Abstract 3335: Inflammatory Cell-Localized Inducible Nitric Oxide Synthase Exacerbates Post-Infarction Left Ventricular Remodeling
Whether inducible nitric oxide synthase (iNOS) plays a beneficial or detrimental role in adverse LV remodeling and heart failure (HF) is controversial. As the failing heart exhibits low-level, but progressive, macrophage infiltration, we hypothesized that iNOS specifically derived from inflammatory cells contributes to remodeling progression. To isolate the in vivo effects of inflammatory cell iNOS, we generated chimeric mice. Wild-type (WT, C57BL/6) mice underwent radiation-induced bone marrow (BM) ablation followed by reconstitution with BM from iNOS knockout (KO) mice (iNOSKOc, n=11) or WT mice (WTc control, n=15). Six weeks later, WTc and iNOSKOc mice were subjected to coronary ligation or sham operation. Compared to WTc sham, 4 weeks after surgery, WTc HF hearts exhibited significant (p<0.05) LV dilatation, systolic dysfunction, hypertrophy, fibrosis, and increased (~2-fold) gene expression of tumor necrosis factor (TNF), interleukin (IL)-6, atrial natriuretic factor (ANF), and connective tissue growth factor (CTGF) as measured by real time-PCR. In contrast, compared to WTc HF, iNOSKOc HF mice exhibited:
improved survival (75% vs. 40%, p<0.05),
reduced LV dilatation (EDV 75±15 vs. 90±16 μL; ESV 49±11 vs. 60±15 μL, p<0.05) with equivalent LVEF (34±2 vs. 32±4, p=NS),
substantially decreased cardiac mRNA expression of the hypertrophic marker ANF (p=0.01), the pro-fibrotic marker CTGF (p=0.038), and the pro-inflammatory cytokine IL-6 (p=0.003), and a strong trend toward increased cardiac gene expression of anti-inflammatory IL-10.
In parallel studies, non-chimeric global iNOS KO (n=8) and WT mice (n=10) underwent coronary ligation. At 4 weeks, iNOS expression was significantly increased in WT HF hearts over sham. In contrast to the results in iNOSKOc HF mice, echocardiography revealed that compared to WT HF mice, iNOS KO HF mice exhibited equivalent LV dilatation and dysfunction 4 weeks after infarction (LVEF 22±15 vs. 23±5%, p=NS). This occurred despite increased (p<0.05) CTGF and IL-6 mRNA expression in iNOS KO HF hearts vs. WT HF. We conclude that inflammatory cell-derived iNOS exacerbates chronic remodeling in the failing heart. These detrimental effects may be counterbalanced by iNOS upregulation in cardiomyocytes.
This research has received full or partial funding support from the American Heart Association, Great Rivers Affiliate (Delaware, Kentucky, Ohio, Pennsylvania & West Virginia).