Abstract 813: Tnf-α Alters Superoxide And Nitric Oxide In The Brain Stem And Hypothalamus Contributes To Sympathoexcitation In Heart Failure Mice
Tumor necrosis factor-alpha (TNF-α) is a multifunctional cytokine that plays an important role in the pathophysiology of cardiovascular disease. Recent evidence suggests that TNF-αinduced oxidative stress contributes to the development of cardiovascular disease. The present study examined the effect of TNF-αon the imbalance between nitric oxide (NO) and superoxide (O2. − ) production in the brain stem and hypothalamus and its contribution to enhanced sympathetic drive in mice with heart failure.
Methods and Results: Myocardial infarction (MI) was induced by ligation of the left coronary artery in wild type (WT) and TNF knockout (TNF KO) mice. After 5 weeks, WT + MI mice exhibited left ventricular (LV) dilatation and a decrease in fractional shortening (%FS). Real time RT-PCR exhibited an increase in the mRNA expression for atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in the LV of WT + MI mice. The mRNA expression for nNOS was significantly reduced in the brain stem, while that of iNOS and Nox2 were elevated in the brain stem as well as hypothalamus of WT + MI mice. Plasma norepinephrine (NE) levels in WT + MI mice were greater in WT + MI mice than that in sham, or TNF KO + MI mice indicating that sympathetic drive was enhanced by TNF-αin this model.
The present study shows that TNF-α contributes to left ventricular hypertrophy leading to ventricular dysfunction.
TNF-αinduces the production of O2. − and modulates the production of nitric oxide in the brain stem of HF mice.
TNF-αcontributes to sympatho-excitation in HF.