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

Abstract

Inflammatory cytokines that act through glycoprotein (gp)130 are elevated in the heart after myocardial infarction and in heart failure. These cytokines are potent regulators of neurotransmitter and neuropeptide production in sympathetic neurons but are also important for the survival of cardiac myocytes after damage to the heart. To examine the effect of gp130 cytokines on cardiac nerves, we used gp130(DBH-Cre/lox) mice, which have a selective deletion of the gp130 cytokine receptor in neurons expressing dopamine beta-hydroxylase (DBH). Basal sympathetic parameters, including norepinephrine (NE) content, tyrosine hydroxylase expression, NE transporter expression, and sympathetic innervation density, appeared normal in gp130(DBH-Cre/lox) compared with wild-type mice. Likewise, basal cardiovascular parameters measured under isoflurane anesthesia were similar in both genotypes, including mean arterial pressure, left ventricular peak systolic pressure, dP/dt(max), and dP/dt(min). However, pharmacological interventions revealed an autonomic imbalance in gp130(DBH-Cre/lox) mice that was correlated with an increased incidence of premature ventricular complexes after reperfusion. Stimulation of NE release with tyramine and infusion of the beta-agonist dobutamine revealed blunted adrenergic transmission that correlated with decreased beta-receptor expression in gp130(DBH-Cre/lox) hearts. Due to the developmental expression of the DBH-Cre transgene in parasympathetic ganglia, gp130 was eliminated. Cholinergic transmission was impaired in gp130(DBH-Cre/lox) hearts due to decreased parasympathetic drive, but tyrosine hydroxylase immunohistochemistry in the brain stem revealed that catecholaminergic nuclei appeared grossly normal. Thus, the apparently normal basal parameters in gp130(DBH-Cre/lox) mice mask an autonomic imbalance that includes alterations in sympathetic and parasympathetic transmission.

• Authors: Diana C Parrish, Eric N Alston, Hermann Rohrer, Sam M Hermes, Sue A Aicher, Paul Nkadi, William R Woodward, Jutta Stubbusch, Ryan T Gardner, Beth A Habecker
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 297 Issue 3 Pg. H960-7 (Sep 2009) ISSN: 1522-1539 [Electronic] United States
• PMID: 19592611 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Il6st protein, mouse
• Cytokine Receptor gp130
• Tyrosine 3-Monooxygenase
• Dopamine beta-Hydroxylase
• Norepinephrine

Topics

• Animals
• Arrhythmias, Cardiac (metabolism, physiopathology)
• Brain Stem (cytology, physiology)
• Cytokine Receptor gp130 (genetics, metabolism)
• Dopamine beta-Hydroxylase (genetics, metabolism)
• Genotype
• Heart (innervation, physiology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Myocardial Reperfusion Injury (metabolism, physiopathology)
• Neurons (enzymology)
• Norepinephrine (metabolism)
• Parasympathetic Nervous System (enzymology, physiopathology)
• Sympathetic Nervous System (enzymology, physiopathology)
• Transgenes (physiology)
• Tyrosine 3-Monooxygenase (metabolism)