Novel Inhibitors for Temporal Modulation of T-Lymphocytes during Chronic Heart Failure

Project Summary
Inflammatory immune responses dictate cardiac healing post-myocardial infarction (MI) and are temporally
regulated to initiate wound-healing and scar formation. Recent studies have shown that, in addition to
immediately after myocardial infarction (MI), circulating, splenic and cardiac inflammatory cells (monocytes,
macrophages, and T-lymphocytes) are augmented even at 8-weeks post-MI (chronic HF), and promote
pathological left ventricular (LV) remodeling. Moreover, we and others have shown that depletion of specific
cell types, including monocytes/macrophages or T-cells during chronic HF blunts LV remodeling and prevents
progressive decline in cardiac function, suggesting a critical role of immune cells in this disease. These
findings underscore the necessity for identifying specific molecular mechanisms that can be targeted to restrain
pathological immune activation for therapeutic immune-modulation.
Recent studies have shown that CD4+ T-cells are obligatory for efficient healing, neovascularization, and to
check excessive fibrosis during MI. However, global knockout mouse models (such as CD4-/-) fail to consider
spatio-temporal alterations that we see during progression from acute-MI to chronic HF. Indeed, our previous
studies showed that CD4+ T-cells undergo a phenotypic shift specifically during chronic HF, promote LV
remodeling in an antigen-dependent manner, and their depletion from 4 to 8 weeks post-MI blunts progressive
cardiac dysfunction. Nonetheless, the molecular signatures that mediate this transition from being protective
during MI to pathological during chronic HF are not known. Using RNA sequencing on cardiac CD4+ T-cells
flow-sorted from the failing hearts of male mice, we showed that, as opposed to MI, T-cells activated during HF
possess upregulated estrogen receptor (ER) α signaling. Since ERα effects are opposed by ERβ activation, we
identified a novel ERβ agonistic drug (OSU-ERb-012). Our preliminary data show that OSU-ERb-012 is highly
efficacious at inhibiting anti-CD3/CD28 (T-cell receptor) mediated T-cell proliferation and expression of pro-
inflammatory cytokines, ex-vivo and in-vivo. Moreover, at 10 mg/kg dose OSU-ERb-012 significantly blunted
LV remodeling and HF progression when administered from 4 to 8 weeks post-MI suggesting its therapeutic
efficacy. Thus, we hypothesize that OSU-ERb-012 selectively inhibits antigenically activated pathological CD4+
T-cells at clinically translatable doses, ameliorate LV remodeling and progressive cardiac dysfunction during
chronic HF, and that ERβ agonists could be used as selective immuno-modulatory drugs. We will test this
hypothesis by i) delineating dose-dependent effects of OSU-ERb-012 in ameliorating LV remodeling, ii) testing
whether the protective effects of OSU-ERb-012 are mediated through T-cell specific ERβ agonism, and iii)
identify effects of OSU-ERb-012 on cardiomyocyte function and cardiac physiology.

Grant Number: 5R01HL167912-04
NIH Institute/Center: NIH
Principal Investigator: Shyam Bansal