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 β-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.

Remodeling of intrinsic cardiac neurons: effects of β-adrenergic receptor blockade in guinea pig models of chronic heart disease

“…Increases in sympathetic outflow have been documented with chronic heart disease (7,18,24). Changes in sympathetic innervation of the heart following MI show regional variation (16,22), but in the atrial regions, where the neurons for this study are located, studies showed either no change in NE innervation or an upregulation of sympathetic innervations (16,21). Even though the tissue damage produced by the MI is small and distant from the cardiac plexus studied, as in previous studies (13), this injury is sufficient to produce functional changes in the intrinsic neurons.…”

Heterogeneity in MT1-MMP activity with ischemia-reperfusion and previous myocardial infarction: relation to regional myocardial function

“…Heart rate, LV end-diastolic pressure, and mean arterial pressure were elevated in animals with a previous MI compared with those without previous MI at baseline. The elevated heart rate and mean arterial pressure were likely due to increased neurohormonal stimulation, specifically from efferent activation (28). The mean pulse pressure, which is proportional to forward stroke volume, was not different between pigs with previous MI and those without previous MI at baseline.…”

Development, Maturation, and Transdifferentiation of Cardiac Sympathetic Nerves

“…Nuclei in the stellate ganglion modify the synthesis of sympathetic neurotransmitters under the influence of humoral factors derived from heart. For example, cardiac hypertrophic factors such as angiotensin II, 107 ET-1, 108 leukemia inhibitory factor (LIF), 24 NGF, 38,83,85 , other growth factors, 109 and cytokines 110 are augmented in failing heart, influencing sympathetic activity, function, plasticity, and phenotype. Complex crosstalk among these neurohumoral factors is thus believed to modulate cardiac sympathetic activation and the pathology of heart failure.…”