High-Density Lipoproteins Protect Isolated Rat Hearts From Ischemia-Reperfusion Injury by Reducing Cardiac Tumor Necrosis Factor-α Content and Enhancing Prostaglandin Release

Abstract

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 ischemiareperfusion 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 ischemiareperfusion injury. Key Words: high-density lipoproteins Ⅲ myocardial ischemia Ⅲ reperfusion Ⅲ tumor necrosis factor-␣ Ⅲ prostaglandins S everal prospective studies have clearly established that plasma high-density lipoprotein (HDL) cholesterol levels are inversely related to the incidence of primary cardiac events. 1 In addition to the strong epidemiological data, there is compelling clinical trial evidence that coronary event rates may be favorably influenced by raising plasma HDL levels, especially in subjects with low HDL cholesterol and elevated triglycerides. [2][3][4] The protective effect of HDLs is believed to be due to their capacity to promote reverse cholesterol transport, the process by which cholesterol in peripheral tissues, including the arterial wall, is routed to the liver for excretion from the body. Through this pathway, HDLs retard formation of lipid-rich arterial lesions, thus preventing plaque rupture and coronary events. 5 Besides being a strong independent predictor of the occurrence of primary coronary events, a low plasma HDL cholesterol level is also associated with unfavorable prognosis in patients who have recovered from a myocardial infarction. 6 -8 Whether this association reflects accelerated atherogenesis...

Therapeutic Potential of HDL in Cardioprotection and Tissue Repair

“…Lipid-free apo A-I or phosphatidylcholine liposomes were not effective in protecting the heart from IRI. rHDL caused a dose-dependent reduction of ischaemia-induced cardiac tumour necrosis factor-α (TNF-α) expression and content, which correlated with the improved functional recovery (Calabresi et al 2003). In agreement with this prior study, rHDL improved cardiac function (Rossoni et al 2004) and reduced infarct size compared to non-treated animals (Gu et al 2007).…”

“…The direct cardioprotective impact of HDL on IRI has been studied by Calabresi and colleagues (Calabresi et al 2003). They reported that treatment with rHDL improved post-ischaemic functional recovery and decreased creatine kinase release in the coronary effluent.…”

High density lipoproteins and endothelial functions: mechanistic insights and alterations in cardiovascular disease

“…Incubation with native HDL increases prostacyclin production in cultured endothelial cells ( 178,179 ), and the effects can be recapitulated partially by delipidated HDL ( 180 ), suggesting that both HDL-associated lipids and apolipoproteins are involved in the process. Prostacyclin release has also been shown to increase when isolated rabbit and rat hearts are infused with HDL ( 181,182 ). The impact of HDL on prostacyclin production in endothelium occurs by both the provision of arachidonate ( 178,180,183 ) and upregulation of Cox-2 expression ( 184,185 ).…”

High-density lipoproteins: an emerging target in the prevention of cardiovascular disease

“…Reports that HDL improves reactivity of vascular rings in organ bath studies [42,43] was extended to the human setting where infusion of rHDL restores endothelial function in subjects with hypercholesterolaemia [44] or low levels of HDLC in the setting of heterozygous ABCA1 deficiency [45]. Reduced tissue injury in models of ischaemia-reperfusion [46,47] and shock in the setting of both hypovolemia [48] and sepsis [49] is likely to result from the combination of antioxidant, antiinflammatory and NOenhancing activities of HDL. HDLs have also been reported to possess antiapoptotic activity [50][51][52][53], although the underlying mechanism for this property remains unresolved.…”