Brain MAP Kinases - Substrate for Sympathetic Excitation in Heart Failure

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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 (SNS) is a cardinal manifestation of the heart failure syndrome, and a strong predictor of morbidity and mortality. Recent studies suggest that altered neurochemical mechanisms in the brain contribute to the augmented SNS activity in heart failure. Several excitatory substances appear in the brain in excess quantities in heart failure. These include angiotensin II (ANG II), aldosterone (ALDO) and the pro-inflammatory cytokines (PIC). All three act to increase the production of reactive oxygen species in the brain, but beyond that it is not at all clear how they activate the SNS. We recently found that blocking one of the three major components of the mitogen-activated protein kinase (MAPK) intracellular signaling cascade in the brain substantially reduced SNS activity in rats with heart failure. These MAPKs are sensitive to the presence of reactive oxygen species, respond to ANG II, ALDO and PIC, and, when activated, lead to the production of more excitatory neurochemical substances that may contribute to persistent activation of the SNS, which is typical of heart failure. The overall goal of this project is to determine to what extent the three major MAPK signaling pathways contribute to the excitatory neurochemical milieu in a key cardiovascular regulatory center of the brain, the paraventricular nucleus of hypothalamus (PVN), that drives SNS activity in heart failure. In rats with systolic heart failure and in normal rats treated with ANG II, ALDO and PIC to induce MAPK activity, we will determine: 1) the effects of the three major MAPK signaling pathways on the expression of excitatory mediators in the PVN; 2) the effects of MAPK signaling in the PVN on SNS activity; 3) the phenotypes of the cells in PVN - neurons, microglia, astrocytes, and perivascular macrophages - that express MAPK signaling, and their influences on the production of excitatory mediators and sympathetic excitation. A combination of molecular, immunohistochemical, and electrophysiological techniques will be used to elucidate the mechanisms by which brain MAPK signaling influences SNS activity. We hope these studies will identify novel targets for therapeutic intervention in systolic heart failure.