High-density lipoproteins protect isolated rat hearts from ischemia-reperfusion injury by reducing cardiac tumor necrosis factor-alpha content and enhancing prostaglandin release.

Abstract

The incidence and severity of primary cardiac events are inversely related to the plasma concentration of high-density lipoproteins (HDLs). We investigated whether HDLs may exert a direct cardioprotection in buffer-perfused isolated rat hearts, which underwent a 20-minute low-flow ischemia followed by a 30-minute reperfusion. The administration of HDLs at physiological concentrations (0.5 and 1.0 mg/mL) during the 10 minutes immediately before ischemia rapidly and remarkably improved postischemic functional recovery and decreased creatine kinase release in the coronary effluent. Reconstituted HDLs containing apolipoprotein A-I (apoA-I) and phosphatidylcholine, but not lipid-free apoA-I or phosphatidylcholine liposomes, were also effective in protecting the heart from ischemia-reperfusion injury. HDLs at reperfusion were less effective than when given before ischemia. HDLs caused a dose-dependent reduction of ischemia-induced cardiac tumor necrosis factor-alpha (TNF-alpha) expression and content, which correlated with the improved functional recovery. A parallel increase of TNF-alpha release in the coronary effluent was observed, due to a direct binding of cardiac TNF-alpha to HDLs. Taken together, these findings argue for a cause-effect relationship between the HDL-mediated removal of TNF-alpha from the ischemic myocardium and the HDL-induced cardioprotection. Indeed, etanercept, a recombinant TNF-alpha-blocking protein, caused a dose-dependent improvement of postischemic functional recovery. HDLs also enhanced ischemia-induced prostaglandin release, which may contribute to the cardioprotective effect. A low plasma HDL level may expose the heart to excessive ischemia-reperfusion damage, and HDL-targeted therapies may be helpful to induce immediate or delayed myocardial protection from ischemia-reperfusion injury.

• Authors: Laura Calabresi, Giuseppe Rossoni, Monica Gomaraschi, Francesca Sisto, Ferruccio Berti, Guido Franceschini
• Journal: Circulation research (Circ Res) Vol. 92 Issue 3 Pg. 330-7 (Feb 21 2003) ISSN: 1524-4571 [Electronic] United States
• PMID: 12595346 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cardiotonic Agents
• Immunoglobulin G
• Lipoproteins, HDL
• Prostaglandins
• RNA, Messenger
• Receptors, Tumor Necrosis Factor
• Tumor Necrosis Factor-alpha
• Creatine Kinase
• Etanercept

Topics

• Animals
• Cardiotonic Agents (pharmacology)
• Creatine Kinase (metabolism)
• Dose-Response Relationship, Drug
• Down-Regulation (drug effects)
• Etanercept
• Heart (drug effects, physiology)
• Humans
• Immunoglobulin G (pharmacology)
• In Vitro Techniques
• Lipoproteins, HDL (pharmacology)
• Male
• Myocardial Ischemia (metabolism)
• Myocardial Reperfusion (adverse effects)
• Myocardial Reperfusion Injury (prevention & control)
• Myocardium (metabolism)
• Prostaglandins (metabolism)
• Protein Binding (physiology)
• RNA, Messenger (metabolism)
• Rats
• Rats, Sprague-Dawley
• Receptors, Tumor Necrosis Factor
• Recovery of Function (drug effects)
• Tumor Necrosis Factor-alpha (antagonists & inhibitors, genetics, metabolism)