Fibroblast growth factor cardioprotection against ischemia-reperfusion injury may involve K+ ATP channels.

We investigated whether the adenosine triphosphate (ATP)-sensitive K+ (K+ATP) channel that was implicated in the ischemic preconditioning (I-PC) phenomenon, has a role in the cardioprotective effects of fibroblast growth factors (FGFs). For this purpose, we administered glibenclamide, a specific K+ATP channel blocker, before acidic fibroblast growth factor (aFGF, FGF-1) treatment, in rat heart subjected to left ventricular ischemia for 20 minutes followed by reperfusion for 24 hours. Creatine kinase (CK) activity was analyzed in myocardial tissue to assess the degree of cardiac injury. FGF-1 treatment markedly maintains CK activity. This cardioprotective effect of FGF-1 was blocked by glibenclamide. As shown by ultrastructural data, Ca2+ overload and associated cardiomyocyte alterations shown in glibenclamide-treated rats were not observed in specimens from the FGF-1 group. These findings suggest that FGF serves as an effector in I-PC and support a clinical interest of these proteins for increasing myocardial ischemic tolerance.

Cardioprotection from ischemia by fibroblast growth factor: role of inducible nitric oxide synthase.

Growing evidence from both animal experiments and clinical observations indicates that fibroblast growth factor (FGF) plays a protective role in myocardial reperfusion injury. The molecular and cellular mechanisms that lead to this postischemic myocardial protection, however, remain largely unexplored. We studied the cardioprotective effects of human recombinant acidic fibroblast growth factor (aFGF, FGF-1) in a rat model of myocardial reperfusion injury, induced by 20 minutes of left coronary artery occlusion followed by 24 hours of reperfusion. Intravenous FGF-1 administration at the onset of heart reperfusion attenuated both the functional impairment and the histological changes of ischemia/reperfusion injury. FGF-1 increases more than twice the left ventricular contractile function (p <0.005) compared to vehicle-treated rats. As shown by histology, myocardial tissue is better preserved with FGF-1 treatment. The infarct size, normalized for the area at risk, was significantly smaller in the FGF-1 group (p <0.01) than in the vehicle group. Furthermore, FGF-1 administration resulted in expression of inducible nitric oxide synthase (iNOS) in the area at risk. Since increased expression of iNOS could potentiate cardioprotection against myocardial reperfusion injury, our findings support a new non-mitogenic role for FGF and add a clinical interest for this protein in increasing myocardial ischemic tolerance.

Fibroblast growth factor protects the kidney against ischemia-reperfusion injury.

Ischemia-reperfusion injury, a common source of renal dysfunction in adults, is associated with tubular epithelial cell damage. Since fibroblast growth factors (FGF) attenuated tissue injury after transient myocardial ischemia, we hypothesized that acidic fibroblast growth factor (aFGF; FGF-1) would attenuate renal ischemia-reperfusion injury. We studied the effects of FGF-1 in a rat model of acute renal failure induced by bilateral renal ischemia (60 min) and 1, 2 or 7 days reperfusion. After FGF-1 administration at the onset of renal reperfusion, there was less functional impairment of the kidneys. The histological changes were not as severe as in controls. Increases in serum creatinine and blood urea nitrogen 24 h after reperfusion were attenuated by 35% (p< 0.01) and by 53% (p< 0.001), respectively, in FGF-1-treated animals compared to vehicle-treated rats. The ischemia/reperfusion-induced increase in tissue myeloperoxidase, a marker of neutrophil infiltration, was mitigated (67% reduction, p< 0.05) with FGF-1 treatment. As shown by histology, neutrophil infiltration and tubular cell necrosis in medulla were less pronounced (p< 0.0001 and p< 0.05, respectively) in animals receiving FGF-1. Furthermore, ischemia-induced apoptosis, prevalent in tubular cells of the cortex, was also attenuated by FGF-1-treatment (83% reduction, p< 0.0001). Pretreatment of animals with Nw-nitro-L-arginine (L-NNA), an inhibitor of nitric oxide synthase, abolished the attenuating effects of FGF-1 on neutrophil infiltration, suggesting that nitric oxide might participate in the anti-inflammatory effects of FGF-1 in this experimental design. Our data support a role for FGF-1 in attenuation of renal damage or failure after ischemia-reperfusion injury of the kidney, in part at least by inhibition of neutrophil infiltration.

Serum levels of basic fibroblast growth factor in acute myocardial infarction.

As it has been reported that basic fibroblast growth factor (bFGF) is a circulating peptide and bFGF gene expression is increased after myocardial ischemia, this study was designed to investigate the serum levels of bFGF in patients with acute myocardial infarction (AMI). Using a bFGF enzyme-linked immunoassay, bFGF levels were determined in venous blood of 15 patients with AMI on admission, at 10 days, and 30 days after infarction, and of 15 age-matched healthy volunteers who were used as controls. bFGF serum levels on admission were similar to normal values (7.48 +/- 2.3 vs 8.14 +/- 2.9 pg/ml). However, they significantly increased (16.82 +/- 3.4 pg/ml; p <0.05) 10 days after the onset of AMI, and at 30 days they returned to baseline (7.07 +/- 2.9 pg/ml). The increased bFGF levels at the second week post AMI suggest that bFGF plays an important role in mediating the development of coronary collateral circulation after myocardial ischemia in humans.

