Mechanism of the cardioprotective effect of transforming growth factor beta 1 in feline myocardial ischemia and reperfusion.

Abstract

We studied the effects of transforming growth factor Pi (TGF-f1) in a feline model of myocardial ischemia (1.5 hr) and reperfusion (4.5 hr). Myocardial ischenma followed by reperfusion resulted in severe myocardial imjury, endothelial dysfunction, high cardiac myeloperoxidase activity indicative of neutrophil accumulation in the ischemic myocardium, and sinicant neutrophil adherence to the ischemic coronary endothelium. In contrast, intravenous administration of TGF-Pi (20 pg/kg) 30 min prior to reperfusion significantly attenuated myocardial necrosis (13.8% ± 3.5% vs. 32.2% ± 2.9% of area-at-risk, P < 0.01) and attenuated endothelial dysfunction (P < 0.01) associated with ischemia- Experimental Protocol. After completing all surgical procedures, the cats were allowed to stabilize for 30 min, at which time a baseline reading of ECG and MABP was recorded and a 3-ml blood sample was drawn. The blood was centrifuged at 2500 x g for 15 min at 4°C to obtain plasma that was used as a vehicle for TGF-,Bl administration. MI was produced by tightening the previously placed reversible ligature around the LAD coronary segment to completely occlude the vessel. This was designated as time 0. One hour after coronary occlusion, 81 (20 ,ug/kg) or its vehicle (1 ml of plasma) was given i.v. as a bolus. After 1.5 hr of ischemia, the LAD ligature was untied and the ischemic myocardium was reperfused (R) for 4.5 hr. The animals were randomly divided into three major groups of six or seven cats each. These groups included sham MI + R cats receiving TGF-f31 and MI + R cats receiving either TGF-(31 or its vehicle. Sham MI + R cats were subjected to the same surgical procedures as MI + R cats except that the LAD coronary artery was not occluded.Myocardial Tissue Analysis. At the end of the experiment, the ligature around the LAD coronary segment was retightened. Twenty milliliters of0.5% Evans blue was injected over a period of 1 min into the left ventricle to stain the area of Abbreviations: TGF-(, transforming growth factor (; MABP, mean arterial blood pressure; LAD, left anterior descending; PRI, pressure-rate index; HR, heart rate; MI, myocardial ischemia; ACh, acetylcholine; MPO, myeloperoxidase; PMN, polymorphonuclear leukocyte; IL-1, interleukin 1; TNF-a, tumor necrosis factor a; LCX, left circumflex; ECG, electrocardiogram; LTB4, leukotriene B4; EDRF, endothelium-derived relaxing factor. tTo whom reprint requests should be addressed. 1018The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

The role of transforming growth factor (TGF)-β in the infarcted myocardium

“…In a model of reperfused feline myocardial infarction, TGF-β1 administration reduced cardiomyocyte death; these protective actions were associated with attenuated neutrophil recruitment in the infarcted myocardium (47). Whether TGF-β-mediated protection in these studies is due to activation of direct pro-survival pathways in cardiomyocytes, or reflects suppression of injurious inflammatory signaling, remains unknown.…”

Activation of invariant natural killer T cells by α-galactosylceramide ameliorates myocardial ischemia/reperfusion injury in mice

“…Endogenous TNF-α and IL-1 play as a mediator of inflammatory reactions, whereas, IL-10 and TGF-β have cardioprotective effects on myocardial I/R injury. Previous studies demonstrated that the blocking of pro-inflammatory cytokines or the administration of cardioprotective cytokines reduced infarct size [32][33][34][35][36][37]. On the other hand, the increases in IL-4 and IFN-γ are characteristic of the activation of iNKT cells [9].…”

Enhancement of the haemodynamic effects of NG‐monomethyl‐l‐arginine by transforming growth factor‐β1 in conscious, normal, but not endotoxaemic, rats

“…For example, TGF-fl, increases biosynthesis and release of the vasoconstrictor, endothelin (ET), in vitro (Kurihara et al, 1989;Ohta et al, 1990;Kanse et al, 1991;Endo et a!., 1992). On the basis of this observation, Kurihara et al (1989) suggested that TGF-fl, could be involved in the local regulation of vascular tone by stimulating ET-l release, but Lefer et al (1993) reported that TGF-/I had no haemodynamic effects in vivo. However, the in vitro experiments of Kurihara et al (1989) showed that the increase in ET mRNA was maximal 2h after TGF-fl, stimulation, whereas in the experiments of Lefer et al (1993) haemodynamic effects of TGF-fI were not looked for over several hours in the absence of other interventions.…”