Understanding signaling mechanisms in biomechanical overload of the myocardium is important for developing new strategies for prevention and treatment of heart failure. In this proposal, we describe experiments to explore the cardioprotective role of a newly discovered cytokine, Interleukin-33 (IL-33). Over seven years ago, we identified an interleukin-1 receptor family member as a novel mechanically-induced gene. Our experiments demonstrated that this receptor, called ST2, is biomechanically-induced in cardiomyocytes and can be detected in a soluble isoform in the serum of patients with cardiovascular disease. We then demonstrated in large human trials that increased serum levels of soluble ST2 (sST2) prospectively predict worse outcome in patients with acute myocardial infarction as well as non-ischemic heart failure. Although these data supported a potential pathophysiological role of this pathway in the cardiac response to overload, determining if activation of this pathway was simply a biomarker or of true pathophysiological importance was challenging due to the lack of a known ligand for this orphan receptor. In November, 2005, after a 15 year search by many laboratories, the ligand for ST2 was finally identified as Interleukin-33, a homologue of Interleukin-1. Here we show new data demonstrating that IL-33 is a powerful antagonist of hypertrophy of cardiac myocytes in the absence of immune or inflammatory cells. We also show that targeted disruption of the ST2 gene in genetically engineered mice causes excessive cardiac fibrosis after mechanical overload, and that wildtype mice treated with recombinant IL-33 have reduced cardiac fibrosis after transverse aortic constriction. These preliminary data reveal IL-33/ST2 signaling as a novel biomechanically-activated and cardioprotective signaling system. Further experimental exploration of this system may not only explain why cardiovascular disease patients with increased serum ST2 protein have a worse prognosis, but will yield insight into a potential therapeutic role of IL-33.
Our Aims i nclude hypothesis-driven experiments that range from molecular mechanism (Aims 1 and 2) to cellular (Aim 3) to organ (Aim 4), all focusing on the role of IL-33 in pressure-overload of the myocardium:
Aim 1. To test the hypothesis that IL-33 inhibits cardiac hypertrophy through induction of iex-1, an antihypertrophic NF-kappaB response gene.
Aim 2. To explore the molecular determinants of binding and signal transduction in IL-33/ST2.
Aim 3. To test the hypothesis that, during pressure overload, the cardiomyocyte ST2L receptor is essential for the anti-hypertrophic effects of IL-33.
Aim 4. To explore the relationship between cardiac fibrosis and cardiomyocyte refreshment through the anti-fibrotic properties of IL-33.

Public Health Relevance

Heart Failure is a leading cause of death, disability, and hospitalization in the United States. This proposal addresses a newly-discovered signaling system in the heart that is activated by overloading the heart muscle. Understanding this signaling system could lead to new therapies for preventing heart failure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL092930-05
Application #
8387779
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Wong, Renee P
Project Start
2008-12-15
Project End
2013-11-30
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
5
Fiscal Year
2013
Total Cost
$387,288
Indirect Cost
$151,668
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Ho, Jennifer E; Chen, Wei-Yu; Chen, Ming-Huei et al. (2013) Common genetic variation at the IL1RL1 locus regulates IL-33/ST2 signaling. J Clin Invest 123:4208-18
Green, Eric M; Lee, Richard T (2013) Proteins and small molecules for cellular regenerative medicine. Physiol Rev 93:311-25
Kakkar, Rahul; Hei, Hillary; Dobner, Stephan et al. (2012) Interleukin 33 as a mechanically responsive cytokine secreted by living cells. J Biol Chem 287:6941-8
Kanki, Sachiko; Jaalouk, Diana E; Lee, Samuel et al. (2011) Identification of targeting peptides for ischemic myocardium by in vivo phage display. J Mol Cell Cardiol 50:841-8
Segers, Vincent F M; Lee, Richard T (2011) Biomaterials to enhance stem cell function in the heart. Circ Res 109:910-22
Kakkar, Rahul; Lee, Richard T (2010) Intramyocardial fibroblast myocyte communication. Circ Res 106:47-57
Segers, Vincent F M; Lee, Richard T (2010) Protein therapeutics for cardiac regeneration after myocardial infarction. J Cardiovasc Transl Res 3:469-77