Heart failure is the most common reason for hospitalization in the United States among those older than 65 years, and this statistic is expected to grow as the population ages. Overactivity of the sympathetic nervous system is a cardinal manifestation of the heart failure syndrome, and a strong predictor of morbidity and mortality. The etiology of increased sympathetic activity in heart failure is multifactorial. Recent studies have implicated inflammatory mechanisms that generate reactive oxygen species, particularly activation of nicotinamide adenine dinucleotide phosphate [NAD(P)H] oxidase dependent superoxide, in cardiovascular regions of the brain. The ability of angiotensin II to generate superoxide and sympathetic drive by this mechanism has been well studied - almost to the exclusion of other inflammatory mediators that are also increased in heart failure and might well contribute. The present project examines the potential role of the pro- inflammatory cytokines, which increase in plasma and brain of rats with ischemia-induced heart failure, are capable of NAD(P)H oxidase driven superoxide production, and are known to contribute to increased sympathetic drive in heart failure. We will test three hypotheses with regard to the mechanisms by which pro- inflammatory cytokines might activate the sympathetic nervous system in a rat model of ischemia-induced heart failure that mimics the most common form of heart failure in humans: 1) pro-inflammatory cytokines increase sympathetic nerve activity in heart failure rats by inducing cyclooxygenase-2 activity and the production of prostaglandin E2, which is sympatho-excitatory in the brain;2) pro-inflammatory cytokines increase sympathetic nerve activity in heart failure rats by upregulating the brain renin-angiotensin system and the production of angiotensin II, which is sympatho-excitatory in the brain in its own right as well as by stimulating superoxide production;and 3) pro-inflammatory cytokines directly stimulate NAD(P)H oxidase dependent superoxide production. This project focuses upon the actions of pro-inflammatory cytokines in the paraventricular nucleus of the hypothalamus, a forebrain cardiovascular regulatory center that has been identified as an important source of the increased sympathetic nerve activity in heart failure. Neurochemical changes in the paraventricular nucleus in heart failure, and the cellular and molecular mechanisms which regulate them, will be investigated using molecular and immunohistochemical/immunofluorescent methods, and the results of those studies will be correlated with functional data from electrophysiological studies examining the effects of manipulating key putative mediators of sympathetic nerve activity. These studies will identify currently unrecognized mechanisms driving the sympathetic nervous system in heart failure, and thus potential targets for preventive intervention.
New approaches are needed to treat heart failure, which remains a devastating disorder despite current therapy. One aspect of heart failure that is not treated and is still poorly understood is the inflammatory response, manifest primarily by an increase in circulating pro-inflammatory cytokines. This project seeks to determine how inflammation contributes to activation of the sympathetic nervous system - a marker of adverse outcome in heart failure - and to discover novel ways of reducing its impact.
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|Felder, Robert B (2010) Mineralocorticoid receptors, inflammation and sympathetic drive in a rat model of systolic heart failure. Exp Physiol 95:19-25|
|Zhang, Zhi-Hua; Yu, Yang; Wei, Shun-Guang et al. (2010) Centrally administered lipopolysaccharide elicits sympathetic excitation via NAD(P)H oxidase-dependent mitogen-activated protein kinase signaling. J Hypertens 28:806-16|
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