Abstract 3338: Inflammatory Cell-Localized Tumor Necrosis Factor Receptors 1 and 2 Have Divergent Effects on Post-Infarction Left Ventricular Remodeling
The effects of tumor necrosis factor-α (TNF) in heart failure (HF) are receptor (R) specific: TNFR1 exacerbates, whereas TNFR2 ameliorates, LV remodeling and inflammation. We hypothesized that TNFR-specific responses localized to inflammatory cells (macrophages) contribute to these dichotomous remodeling responses. We generated chimeric mice using bone marrow (BM)-ablated wild-type (WT) mice reconstituted with BM from TNFR1 KO mice (R1KOc, n=24), TNFR2 KO mice (R2KOc, n=22), or WT mice (WTc control, n=15). These mice, which exhibit loss of either TNFR1 or TNFR2 in inflammatory cells, underwent coronary ligation or sham operation. Compared to WTc sham, 4 weeks after surgery, WTc HF hearts exhibited significantly (p<0.05):
increased LV size (EDV 90±16 vs. 38±6 μL) and dysfunction (LVEF 32±4 vs. 68±5%);
greater hypertrophy (LV/tibia length [TL] 3.9±0.5 vs. 2.9±0.4, ~4-fold greater atrial natriuretic factor [ANF] mRNA;
increased fibrosis (13.4±2.1% vs. 1.4±0.4%) and connective tissue growth factor (CTGF) mRNA expression, and
increased (~2-fold) mRNA levels of TNF, interleukin (IL)-1β, and IL-6.
WTc HF mice also had markedly reduced survival (45% vs. 90%) and increased blood levels of activated F4/80+/CD11b+ monocytes vs. WTc sham mice. In contrast, compared to WTc HF, R1KOc HF mice exhibited significantly (p<0.05):
1) improved survival (75%),
2) less LV dilatation and improved LVEF (43±11%),
3) less hypertrophy (LV/TL 3.1±0.2) and ANF mRNA,
4) less fibrosis (5.1±2.2%) and CTGF mRNA,
6) less cardiac TNF and IL-1β mRNA expression, and
7) higher circulating levels of CD4+/CD25+ anti-inflammatory regulatory T lymphocytes.
Also, compared to WTc HF, R2KOc HF mice exhibited significantly (p<0.05) worse LVEF (23±2%), greater circulating F4/80+/CD11b+ monocytes (7.9±1.3 vs. 4.8±1.2%), increased cardiac IL-1β mRNA expression, and greater cardiac fibrosis (26.9±13.0%). We conclude that inflammatory cell-localized TNFR1 signaling exacerbates LV remodeling, inflammation, and cardiac fibrosis in HF, whereas inflammatory cell TNFR2 signaling moderates many of these effects. Modulation of global inflammatory cell function induces profound localized alterations in LV remodeling; TNFR1/R2 signaling plays an important role in these effects.
This research has received full or partial funding support from the American Heart Association, Great Rivers Affiliate (Delaware, Kentucky, Ohio, Pennsylvania & West Virginia).