PPAR? is a ligand activated transcription factor best known for its role in regulating insulin sensitivity and adipose tissue development and expansion. There is now convincing evidence to support an important beneficial role for endothelial PPAR? in the regulation of endothelial function. However, little is known about the transcriptional targets for PPAR?, how PPAR? selectively activates some targets over others, and their mechanisms of action in the endothelium. Selective expression of a dominant negative mutant of PPAR? in the endothelium (E-V290M) has no effect on endothelial function in aorta, carotid or basilar arteries in young transgenic mice at baseline, but induces severe dysfunction if the mice are challenged by a high fat diet, Ang-II, or are old. The cerebral circulation is particularly sensitive to oxidative stress in response to the interference with PPAR? signaling. Conversely, increased expression of wildtype PPAR? specifically in the endothelium (E- PPAR?-WT) reduced vasoconstriction to Ang-II. These data strongly suggest that PPAR? plays a protective role in the endothelium under stressed conditions, and the dysfunction resulting from PPAR? impairment is caused by oxidative stress. We identified retinol-binding protein 7 (RBP7) as a PPAR? target gene in the endothelium. RBP7 is an intracellular retinol binding protein belonging to the family of intracellular lipid and fatty acid-binding proteins. Expression of RBP7 is endothelial cell-specific. RBP7-deficient mice exhibit the same high fat diet-induced and Ang-II-induced phenotype as E-V290M mice which selectively express a dominant negative mutant of PPAR? in the endothelium. This led us to consider the innovative concept that the beneficial effects of PPAR? in the endothelium may be mediated by RBP7. Intracellular lipid and fatty acid binding proteins have been reported to bind ligands which activate other ligand activated transcription factors. Thus conceptually, we hypothesize that PPAR? and RBP7 may form a transcriptional regulatory loop (or hub) in endothelial cells, which is required to support an anti oxidant state and when impaired induces a pro-oxidant state. We will examine this concept in two Specific Aims.
Specific Aim 1 will test the hypotheses that a) the beneficial effects of wildtype PPAR? over-expression in the endothelium require RBP7, b) that the effects of RBP7 are mediated by its retinol-binding and lipid transport activity, and c) RBP7 is required for the PPAR?- mediated anti-oxidant response, including the expression and function of endothelial adiponectin.
Specific Aim 2 will evaluate the molecular mechanisms by which RBP7 regulates PPAR? transcriptional activity by testing the hypothesis that RBP7 with its intrinsic retinol binding and nuclear translocation activity is required for transcriptional activity of PPAR?.

Public Health Relevance

PAR? is an important transcription factor which as anti-oxidant and anti-inflammatory effects in the endothelium and provides protection against risk factors such as a high fat diet. Little is known about the transcriptional targets for PPAR?, how PPAR? selectively activates some targets over others, and their mechanisms of action in the endothelium. We identified retinol-binding protein 7 (RBP7) as a PPAR? target gene in the endothelium. We hypothesize that PPAR? and RBP7 form a transcriptional regulatory loop in endothelial cells, which is required to support an anti-oxidant state and when impaired induces a pro-oxidant state leading to endothelial dysfunction.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL131689-01
Application #
9078209
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
OH, Youngsuk
Project Start
2016-04-01
Project End
2020-03-31
Budget Start
2016-04-01
Budget End
2017-03-31
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Iowa
Department
Pharmacology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52246
De Silva, T Michael; Li, Ying; Kinzenbaw, Dale A et al. (2018) Endothelial PPAR? (Peroxisome Proliferator-Activated Receptor-?) Is Essential for Preventing Endothelial Dysfunction With Aging. Hypertension 72:227-234
Nair, Anand R; Agbor, Larry N; Mukohda, Masashi et al. (2018) Interference With Endothelial PPAR (Peroxisome Proliferator-Activated Receptor)-? Causes Accelerated Cerebral Vascular Dysfunction in Response to Endogenous Renin-Angiotensin System Activation. Hypertension 72:1227-1235
Forrester, Steven J; Booz, George W; Sigmund, Curt D et al. (2018) Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology. Physiol Rev 98:1627-1738
Shinohara, Keisuke; Nakagawa, Pablo; Gomez, Javier et al. (2017) Selective Deletion of Renin-b in the Brain Alters Drinking and Metabolism. Hypertension 70:990-997
De Silva, T Michael; Hu, Chunyan; Kinzenbaw, Dale A et al. (2017) Genetic Interference With Endothelial PPAR-? (Peroxisome Proliferator-Activated Receptor-?) Augments Effects of Angiotensin II While Impairing Responses to Angiotensin 1-7. Hypertension 70:559-565
Woll, Addison W; Quelle, Frederick W; Sigmund, Curt D (2017) PPAR? and retinol binding protein 7 form a regulatory hub promoting antioxidant properties of the endothelium. Physiol Genomics 49:653-658
Mukohda, Masashi; Lu, Ko-Ting; Guo, Deng-Fu et al. (2017) Hypertension-Causing Mutation in Peroxisome Proliferator-Activated Receptor ? Impairs Nuclear Export of Nuclear Factor-?B p65 in Vascular Smooth Muscle. Hypertension 70:174-182
Hu, Chunyan; Keen, Henry L; Lu, Ko-Ting et al. (2017) Retinol-binding protein 7 is an endothelium-specific PPAR?cofactor mediating an antioxidant response through adiponectin. JCI Insight 2:e91738
Nakagawa, Pablo; Sigmund, Curt D (2017) How Is the Brain Renin-Angiotensin System Regulated? Hypertension 70:10-18
Prasad, Anand M; Ketsawatsomkron, Pimonrat; Nuno, Daniel W et al. (2016) Role of CaMKII in Ang-II-dependent small artery remodeling. Vascul Pharmacol 87:172-179

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