Document text
Principal Investigator: Curt Daniel Sigmund
Organization: MEDICAL COLLEGE OF WISCONSIN
Fiscal Year: 2024
Award: $905,520
Funding agency: National Heart Lung and Blood Institute
Summary/Abstract
Blood vessels play an important role in the regulation of arterial blood pressure (BP). Precise BP regulation
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
contract. Our studies show that the NO pathway is coordinately regulated through transcriptional and post-
translational pathways initiated by PPARγ, a nuclear receptor transcription factor. Our data support the
concepts that PPARγ: 1) acts as a sensor in EC to regulate redox state, and through this, bioavailability of NO,
and 2) regulates the responsiveness of SMC to NO by independently controlling a) a RhoA/Rho kinase
(ROCK) activity that promotes constriction, and b) production and stability of cyclic GMP (cGMP), a critical
mediator of vasodilation. The range of PPARγ-dependent molecular mechanisms in both cell types is
surprisingly complex; requiring novel transcriptional co-factors (e.g. retinol binding protein 7; RBP7) which form
a transcriptional regulatory hub with PPARγ, and post-translational regulation of critical SMC mediators (RhoA
and phosphodiesterase 5, PDE5) by Cullin-3 E3 ubiquitin ligase-mediated protein turnover. Importantly, this
PPARγ initiated “final common pathway” has profound effects on vasomotor function, BP and vascular
stiffness, and the studies proposed herein have potential implications for the treatment of these disorders.
However, the signals which initiate and mediate these responses and the range of molecular targets remain
poorly understood. This proposal will focus on two distinct PPARγ-regulated pathways. We will examine the
PPARγ-RhoBTB1-Cullin-3 pathway in smooth muscle and will 1) determine if the RhoBTB1-Cullin-3 pathway
can be exploited as a potential future therapeutic by assessing if RhoBTB1 can protect and reverse
phenotypes in models of hypertension or in other disease models in which vascular dysfunction is a
comorbidity, 2) determine if RhoBTB1 is important in other cells types including endothelium, and 3) employ a
proteomic strategy to identify novel RhoBTB1 binding partners and Cullin-3 substrates in vascular smooth
muscle. We will also examine the PPARγ-RBP7-anti-oxidant pathway in endothelium and will perform 1)
structure function analysis to identify key mechanisms regulating PPARγ transcriptional activity by RBP7, and
2) genome wide transcriptome and chromatin immunoprecipitation studies to assess the contribution of RBP7
to mediated transcriptional activity of PPARγ and its obligate heterodimer RXR. This program will lead to new
concepts and directions of investigation for the field and will not only deepen our understanding of the role of
two fundamentally important pathways in the vasculature, but will also address fundamental transcriptional and
post-translational mechanisms that are of relevance in many cell types.
Terms: <9-cis-Retinoic Acid Receptor><Actions of Nitric Oxide in the Heart><Address><Antioxidants><BP homeostasis><BP regulation><Basal Transcription Factor><Basal transcription factor genes><Binding><Bioavailability><Biological Availability><Blood Pressure><Blood Vessels><Cell Communication and Signaling><Cell Signaling><ChIP assay><Complex><Contracting Opportunities><Contracts><Cullin Homolog 3><Cyclic GMP><Data><Disease><Disorder><E3 Ligase><E3 Ubiquitin Ligase><Endogenous Nitrate Vasodilator><Endothelium><Endothelium-Derived Nitric Oxide><Future><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Genetic Transcription><Guanosine Cyclic Monophosphate><HUMPPARG><Hypertension><Intracellular Communication and Signaling><Investigation><Involuntary Muscle><Mediating><Mediator><Metabolic Protein Degradation><Modeling><Molecular><Molecular Interaction><Molecular Target><Mononitrogen Monoxide><NR1C3><Nitric Oxide><Nitric Oxide Pathway><Nitrogen Monoxide><Nitrogen Protoxide><Nuclear Receptors><Oxidation-Reduction><PDE 5 enzyme><PPAR gamma><PPAR-g><PPAR-γ><PPARG><PPARG gene><PPARG1><PPARG2><PPARgamma><PPARγ><Pathway interactions><Peroxisome Proliferative Activated Receptor Gamma><Peroxisome Proliferator-Activated Receptor gamma><Peroxisome Proliferator-Activated Receptor γ><Phenotype><Physiologic><Physiologic Availability><Physiological><Play><Post-Translational Regulation><Posttranslational Regulation><Production><Protein Turnover><Proteomics><RNA Expression><RXR><RXR Protein><Redox><Regulation><Regulatory Protein Degradation><Research><Retinoic Acid Receptor RXR><Retinoid Binding Proteins><Retinoid X Receptors><Retinol Binding Proteins><Retinol-Binding Protein 1><Rho-associated kinase><Rho-kinase><Role><Sight><Signal Transduction><Signal Transduction Systems><Signaling><Smooth Muscle><Structure><Therapeutic><Thiazolidinedione Receptor><Transcription><Transcription Factor Proto-Oncogene><Transcription factor genes><Ubiquitin Protein Ligase><Ubiquitin-Protein Ligase Complexes><Ubiquitin-Protein Ligase E3><Vascular Diseases><Vascular Disorder><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><Vascular Smooth Muscle><Vasoactive Agonists><Vasoconstrictor Agents><Vasoconstrictor Drugs><Vasoconstrictors><Vasodilatation><Vasodilating Agent><Vasodilation><Vasodilator Agents><Vasodilator Drugs><Vasodilators><Vasomotor><Vasopressor Agents><Vasorelaxation><Vision><arterial stiffening><arterial stiffness><artery stiffening><artery stiffness><biological signal transduction><blood pressure homeostasis><blood pressure regulation><blood vessel disorder><cGMP><cell type><chromatin immunoprecipitation><co-morbid><co-morbidity><cofactor><comorbidity><constriction><cullin-3><disease model><disorder model><endothelial cell derived relaxing factor><genome scale><genome-wide><genomewide><global gene expression><global transcription profile><high blood pressure><hyperpiesia><hyperpiesis><hypertensive disease><hypertensive disorder><novel><oxidation reduction reaction><pathway><phosphodiesterase V><phosphodiesterase-5><pressure><programs><protein degradation><regulate BP><regulate blood pressure><response><sensor><social role><transcription factor><transcriptome><ubiquitin-protein ligase><vascular><vascular dysfunction><vasculopathy><vasopressor><visual function>