Inhibition of Cyclooxygenase-2 Reduces Hypothalamic Excitation in Rats with Adriamycin-Induced Heart Failure

Min Zheng,Cui-Yu Bao,Wei-Jin Zang,Yu-Ming Kang,Da-Nian Qin,Wei Liu,Wolfgang Rudolf Bauer

doi:10.1371/journal.pone.0048771

Abstract

BackgroundThe paraventricular nucleus (PVN) of the hypothalamus plays an important role in the progression of heart failure (HF). We investigated whether cyclooxygenase-2 (COX-2) inhibition in the PVN attenuates the activities of sympathetic nervous system (SNS) and renin-angiotensin system (RAS) in rats with adriamycin-induced heart failure.Methodology/Principal FindingHeart failure was induced by intraperitoneal injection of adriamycin over a period of 2 weeks (cumulative dose of 15 mg/kg). On day 19, rats received intragastric administration daily with either COX-2 inhibitor celecoxib (CLB) or normal saline. Treatment with CLB reduced mortality and attenuated both myocardial atrophy and pulmonary congestion in HF rats. Compared with the HF rats, ventricle to body weight (VW/BW) and lung to body weight (LW/BW) ratios, heart rate (HR), left ventricular end-diastolic pressure (LVEDP), left ventricular peak systolic pressure (LVPSP) and maximum rate of change in left ventricular pressure (LV±dp/dtmax) were improved in HF+CLB rats. Angiotensin II (ANG II), norepinephrine (NE), COX-2 and glutamate (Glu) in the PVN were increased in HF rats. HF rats had higher levels of ANG II and NE in plasma, higher level of ANG II in myocardium, and lower levels of ANP in plasma and myocardium. Treatment with CLB attenuated these HF-induced changes. HF rats had more COX-2-positive neurons and more corticotropin releasing hormone (CRH) positive neurons in the PVN than did control rats. Treatment with CLB decreased COX-2-positive neurons and CRH positive neurons in the PVN of HF rats.ConclusionsThese results suggest that PVN COX-2 may be an intermediary step for PVN neuronal activation and excitatory neurotransmitter release, which further contributes to sympathoexcitation and RAS activation in adriamycin-induced heart failure. Treatment with COX-2 inhibitor attenuates sympathoexcitation and RAS activation in adriamycin-induced heart failure.

Highlights

Congestive heart failure (HF) is a serious cardiovascular disease that increases morbidity and mortality and causes an economic burden on families and societies
These results suggest that paraventricular nucleus (PVN) COX-2 may be an intermediary step for PVN neuronal activation and excitatory neurotransmitter release, which further contributes to sympathoexcitation and renin-angiotensin system (RAS) activation in adriamycin-induced heart failure
As to how the inflammation factors interact with neurotransmitters, sympathetic nervous system (SNS) and RAS in HF, our previous works in the ischemia-induced HF demonstrated the following relevant findings: (i) increased hypothalamic proinflammatory cytokines (PIC) contribute to the upregulation of central neural systems activity, including the increased SNS, central RAS and the hypothalamicpituitary adrenal (HPA) axis activity in HF [13]; (ii) NF-kB mediates the cross-talk between RAS and PIC in the PVN in HF, and that superoxide stimulates more NF-kB in the PVN and contributes to neurohumoral excitation [12]; and (iii) increased PIC, such as brain tumor necrosis factor-a (TNF-a), modulate

Summary

Introduction

Congestive heart failure (HF) is a serious cardiovascular disease that increases morbidity and mortality and causes an economic burden on families and societies. Researchers demonstrated that a central nervous system mechanism contributes to the sympathetic nervous system (SNS) abnormality in HF [1,2,3]. The paraventricular nucleus (PVN) of hypothalamus is an important center for the integration of sympathetic nerve activity [4] and the regulation of cardiovascular function and fluid homeostasis [5]. Recent findings showed that excess amounts of inflammatory mediators and renin-angiotensin system (RAS) components are present in the PVN and contribute to neurohumoral excitation in HF [3,10,11,12,13,14]. We investigated whether cyclooxygenase-2 (COX-2) inhibition in the PVN attenuates the activities of sympathetic nervous system (SNS) and renin-angiotensin system (RAS) in rats with adriamycin-induced heart failure

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Results

Conclusion