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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 8

Protective effect of RhoBTB1 on Ang-II–induced hypertension.

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Protective effect of RhoBTB1 on Ang-II–induced hypertension.
(A and B) R...
(A and B) Relative mRNA expression of RhoBTB1 was determined by qPCR in aorta from control (A) or S-RhoBTB1 (B) mice after injection of vehicle (corn oil) or Tx and subsequent treatment with Ang-II (490 ng/min/kg) or saline for 14 days. (C and D) Systolic BP (SBP) was measured for 14 days after initiation of Ang-II infusion (arrow) in control (C) and S-RhoBTB1 (D) mice. Sample numbers are indicated in E. (E) Cumulative SBP during the last 4 days of measurement from mice in C and D. (F–K) Cumulative concentration-response curves for ACh (F–I) and SNP (J and K) in aorta (n = 5–8) and basilar artery (n = 4) (H–I). (L and M) Cumulative concentration-response curves for 5-HT. (N) Mutations in either Cullin-3 or PPARγ cause hypertension. Cullin-3 regulates both the Rho/ROCK pathway through BACURD, whereas Cullin-3 regulates PDE5 through RhoBTB1. RhoBTB1 regulates the activity of PDE5 by ensuring that excess PDE5 is targeted for Cullin-3 dependent ubiquitination and proteasomal degradation. Mutations in PPARγ or treatment with Ang-II causes RhoBTB1-deficiency. All data represent the mean ± SEM. *P < 0.05 versus control, saline; #P < 0.05 versus S-RhoBTB1 V plus Ang-II; 1-way ANOVA or 2-way repeated-measures ANOVA.
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