HDL protects against ischemia reperfusion injury by preserving mitochondrial integrity.

Abstract

OBJECTIVE:

High density lipoproteins (HDL) protect against ischemia reperfusion injury (IRI). However the precise mechanisms are not clearly understood. The novel intrinsic prosurvival signaling pathway named survivor activating factor enhancement (SAFE) path involves the activation of tumor necrosis factor (TNF) alpha and signal transducer and activator of transcription 3 (STAT3). SAFE plays a crucial role in cardioprotection against IRI. We propose that HDL protect against IRI via activation of the SAFE pathway and modulation of the mitochondrial permeability transition pore (mPTP) opening.

METHODS AND RESULTS:

Isolated mouse hearts were subjected to global ischemia (35 min) followed by reperfusion (45 min). HDL were given during the first 7 min of reperfusion. In control hearts, the post-reperfusion infarct size was 41.3 ± 2.3%. Addition of HDL during reperfusion reduced the infarct size in a dose-dependent manner (HDL 200 μg protein/ml: 25.5 ± 1.6%, p < 0.001 vs. control). This protective effect was absent in TNF deficient mice (TNF-KO) or cardiomyocyte-STAT3 deficient mice (STAT3-KO). Similarly, HDL, given as a preconditioning stimulus, improved cell survival and inhibited mPTP opening in isolated cardiomyocytes subjected to simulated ischemia. These protective responses were inhibited in cardiomyocytes from TNF-KO and STAT3-KO mice.

CONCLUSION:

Our data demonstrate that HDL protect against IRI by inhibition of mPTP opening, an effect mediated via activation of the SAFE pathway.

• Authors: Miguel A Frias, Sarah Pedretti, Damian Hacking, Sarin Somers, Lydia Lacerda, Lionel H Opie, Richard W James, Sandrine Lecour
• Journal: Atherosclerosis (Atherosclerosis) Vol. 228 Issue 1 Pg. 110-6 (May 2013) ISSN: 1879-1484 [Electronic] Ireland
• PMID: 23497785 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Cholesterol, HDL
• STAT3 Transcription Factor
• Stat3 protein, mouse
• Tumor Necrosis Factor-alpha

Topics

• Animals
• Cell Survival (physiology)
• Cholesterol, HDL (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mitochondria (metabolism)
• Mitochondrial Membranes (metabolism)
• Myocardial Infarction (metabolism, pathology)
• Myocardial Reperfusion Injury (metabolism, pathology)
• Myocytes, Cardiac (metabolism, pathology)
• Phosphorylation (physiology)
• STAT3 Transcription Factor (genetics)
• Signal Transduction (physiology)
• Tumor Necrosis Factor-alpha (genetics)