Emerging data suggest that peroxisome proliferator-activated receptor- ? (PPAR-?) is a critical determinant that may provide functional links between diabetes and CVD. During the past cycle of this R01 funding, our laboratory has made a series of significant contributions to better understand the role of PPAR-? activation in the vasculature. The insulin-sensitizing thiazolidinediones (TZDs) are synthetic ligands of PPAR-? and the first drugs used to treat insulin resistance in patients with type 2 diabetes. Despite of their effectiveness as insulin sensitizers and their protective effects in the vasculature, the therapeutic efficacy of TZDs has been severely compromised due to the appearance of associated cardiovascular events. Thus, the investigation of the molecular mechanisms underlying PPAR-? functions especially in the cardiovascular system are of utmost importance. Of significance, we have identified a nitric oxide (NO) and fatty acid-derived product, nitrated derivatives of fatty acids (NO2-FA) including nitrated oleic acid (OA- NO2) and linoleic acid (LNO2), as potent endogenous PPAR ? ligands. More recent analysis by our laboratories clearly documented that NO2-FA-activated PPAR ? recruits/displaces differential cofactors leading to a pattern of gene expression that mediate different biological responses compared to TZD-activated PPAR ?. Also, we have identified Kruppel-like factor 11 (KLF11) as a novel PPAR3 cofactor. Although KLF11 gene mutations cause MODY7, an early-onset type 2 diabetes mellitus, but its role in the vasculature is entirely unknown. Based on these key results, in this proposal we will test the central hypothesis that NO2-FA-modulated PPAR ? activation and the recruitment of KLF11 play a critical role in protecting the vasculature from vascular lesion formation, thereby contributing to maintenance of vascular homeostasis. Specifically, we will 1) Determine the molecular interactions between NO2-FA and PPAR-? in vascular remodeling;2) Define KLF11 as a novel PPAR-? cofactor required for PPAR-? function during vascular lesion formation. Advances in understanding the mechanisms of endogenous PPAR-? modulation will provide novel therapeutic strategies for treating diabetes and CVD.

Public Health Relevance

Cardiovascular diseases (CVD) are the primary cause of mortality among diabetic patients accounting for almost 2 out of 3 deaths. The insulin-sensitizing thiazolidinediones (TZDs) are synthetic ligands of PPAR-? and the first drugs used to treat insulin resistance in patients with type 2 diabetes. Despite of their effectiveness as insulin sensitizers and their protective effects in the vasculature, the therapeutic efficacy of TZDs has been severely compromised due to the appearance of associated cardiovascular events. This proposal will explore mechanisms how the endogenous PPAR-? ligands, nitro-fatty acids modulate PPAR-? signaling to inhibit vascular lesion formation. The successful implementation of this proposal should lead to a better understanding of endogenous signaling actions of nitro-fatty acids in the vasculature and will provide novel approaches to develop the next generation of PPAR-? drugs with anti-diabetic and anti-CVD properties.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL068878-13
Application #
8387044
Study Section
Special Emphasis Panel (ZRG1-VH-F (02))
Program Officer
Hasan, Ahmed AK
Project Start
2002-01-01
Project End
2015-11-30
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
13
Fiscal Year
2013
Total Cost
$370,090
Indirect Cost
$132,090
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Fan, Jianglin; Kitajima, Shuji; Watanabe, Teruo et al. (2015) Rabbit models for the study of human atherosclerosis: from pathophysiological mechanisms to translational medicine. Pharmacol Ther 146:104-19
Yang, Dongshan; Xu, Jie; Zhu, Tianqing et al. (2014) Effective gene targeting in rabbits using RNA-guided Cas9 nucleases. J Mol Cell Biol 6:97-9
Brown, Nicholas K; Zhou, Zhou; Zhang, Jifeng et al. (2014) Perivascular adipose tissue in vascular function and disease: a review of current research and animal models. Arterioscler Thromb Vasc Biol 34:1621-30
Holmen, Oddgeir L; Zhang, He; Fan, Yanbo et al. (2014) Systematic evaluation of coding variation identifies a candidate causal variant in TM6SF2 influencing total cholesterol and myocardial infarction risk. Nat Genet 46:345-51
Miao, Ruidong; Huang, Shengping; Zhou, Zhou et al. (2013) Targeted disruption of MCPIP1/Zc3h12a results in fatal inflammatory disease. Immunol Cell Biol 91:368-76
Zhang, Jifeng; Zhang, Yuan; Sun, Tingwan et al. (2013) Dietary obesity-induced Egr-1 in adipocytes facilitates energy storage via suppression of FOXC2. Sci Rep 3:1476
Guo, Yanhong; Fan, Yanbo; Zhang, Jifeng et al. (2013) Peroxisome proliferator-activated receptor ýý coactivator 1ýý (PGC-1ýý) protein attenuates vascular lesion formation by inhibition of chromatin loading of minichromosome maintenance complex in smooth muscle cells. J Biol Chem 288:4625-36
Villacorta, Luis; Chang, Lin; Salvatore, Sonia R et al. (2013) Electrophilic nitro-fatty acids inhibit vascular inflammation by disrupting LPS-dependent TLR4 signalling in lipid rafts. Cardiovasc Res 98:116-24
Liu, Ling; Zhou, Zhou; Huang, Shengping et al. (2013) Zc3h12c inhibits vascular inflammation by repressing NF-ýýB activation and pro-inflammatory gene expression in endothelial cells. Biochem J 451:55-60
Wang, Yao; Niimi, Manabu; Nishijima, Kazutoshi et al. (2013) Human apolipoprotein A-II protects against diet-induced atherosclerosis in transgenic rabbits. Arterioscler Thromb Vasc Biol 33:224-31

Showing the most recent 10 out of 58 publications