Date on Master's Thesis/Doctoral Dissertation

12-2010

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Physiology and Biophysics

Committee Chair

Prabhu, Sumanth D.

Author's Keywords

TNF; Heart failure

Subject

Tumor necrosis factor; Heart failure

Abstract

The fundamental question of the exact nature of the role played by TNF in the failing myocardium remains one of contention. Many preclinical studies have demonstrated beneficial effects with TNF antagonism and recently the dichotomous role played by the two TNF receptors in chronic ischemic injury has come to light. The failing heart has also been determined to have low levels of inflammatory cell infiltration. As these cells are known to be potent producers of inflammatory cytokines, we hypothesized that inflammatory cell localized TNF receptors play an important role in the progression of LV remodeling following ischemic injury. To isolate the in vivo effects of inflammatory cell TNF receptors, we generated chimeric mice. Wild-type (WT, C57BLl6) mice underwent radiation-induced bone marrow (BM) ablation followed by reconstitution with BM from WT mice (WTc control, n=30), TNFR 1-/- mice (R1-/-c, n = 30) or TNFR2 -/- mice (R2-/-c, n = 30). Six weeks later, WTc, R1-/-c, and R2-/-c mice were subjected to coronary ligation to induce heart failure (HF) or sham operation. Our results demonstrated that compared to WTc sham, 4 weeks after surgery, WTc HF hearts exhibited significantly (p < O.OS): 1) increased LV size (EDV 96.7 ±. 13.7 vs. 26.6 ± 8.2 IJL) and dysfunction (LVEF 2S.S ± 7.S vs. 69.8 ± 4.S%); 2) greater hypertrophy (LV/tibia length [TL] 3.91 ± 0.S3 vs. 2.9 ± 0.4, -4-fold greater atrial natriuretic factor [ANF] mRNA); 3) increased fibrosis (16.10 ± 8.16% vs. 1.4 ± 0.4%) and connective tissue growth factor (CTGF) mRNA expression, and 4) increased (-2-fold) mRNA levels of TNF, interleukin (IL)-1j3, and IL-6. WTc HF mice also had markedly reduced survival (60% vs. 100%) and increased blood levels of activated F4/80+/CD11 b+ monocytes vs. WTc sham mice. In contrast, compared to WTc HF, R1-1-c HF mice exhibited significantly (p < O.OS): 1) improved survival (80%), 2) less LV dilatation and improved LVEF (42.9 ± 4.2%), 3) less cardiac hypertrophy (LVITL 3.14 ± 0.2) and ANF mRNA expression, 4) less cardiac fibrosis (S.48 ± 2.26%) and CTGF mRNA expression, and S) less cardiac TNF and IL-1j3 mRNA expression. Also, compared to WTc HF, R2-/-c HF mice exhibited significantly (p < O.OS) greater circulating F4/80+/CD11 b+ monocytes (1S.32 ± 4.41 vs. 12.1 ±1.24%), and greater cardiac fibrosis (21.92 ±.10.81%). Also noted was an increase, although not significant, in EDV and ESV. In parallel in vitro studies, the contribution of inflammatory cell TNFR1 and TNFR2 (Le., macrophage-derived) to cardiac contractile dysfunction was investigated. Macrophages isolated from WT mice with HF 4 week postinfarction, when co-cultured with na"lve cardiomyocytes induced contractile dysfunction and myocyte reactive oxygen species (ROS) generation in a juxtacrine but not paracrine maner (p

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