HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text (PDF) All Versions of this Article: 20/1/160 05-4060fjev1    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zvara, A. Articles by Ferdinandy, P. Search for Related Content PubMed PubMed Citation Articles by Zvara, A. Articles by Ferdinandy, P.

Capsaicin-sensitive sensory neurons regulate myocardial function and gene expression pattern of rat hearts: a DNA microarray study

Ágnes Zvara^*, Péter Bencsik, Gabriella Fodor, Tamás Csont, László Hackler, Jr.^*, Mária Dux, Susanna Fürst, Gábor Jancsó, László G. Puskás^* and Péter Ferdinandy^,1

^* Laboratory of Functional Genomics, Biological Research Center, Hungarian Academy of Sciences, Szeged, Hungary;
Neuro-psychopharmacological Research Group, Hungarian Academy of Sciences, and Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary;
Department of Physiology, University of Szeged, Szeged, Hungary; and
Cardiovascular Research Group, Department of Biochemistry, University of Szeged, Szeged, Hungary

¹Correspondence: Cardiovascular Research Group, Department of Biochemistry, University of Szeged, Dóm tér 9, Szeged, H-6720, Hungary. E-mail: peter{at}bioch.szote.u-szeged.hu

SPECIFIC AIMS

To profile changes in cardiac mechanical function and gene expression pattern of the heart in response to sensory chemodenervation by systemic capsaicin pretreatment in rats.

PRINCIPAL FINDINGS

1. We have found that selective chemodenervation by systemic capsaicin pretreatment results in a cardiac mechanical dysfunction characterized by a significant elevation of left ventricular end-diastolic pressure
However, other cardiac functional parameters such as heart rate, coronary flow, aortic flow, left ventricular developed pressure, and its first derivatives (+dP/dt_max, –dP/dt_max) were not changed and no lactate dehydrogenase release was detected.

2. We have found significant alterations in expression of 1% of the 6400 genes examined by DNA micorarray in rat hearts 7 days after systemic capsaicin pretreatment
Forty-seven genes exhibited significant up-regulation and 33 genes were down-regulated (changes ranged from –3.9- to +4.8-fold; Tables 1 , 2 ).

3. Capsaicin-induced chemodenervation resulted in an up-regulation of its own receptor, TRPV1, and other transient receptor potential protein-related genes
It also resulted in altered expression of several other genes of known neural and non-neural function such as GABA receptor rho-3 subunit, 5-hydroxytryptamine 3 receptor B, matrix metalloproteinase-13, cytochrome P450, farnesyl-transferase, ApoB, MMP-13, leptin, etc. (Tables 1 , 2) .

4. Gene expression changes obtained by microarray assay were verified by RT-PCR in case of 10 selected genes with high biological significance
An additional 11 genes strongly related to sensory neural signaling but not available on the DNA-microarray were also investigated by RT-PCR and found that neurokin B, NK-2 receptor, and endothelial nitric oxide synthase were significantly down-regulated by capsaicin pretreatment.

CONCLUSIONS AND SIGNIFICANCE

Capsaicin is a highly selective sensory neurotoxin that leads to a selective functional blockade and/or ablation of a morphologically well-defined population of primary sensory neurons. The selective action of capsaicin and related compounds on a subset of sensory nerve fibers is mediated, at least in part, by an agonist activity on a ligand-gated ion channel called capsaicin receptor or the transient receptor potential vanilloid receptor 1 (TRPV1). So far, the traditional biochemical and pharmacological approaches have been insufficient to explore the key cellular events regulated by sensory nerves and TRPV1. Three years ago, Szallasi and Fowler envisioned in a review that the application of gene chip technologies will address the global profile of capsaicin/vanilloid-induced changes in gene expression and their contribution to cellular events. Surprisingly, no attempt has been made to explore gene expression changes induced by selective chemodenervation of sensory nerves by systemic capsaicin pretreatment in any tissues. Our present study is the first demonstration that capsaicin-induced selective sensory chemodenervation results in cardiac dysfunction characterized by an increase in left ventricular end-diastolic pressure and leads to extensive changes in cardiac expression of genes from various functional clusters.

Our finding that selective chemodenervation by systemic capsaicin pretreatment resulted in an up-regulation of several genes with neural function, including its own receptor TRPV1 and other TRP-related genes, is unexpected, and may be of utmost interest in the light of experimental evidence suggesting a pivotal role of capsaicin-sensitive neuronal function in the modulation of cardiac function in health and disease. Previous investigations and our present study revealed that systemic administration of capsaicin produces neuropeptide depletion and irreversible degeneration in capsaicin-sensitive sensory neurons in adult animals. Together, these findings suggest that the increased expression of TRPV1 and related genes after systemic capsaicin treatment may be attributed to up-regulation of these cardiac genes of non-neural origin. Indeed, TRPV1 has been localized in cardiomyocytes of the developing heart by using RT-PCR, Western blot, and immunohistochemistry analyses.

Selective sensory chemodenervation by systemic capsaicin pretreatment resulted in significant changes in transcription of several genes with a variety of known physiological function not specific for nervous tissue, such as gene regulation, signal transduction, protein processing, and metabolism. In-depth studies of each gene with altered expression should clarify how these changes in cardiac gene expression with known neural and non-neural functions are manifested in the deterioration of cardiac function in normal or diseased heart.

We conclude that selective sensory chemodenervation by systemic capsaicin pretreatment leads to a moderate cardiac mechanical dysfunction and significant changes in expression of a variety of genes of both neural and non-neural functions in heart tissue. This indicates that capsaicin-sensitive sensory nerves may play a significant role in regulating the expression of a variety of neuronal and non-neuronal genes in the heart and possibly in other tissues as well. Our present findings may open new directions in the research of the effects of capsaicin and other synthetic agonists and antagonists on vanilloid receptors.

View larger version (35K): [in this window] [in a new window]   Figure 1. Schematic diagram.

FOOTNOTES

To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.05-4060fje;

This article has been cited by other articles:

				B. Zhong and D. H. Wang N-oleoyldopamine, a novel endogenous capsaicin-like lipid, protects the heart against ischemia-reperfusion injury via activation of TRPV1 Am J Physiol Heart Circ Physiol, August 1, 2008; 295(2): H728 - H735. [Abstract] [Full Text] [PDF]

This Article Full Text (PDF) All Versions of this Article: 20/1/160 05-4060fjev1    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zvara, A. Articles by Ferdinandy, P. Search for Related Content PubMed PubMed Citation Articles by Zvara, A. Articles by Ferdinandy, P.