Ischaemic Preconditioning Protects Cardiomyocytes from Anthracycline-Induced Toxicity via the PI3K Pathway.

Abstract

PURPOSE:

Anthracyclines cause chronic irreversible cardiac failure, but the mechanism remains poorly understood. Emerging data indicate that cardiac damage begins early, suggesting protective modalities delivered in the acute stage may confer prolonged benefit. Ischaemic preconditioning (IPC) activates the pro-survival reperfusion injury salvage kinase (RISK) pathway which involves PI3-kinase and MAPK/ERK1/2.

METHODS:

We investigated whether simulated IPC (sIPC), in the form of a sublethal exposure to a hypoxic buffer simulating ischaemic conditions followed by reoxygenation, protects primary adult rat cardiomyocytes against anthracycline-induced injury. PI3-kinase and MAPK/ERK1/2 were inhibited using LY294002, and PD98059. The role of reactive oxygen species (ROS), mitochondrial membrane potential (Δψm) and mitochondrial permeability transition pore (mPTP) were also investigated in doxorubicin-treated cells. We further examined whether sIPC protected HeLa cancer cells from doxorubicin-induced death.

RESULTS:

sIPC protected cardiomyocytes against doxorubicin-induced death (35.4 ± 1.7% doxorubicin vs 14.7 ± 1.5% doxorubicin + sIPC; p < 0.01). This protection was abrogated by the PI3-kinase inhibitor, LY294002, but not the MAPK/ERK1/2 inhibitor, PD98059. A ROS scavenger failed to rescue cardiomyocytes from doxorubicin toxicity, and no significant influence on Δψm or mPTP opening was identified after subjecting cells to a doxorubicin insult. Importantly, sIPC did not protect HeLa cancer cells from doxorubicin-induced death.

CONCLUSION:

sIPC is able to protect cardiomyocytes against anthracycline injury via a pathway involving PI3-kinase. This mechanism appears to be independent of ROS, changes to Δψm, and mPTP. Further investigation of the mechanism of sIPC-induced protection against anthracycline-injury is warranted.

• Authors: Angshuman Maulik, Sean M Davidson, Izabela Piotrowska, Malcolm Walker, Derek M Yellon
• Journal: Cardiovascular drugs and therapy (Cardiovasc Drugs Ther) Vol. 32 Issue 3 Pg. 245-253 (06 2018) ISSN: 1573-7241 [Electronic] United States
• PMID: 29766336 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibiotics, Antineoplastic
• Doxorubicin
• Phosphatidylinositol 3-Kinase

Topics

• Animals
• Antibiotics, Antineoplastic (toxicity)
• Cardiotoxicity
• Cell Hypoxia
• Doxorubicin (toxicity)
• Female
• HeLa Cells
• Heart Diseases (chemically induced, enzymology, pathology, prevention & control)
• Humans
• Ischemic Preconditioning, Myocardial
• Male
• Myocytes, Cardiac (drug effects, enzymology, pathology)
• Phosphatidylinositol 3-Kinase (metabolism)
• Rats, Sprague-Dawley
• Signal Transduction (drug effects)
• Uterine Cervical Neoplasms (enzymology, pathology)