CD4+ T-cells mediate wound-healing post-myocardial infarction (MI) but exacerbate left-ventricular (LV) remodeling during chronic heart failure (HF). Mechanisms that lead to this transition are unknown. Therefore, we hypothesized that as opposed to MI, T-cells activate specific pathological signals to promote LV-remodeling during chronic HF. To identify such signals, we conducted limited cell RNA-sequencing of CD4+ T-cells sorted from the failing hearts (8 weeks post-MI) of male mice and, surprisingly, found activation of estrogen receptor (ER)-α signaling. As ERα effects are antagonized by ERβ, we tested a novel ERβ agonist (OSU-ERB-012) to modulate T-cell activity and LV remodeling.
In-vitro
assays showed that OSU-ERB-012 dose dependently inhibit activation and proliferation of T-cells isolated from male mice (IC
50
3.4 μM).
In-vivo
assays (60 mg/kg/day; oral) showed no overt toxicity and a significant reduction in circulating T cells without affecting neutrophils, monocytes, or B-cells indicating specificity against T-cells. Furthermore, this effect was specific to TCR-mediated T-cell activation and the drug did not affect T-cells stimulated with PMA/Ionomycin suggesting preferential inhibition of antigenically-activated T-cells. To test therapeutic efficacy, male 10-12 week old mice underwent coronary ligation or sham operation and at 4 weeks post-MI randomized according to their cardiac function to receive either the vehicle or OSU-ERB-012 (60 mg/kg/day, oral) for the next 4 weeks. Consistently, at 8 weeks we observed a significant reduction in T-cells in the circulation and the spleens of drug-treated mice when compared with the vehicle treatment. As expected, vehicle treated HF mice showed progressive LV dilatation with significantly increased end-diastolic and end-systolic volumes (EDV and ESV, respectively) from 4-8 weeks post-MI. Importantly, treatment with OSU-ERB-012 significantly inhibited these changes and blunted LV remodeling from 4-8 weeks post-MI. Significant reduction in tibia-normalized heart weights supported these results. Our studies indicate that OSU-ERB-012 is a novel orally-active drug molecule that selectively inhibits T-cell activation and blunts pathological LV-remodeling during chronic HF.
CD4
+
T Cells Promote the Transition From Hypertrophy to Heart Failure During Chronic Pressure Overload