Rosiglitazone (RSG) is a synthetic agonist of the nuclear hormone Peroxisome Proliferator-Activated Receptor- ? (PPAR-??) and has been successfully used in the clinic for type 2 diabetes as an insulin-sensitizer. However, adverse cardiac side effects have seriously hindered its clinical application. Existing evidence from experimental models revealed that RSG results in cardiac hypertrophy, which may lead to heart failure. Currently, molecular mechanisms underlying RSG-induced cardiac hypertrophy remain unclear. Adipose tissue is a major site of PPAR-?? expression and function. Our preliminary dat showed that activation of PPAR-?? by RSG in adipocytes in a co-culture system resulted in cardiomyocyte hypertrophy. Furthermore, ablation of PPAR-?? in adipocytes attenuated RSG-induced cardiac hypertrophy in vivo. These data imply a functional interplay between adipose and cardiac tissue that regulates cardiac hypertrophy. Adipose tissue plays a critical role as an endocrine organ, and secretes cytokines that regulate systemic homeostasis and the function of other organs. Interestingly, a recent screen as well as our preliminary data revealed that adipocytes are able to release microRNAs (miRs). miRs are a family of highly conserved, small (~22 nucleotide) noncoding RNAs that post-transcriptionally repress gene expression by degrading or inhibiting translation of their target mRNA. The discovery of circulating extracellula miRs in serum suggests they may play a novel role in mediating cell-cell communication. Exosomes are the major transport vesicle of secretory miRs, allowing miR transfer and genetic exchange between cells. Our preliminary studies demonstrated that RSG stimulation of PPAR-?? signaling in adipocytes leads to upregulation of the miR-200a/b/429 cluster, and secretion o mature miR-200a in exosomes. Bioinformatics analysis and experimental investigation demonstrated that miR-200a can target components of the mTOR pathway, which regulates cardiac hypertrophy. In addition, we found that miR-200a was upregulated in a diet-induced obesity-associated cardiomyopathy model. The aforementioned suggest our overall hypothesis is that circulating members of the miR-200a/b/429 cluster mediate communication between adipose and cardiac tissue to adversely affect cardiac remodeling in two distinct models of cardiomyopathy. The overall goal of this project is to elucidate molecular mechanisms underlying adverse cardiac remodeling induced by adipose tissue, and provide insights into a novel exosomal miR-mediated pathway between adipose and cardiac tissue. Accordingly, our Specific Aims are: 1. To examine whether all members of the miR-200a/b/429 cluster are transported from adipocytes to cardiomyocytes in exosomes and to determine potential functional consequences of this in vitro; 2. To elucidate the role of miR-200a and the miR-200a/b/429 cluster in RSG-mediated cardiac hypertrophy in vivo by using adipocyte-specific knockout mouse models; and 3. To understand pathophysiological effects of miR-200a and the miR-200a/b/429 cluster in a mouse model of obesity-associated cardiomyopathy using adipocyte-specific knockout mice.

Public Health Relevance

Proposed studies will help us to gain insights into mechanisms by which adipocyte-derived microRNAs are involved in pathogenic cardiac remodeling in distinct disease settings. These findings will pave the way for potential therapeutic use of antagomirs to treat these diseases. Proposed studies will also impact our general understanding of signal transduction and communication between organs.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL130452-03
Application #
9388374
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Schwartz, Lisa
Project Start
2015-12-21
Project End
2019-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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