Activated Microglia In The Hypothalamic Paraventricular Nucleus Contribute To Sympathoexcitation In Heart Failure

Objective:Recent studies demonstrated the elevation of proinflammatory cytokines(PIC) in paraventricular nucleus of hypothalamus(PVN) contribute to sympathoexcitation in heart failure(HF).But the origin of these cytokines is unknown.We hypothesized that microglia are activated in the PVN,and that contribute significantly to release the PIC that stimulate sympathoexcitatory systems in HF.Methods and Results:Adult male Sprage-Dawley rats(230±30)g underwent left anterior descending coronary artery ligation to induce HF or sham surgery(SHAM).Subsequently, animals were performed PVN infusion of Cycloxygenase-2(COX-2)inhibitor celecoxib, (CEL 20μg/h),or vehicle(VEH) for 4 weeks.Compared with SHAM rats,HF rats had higher left ventricular end-diastolic pressure(LVEDP),decreased left ventricular systolic pressure (LVSP),lower maximal rate of rise and decline of ventricular pressure(±dp/dt_max),higher right ventricle/body weight(BW) and lung/BW.HF rats also had higher levels of TNF-αand more activated microglia in the PVN,and higher TNF-αprotein expression in myocardium cells,and augmented renal sympathetic nerve activity(RSNA)(P<0.05).CEL ameliorated heart function in HF rats,decreased TNF-αin the PVN and cardiac tissues,reduced the numbers of activated microglia,downregulated sympathetic drive(P<0.05).Conclusion:These findings suggest that activated microglia in the PVN contribute to the sympathoexcitation by releasing cytokines in HF,and blockade of COX-2 reduced both proinflammatory cytokines and activated microglia in the PVN.