Central Oxidative Stress Contributes To Sympathoexcitation In Heart Failure

Background:Recent epidemiological studies have demonstrated that the prevalence of heart failure （HF）tended to increase year by year in China, and the5-year survival rates is reported to be nearbetween heart failure and malignant tumors. The mechanisms of heart failure remained to beunresolved.Since the1990s, the interaction between the sympathetic nervous system and therennin-angiotensin-aldosterone system in heart failure caused neuroendocrine （NE） and cytokineactivation, this promote myocardial reconstruction, this vacious cycle lead to heart failure. Sincethe beginning of the21st century, use of β-blockers in treatment of heart failure has become thebasis prescription medicine. Accordingly, the sympathetic nervous system play an important rolein the pathophysiology of heart failure.When heart failure occurred immediately, the heart cannot pump enough blood throughoutthe body. On the one hand, this information input to central neural system and provides for asympathoexcitatory process. Norepinephrine released from sympathetic nerve ending increaseheart rate and myocardium contractility, and to maintain cardiac output. On the other hand,perseverance excess raise of sympathetic nervous activity increase myocardium consummationof oxygen, this vacious cycle lead to heart failure. The baseline plasma norepinephrine level inpatients is an independent predictor of prognosis in patients with heart failure. Prognosis in heartfailure is directly linked to the level of activation of the sympathetic nervous system. Thusinhibition of sympathoexcitation is the basic therapy for heart failure.Recent literatures have implicated that the central nervous system activity was linked in theactivation of cardiovascular center in HF, and also significant changes the peripheral sympatheticnerve activity. Kang et al demonstrated that reactive oxygen species and pro-inflammatorycytokine （such as TNF-α and IL-1β） are increased in the paraventricular nucleus ofhypothalamus （PVN） of HF rats contribute to the increased sympathetic nervous activity, andalso plasma NE are significantly increased. NADPH oxidase is one of the ways to generate oxygen free radicals in the human body. Francis et al also demonstrated that a nerve activity waslinked in the activation of reactive oxygen species in HF. Nevertheless, the mechanisms bywhich the central oxidative stress contribute to the sympathoexcitation in heart failure are notknown.Therefore, we hypothesized that activated NADPH oxidase induce the increased reactiveoxygen species generated in the PVN in HF contribute to the increased sympathetic nervousactivity and the pathophysiology of chronic heart failure.Objective: To observe whether the subunit gp^91phoxof NADPH oxidase and reactive oxygenspecies was increased in PVN of HF rats, and the relationship between NADPH oxidase andsympathetic nerve activity. To investigate whether central oxidative stress increase sympatheticnerve activity in chronic heart failure.Methods: Healthy adult male Sprague-Dawley rats weighing250±30g were randomly dividedinto four groups: Sham+aCSF group, Sham+APO group, HF+aCSF group, HF+APO group. HFwas induced by ligation of left anterior descending coronary artery and SHAM rats underwentthe same surgery but did not undergo coronary ligation. These rats were treated for4-weeks witha continous intracerebroventricular （ICV） infusion of the NADPH oxidase inhibitor apocynin（APO,10μg/hr） or artificial cerebrospinal fluid intervention （aCSF,0.25μl/hr） via osmoticminipump. After four weeks treatment, plasma norepinephrine was measured using highperformance liquid chromatography; Immunofluorescence staining was used for expression ofgp^91phoxand IL-1β in the hypothalamic paraventricular nucleus; reactive oxygen species levels ofthe hypothalamic paraventricular nucleus was measured with DHE staining; plasma andhypothalamus of IL-1β levels were measured using ELISE techniques; heart/body weight ratio（WH/BW） and lung/body weight ratio （Lung/BW） was calculated.Results: Compared with SHAM rats, HF rats had significantly increased of plasma NE（P<0.05）,gp^91phoxprotein expression and reactive oxygen species levels in the PVN were elevated in HFrats （P<0.05）. Besides plasma and hypothalamus of IL-1β levels were also significantlyupregulated than those of SHAM rats （P<0.05）. In addition, HF rats had higher WH/BW andLW/BW than SHAM rats （P<0.05）. However, ICV continue infusion APO for4weeks decreasedplasma NE, gp^91phoxprotein expression and reactive oxygen species levels （P<0.05）. Treatmentwith APO also reduced the contents of IL-1β in the plasma （P<0.05）, but the contents of IL-1β in the paraventricular nuclear of hypothalamic was not statistically significant. The WH/BW andLW/BW were also decreased after ICV-APO （P<0.05）.Conclusions: These results suggest that activated NADPH oxidase, reactive oxygen species andoxidative stress in the PVN in HF contribute to the increased sympathetic nervous activity andthe pathophysiology of chronic heart failure.