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Rhobtb1 Protects Against Hypertension and Arterial Stiffness by Restraining Phosphodiesterase 5 Activity

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Rhobtb1 Protects Against Hypertension and Arterial Stiffness by Restraining Phosphodiesterase 5 Activity RhoBTB1 protects against hypertension and arterial stiffness by restraining phosphodiesterase 5 activity Masashi Mukohda, … , Frederick W. Quelle, Curt D. Sigmund J Clin Invest. 2019. https://doi.org/10.1172/JCI123462. Research In-Press Preview Vascular biology Graphical abstract Find the latest version: https://jci.me/123462/pdf Mukohda et al. 3/13/2019 123462-JCI-RG-RV-2 RhoBTB1 Protects Against Hypertension and Arterial Stiffness by Restraining Phosphodiesterase 5 Activity Masashi Mukohda1, Shi Fang1,2, Jing Wu1,2, Larry N. Agbor1, Anand R. Nair1, Stella-Rita C. Ibeawuchi1, Chunyan Hu1, Xuebo Liu1, Ko-Ting Lu1, Deng-Fu Guo1, Deborah R. Davis1, Henry L. Keen1, Frederick W. Quelle1, and Curt D. Sigmund1,2 1Department of Pharmacology, UIHC Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, IA 52242, USA 2Department of Physiology, Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA Conflict of interest statement: The authors have declared that no conflict of interest exists Corresponding Author: Curt D. Sigmund, Ph.D. Department of Physiology Medical College of Wisconsin 8701 Watertown Plank Road Milwaukee, WI 53226-0509 414-955-8277 [email protected] 1 Mukohda et al. 3/13/2019 123462-JCI-RG-RV-2 Abstract Mice selectively expressing PPAR 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. Brief Summary RhoBTB1 protected from hypertension, vascular dysfunction, and arterial stiffness by augmenting cGMP by restraining activity of phosphodiesterase 5 via a Cullin-3 E3 ubiquitin ligase dependent-mechanism. Keywords: Peroxisome proliferator-activated receptor, vascular smooth muscle, hypertension, arterial stiffness, phosphodiesterase. 2 Mukohda et al. 3/13/2019 123462-JCI-RG-RV-2 Introduction Peroxisome proliferator-activated receptor gamma (PPAR) is a ligand activated transcription factor known to regulate fatty acid metabolism. The clinical significance of PPAR is best illustrated by the improvement in glycemic control in type 2 diabetes patients treated with thiazolidinediones (TZDs), synthetic PPAR agonists (1). The PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events) trial demonstrated that pioglitazone lowered arterial blood pressure and improved vascular function in type 2 diabetes (2), a finding confirmed by a number of other smaller trials and clinical studies (3-5). Although serious adverse effects of the TZDs have been reported, this remains very controversial. The Food and Drug Administration initially restricted the use of some TZDs on the basis of reports showing an increased risk of myocardial infarction compared to other type 2 diabetes treatment regiments (6). That decision was reversed in 2013 when a review of the evidence including the RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes) trial suggested there was no increased risk of overall cardiovascular morbidity or mortality compared with standard glucose-lowering drugs (7, 8). Despite this, new prescriptions for the TZD class continue to decline (9, 10). Thus, identifying PPAR target genes is required to design new therapies that selectively preserve the protective actions of PPAR while eliminating potential adverse effects of TZDs. The best evidence supporting a role for PPAR in blood pressure regulation comes from genetic studies showing that mutations in PPAR cause human hypertension (11-14). Other studies suggested the beneficial effect of PPAR may be mediated through the vasculature (15). Based on the clinical and genetic literature we hypothesized that loss of PPAR function in tissues such as liver, muscle and fat caused type 2 diabetes, whereas, hypertension was caused by a loss of PPAR activity in the blood vessel. This hypothesis 3 Mukohda et al. 3/13/2019 123462-JCI-RG-RV-2 was confirmed by studies of transgenic mice targeting expression of the human hypertension-causing mutations in PPAR selectively to either endothelium or vascular smooth muscle (16-18). PPAR also exerted anti-inflammatory effects in endothelium and smooth muscle (19, 20), and anti-oxidant effects in endothelium (21, 22). Mechanistically, expression