5 and RhoBTB1 in HEK293 cells transfected with either Myc-tagged PDE5 or Myc-tagged PDE5 (Ser92A) and either untagged RhoBTB1 or His-tagged RhoBTB1. Cells in B were treated with MLN4924 (1 μM) for 16 hours. Western blots were probed with the indicated antisera. IP and lysates are labeled. Molecular weight markers were transferred from the original blots.
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