Published online before print December 26, 2002, doi: 10.1161/01.RES.0000054201.60308.1A
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Submitted on June 4, 2002
Revised on December 12, 2002
Accepted on December 13, 2002
High-Density Lipoproteins Protect Isolated Rat Hearts From Ischemia-Reperfusion Injury by Reducing Cardiac Tumor Necrosis Factor-
Content and Enhancing Prostaglandin Release
Laura Calabresi ;
From the Center E. Grossi Paoletti, Department of Pharmacological Sciences (L.C., M.G., G.F.), the Department of Pharmacological Sciences (G.R.), the Institute of Microbiology (F.S.), University of Milano, and the Department of Experimental and Environmental Medicine and Medical Biotechnology (F.B.), University of Milano-Bicocca, Monza, Italy.
* To whom correspondence should be addressed. E-mail: Guido.Franceschini{at}unimi.it.
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-
(TNF-) expression and content, which correlated with the improved functional recovery. A parallel increase of TNF- release in the coronary effluent was observed, due to a direct binding of cardiac TNF- to HDLs. Taken together, these findings argue for a cause-effect relationship between the HDL-mediated removal of TNF- from the ischemic myocardium and the HDL-induced cardioprotection. Indeed, etanercept, a recombinant TNF--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.
Key words: high-density lipoproteins • myocardial ischemia • reperfusion • tumor necrosis factor-
•
prostaglandins
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