Lack of oxygen affects transmittance of signals between heart cells
Heart attack is common in humans, and with a high incidence of death due to heart failure. The failure is due to disturbed transmittance of the electrical signal that normally makes the heart to contract in a controlled and synchronized manner. Svein-Ole Mikalsen, professor at NVD, and his collaborators in Oslo and Tromsø, Norway, have experimentally studied some of the factors involved in the transfer of the electrical signal during and immediately after a period with lack of oxygen. The work is published in the journal “Cellular Physiology and Biochemistry”.
THE HEARTBEAT IS DEPENDENT ON AN ELECTRICAL IMPULSE
During the heartbeat, the different parts of the heart need to contract in a synchronized and controlled manner. This synchronized contraction is controlled by an electrical impulse travelling through the heart, partly through a specialized conduction system, and partly from heart cell to heart cell. The muscle cells in the heart are very elongated, and the cells meet end-to-end in a specialized structure called the intercalated disc (Fig. 1). The intercalated disc contains gap junction channels, directly connecting the neighboring cells. Each of the neighboring cells contributes with one half-channel that is lined up with a corresponding half-channel from the neighboring cell to form the intact channel (Fig. 2). The electrical impulse travels through these channels, causing the impulse to move in the longitudinal direction of the cells. The channels are very dynamic structures, they can open and close upon different signals, they can be re-organized , and their number can increase by making more of them upon demand, or their number can be decreased by degradation.
LACK OF OXYGEN AFFECTS THE ELECTRICAL IMPULSE
A prominent feature during a heart attack is the lack of oxygen transport to a part of the heart muscle because a blood vessel is blocked. It has been known for some time that the heart attack cause disturbance in the transfer of the electrical impulse. Even if the blocking of the blood vessel is removed by operation or by drugs, there is a large chance for disturbances of the heart beat. The reason for the disturbances is that a lack of oxygen changes the opening and closing behavior of the channels by making the channels more prone to be closed, it decreases the channel number, and it changes the organization of the channels by moving them from their normal position in the intercalated disk to positions on the long sides of the cells, making much of the electrical impulse to travel in the transverse (sideways) direction. The disorganization of the channels strongly increases the chance of the heart to become arrhythmic, or even go into fibrillation, with a prominent chance of a fatal outcome.
We have studied the effects of decreased oxygen on the gap junction channels in an experimental system using cells isolated from rat heart. The oxygen has been removed by a chemical, dithionite, that reacts with oxygen, and thereby lowers the oxygen content in the medium. The gap junction channels closed within 30 minutes, and remained closed even when oxygen was returning to the system. The channels became disorganized, and number of channels started to decrease within 1 hour (Fig. 3). Concurrently, the channel proteins became modified, which possibly could act as a signal for the protein to be degraded. We also found half-channels opening themselves to the exterior of the cell. All these effects will contribute to the disturbances in the transfer of an electrical impulse. The opening of half-channels to the exterior of the cell could easily cause the death of the cells in a relatively short period of time.
We showed that a peptide modelled according to the extracellular sequence of the channel protein could prohibit the opening of the half-channels. Could this have some relevance for the intact heart? This was studied in a perfusion model of the rat heart. In this system, the rat heart is removed from the body, and connected to an artificial circulatory system. Then one of the coronary blood vessels is blocked, thereby causing an artificial heart attack. Later, the size of the damage in the heart muscle was measured. The damaged area in the hearts was decreased to around 1/3 in hearts that received the peptide during the heart attack.
Speculatively, these results could lead to a future development of a strategy to decrease the damage in the human heart during a heart attack.
V. Cruciani and S.-O. Mikalsen were previously working at the Norwegian Radium Hospital (now a part of Oslo University Hospital), Norway. This study was initiated while David Johansen, who is doctoral student in medicine at the University of Tromsø, was visiting the Norwegian Radium Hospital. Later parts of the laboratory work were done at the University of Tromsø.
Reference: D. Johansen, V. Cruciani, R. Sundset, K. Ytrehus, S.-O. Mikalsen (2011) Ischemia induces closure of gap junctional channels and opening of hemichannels in heart-derived cells and tissue. Cell Physiol Biochem 28, 103-114.
Read the abstract here.
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