title: Infarction-induced cytokines cause local depletion of tyrosine hydroxylase in cardiac sympathetic nerves.
abstract: Myocardial infarction causes a heterogeneity of noradrenergic transmission that contributes to the development of ventricular arrhythmias and sudden cardiac death. Ischaemia-induced alterations in sympathetic transmission include regional variations in cardiac noradrenaline (NA) and in tyrosine hydroxylase, the rate-limiting enzyme in NA synthesis. Inflammatory cytokines that act through gp130 are elevated in the heart after myocardial infarction. These cytokines decrease expression of tyrosine hydroxylase in sympathetic neurons, and indirect evidence suggests that they contribute to the local depletion of tyrosine hydroxylase in the damaged left ventricle. However, gp130 cytokines are also important for the survival of cardiac myocytes following damage to the heart. To examine the effect of cytokines on tyrosine hydroxylase and NA content in cardiac nerves we used gp130(DBH-Cre/lox) mice, which have a deletion of the gp130 receptor in neurons expressing dopamine beta-hydroxylase. The absence of neuronal gp130 prevented the loss of tyrosine hydroxylase in cardiac sympathetic nerves innervating the left ventricle 1 week after ischaemia-reperfusion compared with wild-type C57BL/6J mice. Surprisingly, restoration of tyrosine hydroxylase in the damaged ventricle did not return neuronal NA content to normal levels. Noradrenaline uptake into cardiac nerves was significantly lower in gp130 knockout mice, contributing to the lack of neuronal NA stores. There were no significant differences in left ventricular peak systolic pressure, dP/dt(max) or dP/dt(min) between the two genotypes after myocardial infarction, but ganglionic blockade revealed differences in autonomic tone between the genotypes. Stimulation of the heart with dobutamine or release of endogenous NA with tyramine generated similar responses in both genotypes. Thus, the removal of gp130 from sympathetic neurons prevents the post-infarct depletion of tyrosine hydroxylase in the left ventricle, but does not alter NA content or cardiac function.
authors.affiliation: Department of Physiology and Pharmacology, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
authors.forename: Diana C
authors.initials: DC
authors.lastname: Parrish
authors.forename: Eric N
authors.initials: EN
authors.lastname: Alston
authors.forename: Hermann
authors.initials: H
authors.lastname: Rohrer
authors.forename: Paul
authors.initials: P
authors.lastname: Nkadi
authors.forename: William R
authors.initials: WR
authors.lastname: Woodward
authors.forename: Günther
authors.initials: G
authors.lastname: Schütz
authors.forename: Beth A
authors.initials: BA
authors.lastname: Habecker
mesh_terms: D000818:Animals; D050822:Cytokine Receptor gp130 / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism*; D006352:Heart Ventricles / Q000294:innervation / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism*; D013564:Sympathetic Nervous System / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism*
chemical_list: D016207:Cytokines; D050822:Cytokine Receptor gp130; D012964:Sodium; D014446:Tyrosine 3-Monooxygenase