The lack of cardiotrophin-1 alters expression of interleukin-6 and leukemia inhibitory factor mRNA but does not impair cardiac injury response

Abstract

Cardiotrophin-1 (CT-1) was identified as a growth factor for cardiac myocytes, and CT-1 protects myocytes from cell death. Adult CT-1−/− mice exhibit neural deficits including the loss of preganglionic sympathetic neurons, but their autonomic and cardiac parameters have not been examined. We used these mice to determine if the absence of CT-1 or loss of preganglionic sympathetic input altered heart rate, left ventricular pressure, cardiac contractility (dP/dt), or cell death following ischemia-reperfusion. Basal heart rate was increased in CT-1−/− mice, and this difference was abolished by ganglionic block. Left ventricular pressure and dP/dt were unchanged. Dobutamine stimulated similar increases in heart rate and dP/dt in both genotypes, but ventricular pressure was significantly lower in CT-1 nulls. Cardiac expression of interleukin-6 (IL-6) mRNA was increased significantly in CT-1 null mice, while leukemia inhibitory factor (LIF) mRNA was unchanged. Infarct size normalized to area at risk was no different in CT-1 −/− mice (33.8±1.0 % vs. 37.7±3.2 % WT) 24 hours after ischemia-reperfusion. Induction of IL-6 mRNA after infarct was significantly abrogated in CT-1 null mice compared to wild type mice, but LIF mRNA induction remained significant in CT-1 null mice and might contribute to cardiac protection in the absence of CT-1.

The immune system and cardiac repair

“…CT-1 administration resulted in decreased infarct size and reduced cardiomyocyte apoptosis in a rat model of myocardial ischemia and reperfusion [171]. However, CT-1 absence did not affect infarct size in a mouse model of reperfused infarction suggesting that endogenous CT-1 does not play an essential role in acute ischemic cardiac injury [172]. Prolonged CT-1 upregulation in the infracted myocardium may modulate the fibrotic response through effects on fibroblast proliferation [173].…”

Cardiotrophin-1 Review

“…These results provide evidence that the CT-1 receptor is composed of a tripartite complex, a situation similar to the high affi nity receptor for ciliary neurotrophic factor 15 . Results indicate that gp130 plays a crucial role in myocardial development and hematopoiesis during embryogenesis 5,106 . Factors regulating CT-1 expression and regulated by CT-1 are presented in tables 1 and 2.…”

Absence of gp130 in dopamine β-hydroxylase-expressing neurons leads to autonomic imbalance and increased reperfusion arrhythmias

“…Saline control injections confirmed that the 20-l volume bolus dose did not trigger changes in arterial pressure or HR. In another set of mice, ganglionic block was established with hexamethonium, and increasing doses (4,8,16,32, and 64 g/kg, volumes: 5-20 l) of the ␤-agonist dobutamine were then administered. The next dose was injected as soon as the increasing HR leveled off.…”

“…Ischemia-reperfusion was carried out as previously described (8). Adult mice were placed in an induction chamber and anesthetized with 4% isoflurane.…”