Intersection of the PPARγ-RhoBTB1-Cullin-3 Pathway and Renin-Angiotensin System in Blood Pressure, Vascular Function and Arterial Stiffness - Summary/Abstract According to the National Health and Nutrition Examination Survey (NHANES) adjusted for the 2017 ACC/AHA Guidelines, nearly 50% of American adults have hypertension (HT), a major risk factor for cardiovascular disease (CVD) mortality. Arteries play an important role in the regulation of blood pressure (BP); and this requires coordination between vasodilator and vasoconstrictor signals in the endothelium (EC) and smooth muscle (SMC). EC-derived nitric oxide (NO) is among the key signals which instruct the SMC to dilate or constrict. Arterial structure is also critical, as arterial stiffness is an independent risk factor for CVD. We advanced the concept that vascular function is dependent on a unique transcriptional and post-translational regulatory circuit involving PPARγ-RhoBTB1-Cullin-3 (CUL3) and its target proteins which govern both the bioavailability of EC NO and the responsiveness of the underlying SMC to EC-derived NO. We also advanced the concept that SMC is not just a passive responder to the EC, but employs this regulatory circuit to precisely modulate the NO response. Defects in this pathway cause impaired vascular function, arterial stiffness, and HT. Significantly, activating this pathway can rapidly regress established arterial stiffness. RhoBTB1 is interesting because it contains a BTB-domain; and BTB-domain containing proteins act as substrate adaptors for the CUL3 E3 Ring Ubiquitin Ligase. CUL3 target proteins are selected by virtue of their binding to BTB domain-containing substrate recognition proteins (SRP), which function by delivering target proteins to the CUL3 complex where they become polyubiquitinated and targeted for proteasomal degradation. Genetic and physiologic evidence strongly support the importance of RhoBTB1-CUL3. Mutations in CUL3 cause human HT, and RhoBTB1 is associated with diastolic BP and an interacting locus in a large HT GWAS of more than a million people. This proposal delineates two visions for the next 7-years of research elucidating molecular and physiological mechanisms controlling vasomotor function, arterial stiffness and blood pressure at the intersection of the renin-angiotensin system (RAS) and the PPARγ-RhoBTB1-CUL3 pathways. The program will ask the following questions: a) what are the substrates of CUL3-RhoBTB1 in vascular SMC (and other cells) and how do they contribute to vasomotor function, arterial stiffness and BP control, b) is RhoBTB1 a multifunctional protein, that is, does its GTPase and proline rich domains, which are dispensable for its role as an SRP, play a role in CV regulation, c) can the protective effects of RhoBTB1 (or its individual targets) be exploited therapeutically, d) why is hypertension in mice with selective loss of CUL3 in vascular SMC RAS dependent, and e) are the actions of ANG to antagonize the protective effects of PPARγ-RhoBTB1-CUL3 mediated by Gαq or β-arrestin downstream of ANG AT1 receptor.
