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Effects of endothelin-1 on mitochondrial function during the protection against myocardial cell apoptosis
Eri Iwai-Kanai1, Koji Hasegawa, Souichi Adachi
1Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Abstract:
Endothelin-1 is a potent survival factor against myocardial cell apoptosis. While apoptotic stimuli often perturb mitochondrial function by decreasing the membrane potential as well as oxygen consumption, it is unknown whether ET-1 can rescue such perturbation by apoptotic stimuli. Administration of endothelin-1 inhibited the H(2)O(2)-induced release of cytochrome c from mitochondria to the cytosol in cardiac myocytes, indicating the involvement of the mitochondria-dependent pathway in the anti-apoptotic effect of endothelin-1. We showed here by cytofluorimetric analysis that endothelin-1 prevented the H(2)O(2)-induced decrease of membrane potential. However, endothelin-1 was unable to reverse the H(2)O(2)-mediated decrease in oxygen consumption and electron transport in the mitochondria of cardiac myocytes. Endothelin-1 was unable to rescue cardiac myocytes from apoptosis when administered after the decrease in mitochondrial membrane potential. These data suggest that endothelin-1 does not target the mitochondrial respiratory chain, but rather stabilizes the mitochondrial membrane during the protection against apoptosis.
Insights
Endothelin-1 (ET-1) protects cardiac cells from apoptosis by stabilizing mitochondrial membranes. While ET-1 prevents mitochondrial damage, it does not restore oxygen consumption, suggesting a specific protective mechanism.
Area of Science:
- Cardiovascular Biology
- Mitochondrial Medicine
- Cell Death Pathways
Background:
- Endothelin-1 (ET-1) is a known survival factor for myocardial cells.
- Apoptotic stimuli commonly impair mitochondrial function, reducing membrane potential and oxygen consumption.
- The capacity of ET-1 to counteract these specific mitochondrial perturbations remains unclear.
Purpose of the Study:
- To investigate whether Endothelin-1 can prevent or reverse mitochondrial dysfunction induced by apoptotic stimuli in cardiac myocytes.
- To elucidate the specific mechanisms underlying the anti-apoptotic effects of ET-1 concerning mitochondrial integrity.
Main Methods:
- Cardiac myocytes were treated with hydrogen peroxide (H2O2) to induce apoptosis.
- Cytofluorimetric analysis was used to assess mitochondrial membrane potential.
- Cytochrome c release, oxygen consumption, and electron transport were measured to evaluate mitochondrial function.
Main Results:
- Endothelin-1 inhibited H2O2-induced cytochrome c release, indicating involvement of the mitochondria-dependent apoptosis pathway.
- ET-1 prevented the decrease in mitochondrial membrane potential caused by H2O2.
- However, ET-1 did not reverse H2O2-mediated reductions in oxygen consumption and electron transport.
- Cardiac myocytes could not be rescued from apoptosis if ET-1 was administered after mitochondrial membrane potential decreased.
Conclusions:
- Endothelin-1's anti-apoptotic effect in cardiac myocytes involves stabilizing the mitochondrial membrane.
- ET-1 does not directly target or restore the mitochondrial respiratory chain function.
- The timing of ET-1 administration is critical, highlighting its role in preventing early-stage mitochondrial damage.