The role of Fli1 in myeloid cells and its contribution to cardiac fibrosis

ABSTRACT
Heart disease is the leading cause of death in the USA and fibrosis is a common endpoint for most cardiac
diseases. Recent research has shown monocytes and macrophages are important mediators of heart fibrosis.
We found reduced levels of the transcription factor Fli1 in monocytes isolated from systemic sclerosis (SSc)
patients, an autoimmune connective tissue disease characterized by widespread tissue fibrosis and fibrotic
cardiomyopathy. Co-culture of human cardiac fibroblasts and Fli1 depleted monocytes resulted in potent
induction of galectin-3, and alternative activation markers in myeloid cells, and abundant collagen deposition by
fibroblasts, and this was blocked by the mTOR inhibitor Rapamycin. Preliminary experiments revealed that
deletion of Fli1 in monocytes/macrophages via Cre-mediated recombination using LysMCre mice
(LysMCre/Fli1fl/fl) predisposed mice to develop myocardial fibrosis.
Based on published data and our preliminary results, we hypothesize that Fli1 deficiency in macrophages
contributes to SSc fibrosis and cardiomyopathy, and that Rapamycin may block these effects. To test this
hypothesis, we propose the following specific aims:
Specific aim 1: Determine the molecular mechanism leading to fibrosis following Fli1 depletion in
monocytes/macrophages. We expect that decreased Fli1 in monocytes/macrophages will result in enhanced
migration, cardiomyocyte hypertrophy, and will promote the production of extracellular matrix via Fli1/galetin-
3/mTOR pathway.
Specific aim 2: Determine whether loss of Fli1 in macrophages leads to cardiomyopathy in vivo. We
expect that the LysMCre/Fli1fl/fl mice will have enhanced inflammatory infiltrates, heart fibrosis and diastolic
dysfunction in response to Angiotensin II, which will be inhibited by Rapamycin.
Specific aim 3. Investigate whether myeloid Fli1 has a role in SSc-associated cardiomyopathy. We expect
that monocytes and macrophages from SSc patients with cardiomyopathy will display a similar phenotype to the
LysMCre/Fli1fl/fl macrophages.
The studies proposed should allow us to gain better understanding of the molecular mechanisms of heart fibrosis
in SSc, and determine whether future treatments for SSc-cardiomyopathy, should target Fli1 and the myeloid
system via Rapamycin, thus providing the basis for potentially safer, more effective therapies.

Grant Number: 5R01HL155955-05
NIH Institute/Center: NIH
Principal Investigator: Andreea Bujor