Rho-related BTB Domain-containing Protein 1 (RhoBTB1) Attenuates Established Arterial Stiffness In Ang-ii-treated Mice

RhoBTB1 is a transcription target of PPARγ but its function remains unclear. Restoration ofRhoBTB1 by genetic complementation in S-P467L mice expressing dominant negative PPARγmutation reversed hypertension, arterial stiffness, and vascular dysfunction. Here, we asked ifrestoring RhoBTB1 can reverse Ang-II-mediated hypertension and arterial stiffness.To test this hypothesis, S-RhoBTB1 mice, which expressed smooth muscle-specific, tamoxifen(Tx)-inducible RhoBTB1, were implanted with minipumps which released Ang-II (490ng/kg/min, 6weeks) or vehicle. Concurrently, littermate ISM-Cre mice, which expressed smooth muscle-specific, Tx-inducible Cre (but not RhoBTB1), were used as control. Transgenes were induced by5 daily Tx injections 2 weeks after Ang-II pump implantation, and tissue was harvested 2 weeksafter Tx. Measurements were made during a 1 week baseline period, 2 weeks of Ang-II, and 2weeks after transgene activation.Aortic RhoBTB1 expression was decreased in Ang-II-treated ISM-Cre mice (ISM-Cre, Ang-II vs.ISM-Cre, vehicle dCT: 13.6±0.1 vs. 12.4±0.1, n=10), and restored to normal in Ang-II-treated S-RhoBTB1 mice (S-RhoBTB1, Ang-II vs. ISM-Cre, vehicle dCT: 12.8±0.2 vs. 12.4±0.1, n=10-12).Interestingly, pulse-wave velocity, a clinical indicator of arterial stiffness, was significantlydecreased upon RhoBTB1 restoration in Ang-II-treated mice (S-RhoBTB1 vs. ISM-Cre: 2.9±0.1vs. 3.8±0.2, n=22-26). Concomitantly, measures of both pressure-diameter and stress-strainshowed that aortic compliance was improved by RhoBTB1 restoration in Ang-II-treated mice.Interestingly, restoring RhoBTB1 was insufficient to attenuate Ang-II-mediated hypertension (S-RhoBTB1, Ang-II vs. ISM-Cre, Ang-II vs. ISM-Cre, vehicle SBP: 152.1±1.7 vs. 148.0±3.7 vs.115.4± 0.7 mmHg n=12, 8, 6). Currently, we are investigating the mechanism by which RhoBTB1attenuates arterial stiffness.In summary, RhoBTB1 restoration ameliorated Ang-II-mediated arterial stiffness but nothypertension, suggesting that arterial stiffness is not merely a consequence of hypertension butcan be independently regulated from blood pressure. Moreover, there may be novel targets ofRhoBTB1 that can regulate aortic stiffness and be therapeutic.