A non-mitogenic form of acidic fibroblast growth factor reduces neutrophil infiltration in rat ischemic reperfused heart.

We studied the effects of a non-mitogenic form of acidic fibroblast growth factor (aFGF) on neutrophil infiltration in a rat model of myocardial ischemia (20 min) and reperfusion (24 hr). Neutrophil infiltration, as assessed by measurement of myeloperoxidase (MPO) activity was compared in homogenates of the infarcted left ventricle and the non-infarcted septum which was used as a reference of normal tissue. Myocardial ischemia followed by reperfusion resulted in severe myocardial injury and high cardiac MPO activity indicative of neutrophil accumulation in the ischemic myocardium. A systemic bolus (i.v.) of aFGF (2.6 microg) administered immediately after myocardial ischemia, significantly reduced (p<0.001) the MPO activity in the ischemic reperfused left ventricle compared to vehicle-treated rats. Furthermore, aFGF significantly attenuated tissue damage and neutrophil accumulation in the area at risk after myocardial ischemia and reperfusion as assessed by conventional histology. The mechanism of this protective effect appears to be related to inhibition of neutrophil extravasation, a critical step in neutrophil-induced myocardial reperfusion injury. Thus, non-mitogenic aFGF appears as an effective cardioprotective treatment for myocardial infarction.

Protective effects of acidic fibroblast growth factor against cardiac arrhythmias induced by ischemia and reperfusion in rats.

An in vivo study has been conducted to evaluate the effect of acidic fibroblast growth factor (aFGF) on cardiac arrhythmias which occur in transient myocardial ischemia followed by reperfusion. In a rat model of myocardial ischemia and reperfusion, cardiac arrhythmias were assessed during the first three minutes of reperfusion. Systemic administration of 2.6 micrograms aFGF just before coronary recirculation resulted in a significant reduction in incidence and severity of ventricular extra beats (VEBs), ventricular tachycardia (VT) and ventricular fibrillation (VF), compared with control rats (VT incidence: 30% vs 80%, VF incidence: 10% vs 40%; episodes of VT: 4.1 +/- 0.34 vs 8.8 +/- 0.95; episodes of VF: 4.8 +/- 0.32 vs 11.5 +/- 1.47). Our results suggest a novel role for FGFs as potential antiarrhythmic agents.

Fibroblast growth factor-1 prevents myocardial apoptosis triggered by ischemia reperfusion injury.

BACKGROUND: Apoptosis is a constant feature of reperfusion injury in ischemic cardiac myocytes, leading to late cell death. Since fibroblast growth factors (FGFs) inhibit apoptosis in differentiated cells, we hypothesized that FGF-1 (acidic FGF), in its native form, and a non-mitogenic isoform would attenuate myocardial ischemia-reperfusion- induced apoptosis. METHODS AND RESULTS: The effect of native and non-mitogenic fibroblast growth factor-1 mutein (FGF-1 and m-FGF-1) on apoptosis assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) method was tested in a rat model of 20 min regional myocardial ischemia and 24h reperfusion. Myocardial ischemia followed by reperfusion resulted in a high myocardial apoptosis rate in the area at risk. When given as a systemic bolus inmediately after myocardial ischemia, both FGF-1 and m-FGF-1 significantly reduced apoptosis (by 60 and 61.2, respectively; p<0.0001). CONCLUSIONS: The programed myocyte cell death triggered by ischemia-reperfusion injury is attenuated by FGF-1 in its native or non mitogenic isoforms, suggesting that this effect does not depend on the mitogenic properties of this protein. FGF-1 would contribute to the functional preservation of the myocardium after acute myocardial infarction.

Correction of hypertension by normalization of endothelial levels of fibroblast growth factor and nitric oxide synthase in spontaneously hypertensive rats.

Acidic and basic fibroblast growth factors (FGFs) share a wide range of diverse biological activities. To date, low levels of FGF have not been correlated with a pathophysiologic state. We report that blood vessels of spontaneously hypertensive rats are shown to be associated with a marked decrement in endothelial basic FGF content. This decrement correlates both with hypertension and with a decrease in the endothelial content of nitric oxide synthase. Restoration of FGF to physiological levels in the vascular wall, either by systemic administration or by in vivo gene transfer, significantly augmented the number of endothelial cells with positive immunostaining for nitric oxide synthase, corrected hypertension, and ameliorated endothelial-dependent responses to vasoconstrictors. These results suggest an important role for FGFs in blood pressure homeostasis and open new avenues for the understanding of the etiology and treatment of hypertension.