Tumor necrosis factor induced oxidative stress in the central nervous system contributes to sympathoexcitation in heart failure

Abstract

Despite advanced therapeutic strategies for post-myocardial infarction (MI) patients, many ultimately develop congestive heart failure (CHF), rendering the disease a major cause of death in the United States. MI is associated with an acute increase in sympathetic nervous system activity, becoming persistent in CHF patients. Increased pro-inflammatory cytokines (PICs) following MI are implicated in the pathogenesis of CHF. The increase in tumor necrosis factor (TNF), a primary PIC, correlates closely with heart disease severity. Moreover, central PIC production increases post-MI, and can affect the brain’s cardiovascular regulatory regions that control sympathoexcitation. Therefore, understanding how PICs modulate sympathoexcitation is important for development of new therapeutics. Recent studies underscore the importance of central NADPH oxidases in the pathogenesis of hypertension. However, the role of central NADPH oxidase-induced reactive oxygen species (ROS) production in the development of CHF remains limited. In this dissertation, the hypothesis that central PICs induce ROS production and modulate sympathoexcitatory neurons of the paraventricular nucleus (PVN) is explored through an array of selective animal models combined with novel technologies for sympathoexcitation and cardiovascular function assessment. The effect of the TNF blocker, pentoxyfylline, was investigated on the expression of the catalytic subunits of NADPH oxidase (Noxs) in the PVN neurons and on the sympathetic activity in CHF rats. Additionally, effects of TNF inhibition on central nitric oxide were explored, as this ROS restrains sympathoexcitation. More specifically, central TNF was inhibited to understand the interaction between superoxide and nitric oxide in the PVN neurons during CHF. TNF knock-out mice were also used to study the effect of TNF on volume overload associated with CHF. Finally, to understand the role of peripheral TNF on the PVN’s sympathoexcitatory neurons, and to exclude the effects of neurohormones in CHF, human recombinant TNF was injected 5-days systemically to achieve the levels observed following MI in conjunction with ROS and angiotensin II type-1 receptor blockers. These studies provide new evidence that TNF induces oxidative stress in the PVN through an AT1R mediated mechanism in CHF, and offers new insight into the sympathoexcitatory mechanisms in the brain possibly involved in the pathogenesis of CHF.