of dominant negative PPAR mutations (P467L or V290M) selectively in vascular smooth muscle caused vascular dysfunction and hypertension that was dependent on increased RhoA/ROCK signaling (16, 23). Gene expression profiling of aorta from S-P467L mice led us to identify RhoBTB1 as one of approximately 250 genes altered by dominant negative PPAR. RhoBTB1 is an atypical member of the Rho GTPase family and a member of the family of the Broad-Complex, Tramtrack and Bric a brac (BTB) domain-containing proteins (24). BTB domain-containing proteins are notable for their activity as substrate adaptors for the Cullin-3 E3 RING ubiquitin ligase complex (CRL3) (25). RhoBTB1 has been shown to bind Cullin-3 (23, 26), and we provided compelling evidence that RhoBTB1 is a PPAR target gene in smooth muscle cells (23). This identification of RhoBTB1 as a PPAR target and its connection with the CRL3 complex suggested that Cullin-3 may play a role in regulating vasomotor function. Consistent with this, Cullin-3 mediates RhoA turnover (27, 28). S-P467L mice exhibit impaired levels of Cullin-3, impaired turnover of RhoA, and increased RhoA/Rho kinase activity in response to G-protein coupled receptor agonists (23). Further supporting the importance of this pathway is genetic data showing that mutations in Cullin-3 cause human hypertension (29). Smooth muscle-specific expression of the hypertension-causing mutation in Cullin-3 causes vascular dysfunction and hypertension through a RhoA and Rho kinase-dependent mechanism (30). However, Cullin-3 mediates its effects on RhoA through the BTB-domain containing protein BACURD, not RhoBTB1 (27). Thus, the mechanism by which decreased expression of 4 Mukohda et al. 3/13/2019 123462-JCI-RG-RV-2 RhoBTB1 regulates vasomotor function and blood pressure remains unclear. Herein, we used a genetic complementation approach to assess the importance of RhoBTB1 and define the mechanism of action of RhoBTB1 in vascular smooth muscle cells. The premise is that if the adverse cardiovascular effects of dominant negative PPAR are mediated by a loss of RhoBTB1 expression, restoring its expression should complement those physiological defects. We provide evidence that RhoBTB1 provides protection from vascular dysfunction characterized by nitric oxide resistance, arterial stiffness and hypertension by restraining the activity of phosphodiesterase 5 (PDE5) and promoting the cGMP-dependent relaxation of vascular SMC. We also show this protective effect is not limited to a model of PPAR-deficiency but also affects angiotensin-II (Ang-II)-induced hypertension. We identify RhoBTB1 as a novel gene providing protection from hypertension, vascular dysfunction and arterial stiffness. 5 Mukohda et al. 3/13/2019 123462-JCI-RG-RV-2 Results We generated transgenic mice (RhoBTB1IND) carrying a conditionally activatable transgene designed for PPAR-independent inducible co-expression of RhoBTB1 and the tdTomato reporter gene in response to Cre-recombinase (Figure 1A). Cotransfection of HEK293 cells with vectors encoding RhoBTB1IND and Cre-recombinase resulted in co-expression of both RhoBTB1 and tdTomato (Figure 1B). RhoBTB1IND mice were bred with smooth muscle cell-specific tamoxifen-inducible Cre-recombinase (SMC-CreERT2) mice to establish S-RhoBTB1 double transgenic mice inducibly expressing RhoBTB1 selectively in vascular smooth muscle (Figure 1C). As a second step, S-RhoBTB1 mice were crossed with S-P467L mice to produce a triple transgenic experimental model termed S-P467L/S-RhoBTB1. In this model, reduced expression of endogenous RhoBTB1 in smooth muscle cells caused by dominant negative PPAR could be reversed by tamoxifen (Tx) by induction of the PPAR-independent transgene. This genetic complementation strategy was successful as RhoBTB1 mRNA expression was decreased in S-P467L aorta, but was restored to normal levels in Tx-treated S-P467L/S-RhoBTB1 mice (Figure 1D). Tx also induced tdTomato mRNA and protein, but importantly did not alter the level of P467L PPAR mRNA or protein (Figure 1D-E). Cre-recombinase-mediated expression of tdTomato was specifically localized to smooth muscle cells but not endothelium demonstrating cell-specificity (Figure 1F). To test the hypothesis that loss of RhoBTB1 expression is mechanistically linked to hypertension in S-P467L mice, we
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