Abstract 385: Chronic Systemic Tumor Necrosis Factor Treatment Increases Tyrosine Hydroxylase And Arginine Vasopressin Gene Expression In The Paraventricular Nucleus And Contributes To Sympathoexcitation And Cardiac Dysfunction
Evidence suggests that increased tumor necrosis factor (TNF) in chronic inflammatory conditions contributes to cardiovascular disease. Our recent studies show that increased TNF expression in the paraventricular nucleus (PVN) of the hypothalamus of heart failure rats contributes to sympathoexcitation and cardiac remodeling. In this study, we examined whether chronic TNF treatment induced sympathoexcitation and cardiac dysfunction are due to modulation of tyrosine hydroxylase (TH) and arginine vasopression (AVP) expression in the PVN.
Methods: Male Sprague-dawley rats received TNF (10 μg/kg/day, i.p.) or vehicle for 5 days. One group of rats received angiotensin receptor-1 (AT-1R) blocker, losartan (1mg/kg/day, i.p.) along with TNF. After 5 days, echocardiography and pressure-volume conductance catheter were used to study left ventricular structure and function. Micropunches of the PVN were collected to study gene expression by real-time RT-PCR. Plasma norepinephrine (NE) levels were measured by HPLC.
Results and discussion: Echocardiography revealed concentric myocardial hypertrophy, as shown by increased left ventricular wall thickness in diastole (LVWTd), with TNF treatment. The slope of left ventricular end-diastolic pressure-volume relationship curve (EDPVR) was also elevated with TNF treatment compared to the control and losartan treated groups, indicating diastolic dysfunction with TNF treatment. The mRNA levels of TNF, AVP, TH and AT-1R were significantly increased in the PVN of rats that were treated with TNF alone, and were decreased by losartan treatment. The elevated NE levels with TNF treatment were also reduced by losartan.
Conclusion: These results indicate that chronic systemic TNF treatment increases sympathoexcitation and cardiac dysfunction by increasing TH gene expression via modulation of AVP expression in the PVN. The TNF induced sympathoexcitation and cardiac dysfunction are mediated via renin-angiotensin system.