Sustained activation of microglia in the hypothalamic PVN following myocardial infarction


      Microglia are the immune cells in the central nervous system and can produce cytokines when they are activated by an insult or injury. In the present study, we investigated in detail the time frame of the activation of microglia in the hypothalamic paraventricular nucleus (PVN) following myocardial infarction in rats. Morphological changes and immunohistochemistry to detect CD11b (clone OX-42) were used to identify activated microglia. Compared to rats that had undergone sham surgical procedures, there was a significant increase of between 40 and 50% in the proportion of activated microglia in the PVN 4–16 weeks following myocardial infarction (P<0.001, One way ANOVA). At 24 h or 1 week post myocardial infarction, however, there was no significant increase in the proportion of activated microglia. Echocardiography and haemodynamic parameters after myocardial infarction indicated significantly reduced left ventricular function. In conclusion, following myocardial infarction, activation of microglia in the PVN does not occur immediately but once manifested, activation is sustained. Thus, activated microglia may contribute to the chronic elevation in cytokine levels observed following myocardial infarction. Since cytokines elicit sympatho-excitatory effects when locally microinjected into the PVN, activated microglia may contribute to the mechanisms mediating the chronic increase in sympathetic nerve activity in animals with reduced left ventricular function induced following myocardial infarction.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Autonomic Neuroscience: Basic and Clinical
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Badoer E.
        Microglia: activation in acute and chronic inflammatory states and in response to cardiovascular dysfunction.
        Int. J. Biochem. Cell Biol. 2010; 42: 1580-1585
        • Badoer E.
        Role of the hypothalamic PVN in the regulation of renal sympathetic nerve activity and blood flow during hyperthermia and in heart failure.
        Am. J. Physiol. Renal Physiol. 2010; 298: F839-F846
        • Colton C.A.
        • Gilbert D.L.
        Production of superoxide anions by a CNS macrophage, the microglia.
        FEBS Lett. 1987; 223: 284-288
        • Felder R.B.
        • Francis J.
        • Zhang Z.H.
        • Wei S.G.
        • Weiss R.M.
        • Johnson A.K.
        Heart failure and the brain: new perspectives.
        Am. J. Physiol. Regul. Integr. Comp. Physiol. 2003; 284: R259-R276
        • Francis J.
        • Chu Y.
        • Johnson A.K.
        • Weiss R.M.
        • Felder R.B.
        Acute myocardial infarction induces hypothalamic cytokine synthesis.
        Am. J. Physiol. Heart Circ. Physiol. 2004; 286: H2264-H2271
        • Francis J.
        • Zhang Z.H.
        • Weiss R.M.
        • Felder R.B.
        Neural regulation of the proinflammatory cytokine response to acute myocardial infarction.
        Am. J. Physiol. Heart Circ. Physiol. 2004; 287: H791-H797
        • Frucht D.M.
        • Fukao T.
        • Bogdan C.
        • Schindler H.
        • O'Shea J.J.
        • Koyasu S.
        IFN-gamma production by antigen-presenting cells: mechanisms emerge.
        Trends Immunol. 2001; 22: 556-560
        • Guggilam A.
        • Haque M.
        • Kerut E.K.
        • McIlwain E.
        • Lucchesi P.
        • Seghal I.
        • Francis J.
        TNF-alpha blockade decreases oxidative stress in the paraventricular nucleus and attenuates sympathoexcitation in heart failure rats.
        Am. J. Physiol. Heart Circ. Physiol. 2007; 293: H599-H609
        • Helwig B.
        • Musch T.
        • Craig R.
        • Kenney M.
        Increased interleukin-6 receptor expression in the paraventricular nucleus of rats with heart failure.
        Am. J. Physiol. Regul. Integr. Comp. Physiol. 2007; 292: R1165-R1173
        • Kang Y.M.
        • Zhang Z.H.
        • Xue B.
        • Weiss R.M.
        • Felder R.B.
