Abstract
Visfatin is an adipocytokine capable of mimicking the glucose-lowering effects of insulin and activating the pro-survival kinases phosphatidylinositol-3-OH kinase (PI3K)-protein kinase B (Akt) and mitogen-activated protein kinase kinase 1 and 2 (MEK1/2)-extracellular signal-regulated kinase 1 and 2 (Erk 1/2). Experimental studies have demonstrated that the activation of these kinases confers cardioprotection through the inhibition of the mitochondrial permeability transition pore (mPTP). Whether visfatin is capable of exerting direct cardioprotective effects through these mechanisms is unknown and is the subject of the current study. Anaesthetized C57BL/6 male mice were subjected to in situ 30 min. of regional myocardial ischaemia and 120 min. of reperfusion. The administration of an intravenous bolus of visfatin (5 × 10−6μmol) at the time of myocardial reperfusion reduced the myocardial infarct size from 46.1 ± 4.1% in control hearts to 27.3 ± 4.0% (n≥ 6/group, P < 0.05), an effect that was blocked by the PI3K inhibitor, wortmannin, and the MEK1/2 inhibitor, U0126 (48.8 ± 5.5% and 45.9 ± 8.4%, respectively, versus 27.3 ± 4.0% with visfatin; n≥ 6/group, P < 0.05). In murine ventricular cardiomyocytes subjected to 30 min. of hypoxia followed by 30 min. of reoxygenation, visfatin (100 ng/ml), administered at the time of reoxygenation, reduced the cell death from 65.2 ± 4.6% in control to 49.2 ± 3.7%(n > 200 cells/group, P < 0.05), an effect that was abrogated by wortmannin and U0126 (68.1 ± 5.2% and 59.7 ± 6.2%, respectively; n > 200 cells/group, P > 0.05). Finally, the treatment of murine ventricular cardiomyocytes with visfatin (100 ng/ml) delayed the opening of the mPTP induced by oxidative stress from 81.2 ± 4 sec. in control to 120 ± 7 sec. (n > 20 cells/group, P < 0.05) in a PI3K- and MEK1/2-dependent manner. We report that the adipocytokine, visfatin, is capable of reducing myocardial injury when administered at the time of myocardial reperfusion in both the in situ murine heart and the isolated murine cardiomyocytes. The mechanism appears to involve the PI3K and MEK1/2 pathways and the mPTP.
Highlights
Visceral fat accumulation, a key feature of the metabolic syndrome, is associated with the development of diabetes mellitus, a three-fold increased risk of developing coronary heart disease [1], a two to three times increase in cardiovascular mortality [2] and worse clinical outcome following an acute myocardial infarction [3,4,5] or a primary percutaneous coronary intervention [6]
The pivotal findings of the current study are as follows: (1) we demonstrate for the first time that the administration of the novel adipocytokine, visfatin, at the time of myocardial reperfusion, dramatically reduces the myocardial infarct size using an in vivo murine infarction model; (2) the cardioprotective effect induced by visfatin is demonstrated to be a direct cellular effect, as demonstrated by the improved cardiomyocyte viability observed using isolated cardiomyocytes treated with visfatin at the time of reoxygenation; (3) visfatin treatment delays the opening of the mitochondrial permeability transition pore (mPTP) in isolated cardiomyocytes subjected to oxidative stress and (4) importantly, the cardioprotective effect is dependent on the activation of the pro-survival kinases, phosphatidylinositol-3-OH kinase (PI3K) and mitogen-activated protein kinase kinase 1 and 2 (MEK1/2)
The authors demonstrated that visfatin phosphorylated the insulin receptor, insulin receptor substrate-1 (IRS-1) and -2 (IRS-2), PI3K, Akt and mitogen-activated protein kinase (MAPK) [11]
Summary
A key feature of the metabolic syndrome, is associated with the development of diabetes mellitus, a three-fold increased risk of developing coronary heart disease [1], a two to three times increase in cardiovascular mortality [2] and worse clinical outcome following an acute myocardial infarction [3,4,5] or a primary percutaneous coronary intervention [6]. The recently discovered adipocytokine, visfatin, has been demonstrated to mimic the glucose-lowering effect of insulin and improve insulin sensitivity [11]. By binding to the insulin receptor, visfatin has been demonstrated to activate intracellular kinase signalling cascades, such as the PI3K-Akt and mitogen-activated protein kinase (MAPK) pathways [11], through which it may exert an antiapoptotic effect [12]. Experimental studies have indicated that the activation of pro-survival protein kinases such as PI3K-Akt and MEK1/2-Erk1/2 MAPK, at the time of myocardial reperfusion [13, 14], confers powerful cardioprotection, an effect attributable, in part, to the inhibition of the mitochondrial permeability transition pore (mPTP) [15].
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