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Role of integrins in cardiac innervation and function

Institution: University of California, Santa Barbara
Investigator(s): Dennis Clegg, Ph.D.
Award Cycle: 2000 (Cycle 9) Grant #: 9RT-0212 Award: $293,277
Subject Area: Cardiovascular Disease
Award Type: Research Project Awards
Abstracts

Initial Award Abstract
Sympathetic neurons convey stress signals from the brain to the heart and blood vessels, resulting in an increased pulse and increased blood pressure. Clusters of these neurons reside in the Superior Cervical and Thoracic ganglia near the spinal cord. They receive input from spinal cord neurons, which contact the sympathetic cell bodies in the ganglia. In response, an electrical signal is conveyed down the sympathetic axons that extend to the heart and to blood vessels. When the signal reaches the axon terminals, they release norepinephrine, a neurotransmitter that increases the rate of heart contraction and constricts smooth muscle of the blood vessels. This relay system functions in the “fight or flight” response that allows animals to take action in times of stress. However, excess stimulation of the sympathetic nerves can lead to hypertension, a condition characterized by high blood pressure and abnormal growth of the heart tissue. Improper sympathetic activity can also lead to an arrhythmic heart beat and heart attacks.

Smoking is known to be a high risk factor in heart disease. Smoking may contribute to heart disease via long term stimulation of the sympathetic innervation of heart muscle and blood vessels. Thus, it may be beneficial to use drugs to decrease the sympathetic innervation of the heart to treat hypertension. However, the molecular interactions that underlie the in growth of axons into heart tissue during development, and the factors that maintain the innervation of the heart are not understood. It is thought that receptor proteins on the surface of sympathetic neuronal cells recognize proteins on heart cell surfaces and this leads to extension of axons into the heart. These same interactions may result in maintenance of the innervation in the adult.

We have obtained preliminary evidence suggesting that an 4 integrin receptor on sympathetic neurons interacts with Vascular Cell Adhesion Molecule-1 (VCAM-1) on heart cells to guide axons into the heart during development. Experiments are proposed to test this hypothesis. If we can show that the interaction between these two proteins is important in establishing the innervation of the heart, it may be possible to treat hypertension and other types of heart disease with drugs that block the interaction between 4 integrin. and VCAM-1. Such treatments would result in a decrease in sympathetic innervation and therefore less norepinephrine would be released. Thus, strategies might be developed to treat heart disease associated with smoking.
Publications

Novel roles for integrins in the nervous system
Periodical: Molecular and Cellular Biology Index Medicus:
Authors: Clegg DO ART
Yr: 2000 Vol: 3 Nbr: Abs: Pg: 1-7

Inward rectifier potassium channel Kir2.2 is associated with synapse-associated protein SAP97
Periodical: Journal of Cell Science Index Medicus:
Authors: Leonoudakis D, Mailliard WS, Wingerd KL, Clegg DO, Vandenberg CA ART
Yr: 2001 Vol: 114 Nbr: Abs: Pg: 987-998

Laminin-5 promotes neurite outgrowth from central and peripheral chick embryonic neurons
Periodical: Neuroscience Letters Index Medicus:
Authors: Culley B, Murphy J, Babaie J, Nguyen D, Rousselle P, Clegg DO ART
Yr: 2001 Vol: 301 Nbr: Abs: Pg: 83-86

Alpha4 integrins & VCAM-1 play a role in sympathetic innervation of the heart.
Periodical: Journal of Neuroscience Index Medicus:
Authors: Wingerd KL, Goodman NL, Smail ML, Rohan SJ, Leu ST, Clegg DO ART
Yr: 2001 Vol: 22 Nbr: Abs: Pg: 10772-10780

Integrin alpha4beta1 VLA-4 expression and activity in retinal and peripheral neurons.
Periodical: Molecular and Cellular Neuroscience Index Medicus:
Authors: Hikita ST, Cann GM, Wingerd KL, Mullick LH, Wayne WC, Webb SW, Clegg DO ART
Yr: 2003 Vol: 23 Nbr: Abs: Pg: 427-439

Expression and functions of beta-1 integrins in the developing chick retina.
Periodical: Investigative Ophthalmology and Visual Science Index Medicus:
Authors: Clegg DO, Wingerd KL, Leu ST< Mullick LH ABS
Yr: 2000 Vol: 41 Nbr: 4 Abs: Pg: S846

Inward rectifier potassium channel Kir2.2 is associated with SAP97.
Periodical: Biophysical Journal Index Medicus:
Authors: Leonoudakis D, Mailliard W, Wingerd K, Clegg D, Vandenberg C ABS
Yr: 2001 Vol: 80 Nbr: 1 Abs: Pg: 630a

Inhibition of alpha-4/beta-1 in developing chick retina results in increased apoptosis.
Periodical: American Society for Cell Biology Index Medicus:
Authors: Clegg DO, Leu ST, Jacques S, Wingerd KL, Goodman N ABS
Yr: 2002 Vol: Nbr: Abs: Pg: