Cardiac sympathetic innervation and PGP9.5 expression by cardiomyocytes after myocardial infarction: effects of central MR blockade.

Abstract

Central mechanisms involving mineralocorticoid receptor (MR) activation contribute to an increase in sympathetic tone after myocardial infarction (MI). We hypothesized that this central mechanism also contributes to cardiac sympathetic axonal sprouting and that central MR blockade reduces cardiac sympathetic hyperinnervation post-MI. Post-MI, tyrosine hydroxylase (TH) and norepinephrine transporter protein content in the noninfarcted base of the heart remained unaltered. In contrast, protein gene product (PGP)9.5 protein was increased twofold in the base of the heart and sixfold in the peri-infarct area at 1 wk post-MI and was associated with increased ubiquitin expression. These changes persisted to a lesser extent at 4 wk post-MI and were no longer present at 12 wk. Cardiac myocytes rather than sympathetic axons were the main source of this elevated PGP9.5 expression. At 7-10 days post-MI, in the peri-infarct area, sympathetic hyperinnervation was observed with a fourfold increase in growth-associated protein 43, a twofold increase in TH, and a 50% increase in PGP9.5-positive fibers compared with the epicardial side of the left ventricle in sham rats. Central infusion of the MR blocker eplerenone markedly attenuated these increases in nerve densities but did not affect overall cardiac PGP9.5 and ubiquitin protein overexpression. We conclude that central MR activation contributes to sympathetic hyperinnervation, possibly by decreasing cardiac sympathetic activity post-MI, or by affecting other mechanisms, such as the expression of nerve growth factor. Marked PGP9.5 expression occurs in cardiomyocytes early post-MI, which may contribute to the increase in ubiquitin.

• Authors: Anastasia Drobysheva, Monir Ahmad, Roselyn White, Hong-Wei Wang, Frans H H Leenen
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 305 Issue 12 Pg. H1817-29 (Dec 2013) ISSN: 1522-1539 [Electronic] United States
• PMID: 24124186 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Mineralocorticoid Receptor Antagonists
• Norepinephrine Plasma Membrane Transport Proteins
• Receptors, Mineralocorticoid
• UCHL1 protein, human
• Ubiquitin
• Tyrosine 3-Monooxygenase
• Ubiquitin Thiolesterase

Topics

• Animals
• Heart (drug effects, innervation)
• Male
• Mineralocorticoid Receptor Antagonists (pharmacology)
• Myocardial Infarction (metabolism)
• Myocardium (metabolism)
• Myocytes, Cardiac (drug effects, metabolism)
• Norepinephrine Plasma Membrane Transport Proteins (metabolism)
• Rats
• Rats, Wistar
• Receptors, Mineralocorticoid (metabolism)
• Sympathetic Nervous System (drug effects, metabolism)
• Tyrosine 3-Monooxygenase (metabolism)
• Ubiquitin (metabolism)
• Ubiquitin Thiolesterase (metabolism)