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Nicotine regulates cardiac toxicity with lipopolysaccharide

Institution: University of California, San Diego
Investigator(s): Wilbur Lew, M.D.
Award Cycle: 2000 (Cycle 9) Grant #: 9RT-0166 Award: $100,000
Subject Area: Cardiovascular Disease
Award Type: Research Project Awards

Initial Award Abstract
Heart function is depressed during infections of the bloodstream (sepsis). This is related to the toxic effects of lipopopolysaccharide (LPS), a part of the cell wall of bacteria commonly responsible for infections. The major function of the heart is to pump blood to the body. This is accomplished by contraction of the individual muscle cells of the heart, or myocytes; LPS weakens contraction of myocytes, leading to depressed pumping function of the heart with a severe fall in blood pressure, or shock. Septic shock is highly fatal (death in 20-50%) and is the leading cause of death in the intensive care unit.

Smoking doubles the death rate from severe sepsis in older patients. This may be related to the fact that smoking not only increases the susceptibility to infections, but also impairs normal defense mechanisms to fight against infections. Smoking also contributes to the development of heart disease, as well as impairs the normal response to acute injury of the heart. This proposal examines how nicotine, an active component of tobacco smoke, regulates the toxic effects of LPS on myocytes isolated from the heart. Paradoxically, nicotine exposure may have beneficial effects by inhibiting a unique form of cell death induced by LPS, termed apoptosis. Apoptosis leads to the permanent loss of myocytes from the heart, and can contribute to the development of chronic heart failure (as the work of the entire heart must be performed by a smaller number of individual muscle cells or myocytes).

This study will be performed in adult rats exposed to nicotine by implanting minature pumps under their skin. These pumps will infuse nicotine continuously to produce blood nicotine levels comparable to those of a heavy smoker. After one week of nicotine exposure, myocytes will be isolated from the heart and exposed to LPS. The effects of LPS on myocyte apoptosis will be measured. Based on preliminary data, it is anticipated that nicotine exposure will have protective effects to prevent myocyte death by apoptosis. Several intermediate steps involved in LPS activation of myocytes will be measured to understand potential mechanisms for nicotine to regulate LPS effects on the heart.

Information derived from these studies will have practical benefits. Survivors from sepsis are at increased risk of death for five years. Sepsis can have longterm consequences by inducing apoptosis in the heart, leading to chronic loss of myocytes with chronic heart failure. Utilizing nicotine-related pathways to inhibit apoptosis may prove beneficial in preventing longterm impairments in heart function in survivors of sepsis, including non-smokers.

Lipopolysaccharide induces apoptosis in adult rat ventricular myocytes via cardiac AT1 receptors.
Periodical: American Journal of Physiology Index Medicus:
Authors: Li HL, Suzuki J, Bayna E, Zhang FM, Dalle Mille E, Clark A, Engler RL, and Lew WYW ART
Yr: 2002 Vol: 283 Nbr: Abs: Pg:

Lipopolysaccharide induces apoptosis in adult rat ventricular myocytes by activating cardiac angiotensin-11 type 1 receptors.
Periodical: Circulation Index Medicus:
Authors: Li HL, Suzuki J, Bayna E, Zhang FM, Dalle Mille E, Clark A, Engler RL, and Lew WYW ABS
Yr: 2001 Vol: 104 Nbr: Abs: Pg: II-143 - 144