        Inhibition of brain proinflammatory cytokine synthesis reduces hypothalamic excitation in rats with ischemia-induced heart failure.
        Am. J. Physiol. Heart Circ. Physiol. 2008; 295: H227-H236
        • Kaye D.M.
        • Lefkovits J.
        • Jennings G.L.
        • Bergin P.
        • Broughton A.
        • Esler M.D.
        Adverse consequences of high sympathetic nervous activity in the failing heart.
        J. Am. Coll. Cardiol. 1995; 26: 1257-1263
        • Kim W.G.
        • Mohney R.P.
        • Wilson B.
        • Jeohn G.H.
        • Liu B.
        • Hong J.S.
        Regional difference in susceptibility to lipopolysaccharide-induced neurotoxicity in the rat brain: role of microglia.
        J. Neurosci. 2000; 20: 6309-6316
        • Kleiber A.C.
        • Zheng H.
        • Sharma N.M.
        • Patel K.P.
        Chronic AT1 receptor blockade normalizes NMDA-mediated changes in renal sympathetic nerve activity and NR1 expression within the PVN in rats with heart failure.
        Am. J. Physiol. Heart Circ. Physiol. 2010; 298: H1546-H1555
        • Kompa A.R.
        • See F.
        • Lewis D.A.
        • Adrahtas A.
        • Cantwell D.M.
        • Wang B.
        • Krum H.
        Long-term but not short-term p38 MAPK inhibition improves cardiac function and reduces cardiac remodeling post-MI.
        J. Pharmacol. Exp. Ther. 2008; 325: 741-750
        • Li Y.F.
        • Patel K.P.
        Paraventricular nucleus of the hypothalamus and elevated sympathetic activity in heart failure: the altered inhibitory mechanisms.
        Acta Physiol. Scand. 2003; 177: 17-26
        • Lindley T.E.
        • Doobay M.F.
        • Sharma R.V.
        • Davisson R.L.
        Superoxide is involved in the central nervous system activation and sympathoexcitation of myocardial infarction-induced heart failure.
        Circ. Res. 2004; 94: 402-409
        • Mann D.L.
        Mechanisms and models in heart failure: a combinatorial approach.
        Circulation. 1999; 100: 999-1008
        • Mizuno T.
        • Sawada M.
        • Suzumura A.
        • Marunouchi T.
        Expression of cytokines during glial differentiation.
        Brain Res. 1994; 656: 141-146
        • Mizuno T.
        • Kawanokuchi J.
        • Numata K.
        • Suzumura A.
        Production and neuroprotective functions of fractalkine in the central nervous system.
        Brain Res. 2003; 979: 65-70
        • Nakajima K.
        • Kohsaka S.
        Microglia: activation and their significance in the central nervous system.
        J. Biochem. 2001; 130: 169-175
        • Ng C.W.
        • De Matteo R.
        • Badoer E.
        Effect of muscimol and L-NAME in the PVN on the RSNA response to volume expansion in conscious rabbits.
        Am. J. Physiol. Renal Physiol. 2004; 287: F739-F746
        • Nimmerjahn A.
        • Kirchhoff F.
        • Helmchen F.
        Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo.
        Science. 2005; 308: 1314-1318
        • Pacher P.
        • Nagayama T.
        • Mukhopadhyay P.
        • Batkai S.
        • Kass D.A.
        Measurement of cardiac function using pressure–volume conductance catheter technique in mice and rats.
        Nat. Protoc. 2008; 3: 1422-1434
        • Packer M.
        Neurohormonal interactions and adaptations in congestive heart failure.
        Circulation. 1988; 77: 721-730
        • Patel K.P.
        Role of paraventricular nucleus in mediating sympathetic outflow in heart failure.
        Heart Fail. Rev. 2000; 5: 73-86
        • Patel K.P.
        • Zhang P.L.
        • Krukoff T.L.
        Alterations in brain hexokinase activity associated with heart failure in rats.
        Am. J. Physiol. 1993; 265: R923-R928
        • Phrommintikul A.
        • Tran L.
        • Kompa A.
        • Wang B.
        • Adrahtas A.
        • Cantwell D.
        • Kelly D.J.
        • Krum H.
        Effects of a Rho kinase inhibitor on pressure overload induced cardiac hypertrophy and associated diastolic dysfunction.
        Am. J. Physiol. Heart Circ. Physiol. 2008; 294: H1804-H1814
        • Rana I.
        • Stebbing M.
        • Kompa A.
        • Kelly D.J.
        • Krum H.
        • Badoer E.
        Microglia activation in the hypothalamic PVN following myocardial infarction.
        Brain Res. 2010; 1326: 96-104
        • Sawada M.
        • Kondo N.
        • Suzumura A.
        • Marunouchi T.
        Production of tumor necrosis factor-alpha by microglia and astrocytes in culture.
        Brain Res. 1989; 491: 394-397
        • Schiller N.B.
        • Shah P.M.
        • Crawford M.
        • DeMaria A.
        • Devereux R.
        • Feigenbaum H.
        • Gutgesell H.
        • Reichek N.
        • Sahn D.
        • Schnittger I.
        • et al.
        Recommendations for quantitation of the left ventricle by two-dimensional echocardiography. American Society of Echocardiography Committee on Standards, Subcommittee on Quantitation of Two-Dimensional Echocardiograms.
        J. Am. Soc. Echocardiogr. 1989; 2: 358-367
        • Shafton A.D.
        • Ryan A.
        • Badoer E.
        Neurons in the hypothalamic paraventricular nucleus send collaterals to the spinal cord and to the rostral ventrolateral medulla in the rat.
        Brain Res. 1998; 801: 239-243
        • Stence N.
        • Waite M.
        • Dailey M.
        Dynamics of microglial activation: a confocal time-lapse analysis in hippocampal slices.
        Glia. 2001; 33: 256-266
        • Streit W.J.
        • Kreutzberg G.W.
        Response of endogenous glial cells to motor neuron degeneration induced by toxic ricin.
        J. Comp. Neurol. 1988; 268: 248-263
        • Streit W.J.
        • Graeber M.B.
        • Kreutzberg G.W.
        Functional plasticity of microglia: a review.
        Glia. 1988; 1: 301-307
        • Suzumura A.
        • Sawada M.
        • Marunouchi T.
        Selective induction of interleukin-6 in mouse microglia by granulocyte–macrophage colony-stimulating factor.
        Brain Res. 1996; 713: 192-198
        • Swanson L.W.
        • Sawchenko P.E.
        Hypothalamic integration: organization of the paraventricular and supraoptic nuclei.
        Annu. Rev. Neurosci. 1983; 6: 269-324
        • Tsuda M.
        • Shigemoto-Mogami Y.
        • Koizumi S.
        • Mizokoshi A.
        • Kohsaka S.
        • Salter M.W.
        • Inoue K.
        P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury.
        Nature. 2003; 424: 778-783
        • Yu Y.
        • Wei S.
        • Zhang Z.
        • Gomez-Sanchez E.
        • Weiss R.
        • Felder R.
        Does aldosterone upregulate the brain renin–angiotensin system in rats with heart failure?.
        Hypertension. 2008; 51: 727-733
        • Zhang Z.H.
        • Wei S.G.
        • Francis J.
        • Felder R.B.
        Cardiovascular and renal sympathetic activation by blood-borne TNF-alpha in rat: the role of central prostaglandins.
        Am. J. Physiol. Regul. Integr. Comp. Physiol. 2003; 284: R916-R927
        • Zheng H.
        • Li Y.F.
        • Wang W.
        • Patel K.P.
        Enhanced angiotensin-mediated excitation of renal sympathetic nerve activity within the paraventricular nucleus of anesthetized rats with heart failure.
        Am. J. Physiol. Regul. Integr. Comp. Physiol. 2009; 297: R1364-R1374