Bromelain induces cardioprotection against ischemia-reperfusion injury through Akt/FOXO pathway in rat myocardium

Abstract

Thrall RS, Maulik N. Bromelain induces cardioprotection against ischemia-reperfusion injury through Akt/FOXO pathway in rat myocardium. Am J Physiol Heart Circ Physiol 294: H1365-H1370, 2008. First published January 11, 2008 doi:10.1152/ajpheart.01005.2007, a proteolytic enzyme extracted from the stem of the pineapple, is known to possess anti-inflammatory activity and has been shown to reduce blood viscosity, prevent the aggregation of blood platelets, and improve ischemia-reperfusion (I/R) injury in a skeletal muscle model. We investigated the capacity of Br to limit myocardial injury in a global I/R model. Adult male Sprague-Dawley rats were divided into two groups: control (PBS) and Br at 10 mg/kg in PBS administered via intraperitoneal injection (twice/day) for 15 consecutive days. On day 16, the hearts were excised and subjected to 30 min of global ischemia followed by 2 h of reperfusion. Br treatment showed higher left ventricular functional recovery throughout reperfusion compared with the controls [maximum rate of rise in intraventricular pressure (dP/dt max), 2,225 vs. 1,578 mmHg/s at 2 h reperfusion]. Aortic flow was also found to be increased in Br treatment when compared with that in untreated rats (11 vs. 1 ml). Furthermore, Br treatment reduced both the infarct size (34% vs. 43%) and the degree of apoptosis (28% vs. 37%) compared with the control animals. Western blot analysis showed an increased phosphorylation of both Akt and FOXO3A in the treatment group compared with the control. These results demonstrated for the first time that Br triggers an Akt-dependent survival pathway in the heart, revealing a novel mechanism of cardioprotective action and a potential therapeutic target against I/R injury. apoptosis; myocardial infarction; Ananas comosus; forkhead transcription factor MYOCARDIAL ISCHEMIA-REPERFUSION (I/R) injury occurs in a wide spectrum of disorders ranging from cardiac arrest to acute myocardial infarction and represents a major public health concern. Ischemia induces several pathological changes due to lack of oxygen supply to the myocardium (16), and postischemic reperfusion worsens the injury. Modulation of the adaptive response to ischemic heart disease has become a major research interest. Pharmacological preconditioning plays a prominent role in reducing such tissue damage in response to I/R injury. In this respect, bromelain (Br), which is a descriptor for a family of sulfhydryl proteolytic enzymes extracted from the stem of Ananas comosus, the common pineapple plant (13, 23), has shown promise. Br is composed of several distinct cysteine proteolytic fractions ranging in size from 15 to 27 kDa and is commonly delivered as a powder in a gelatin or enteric-coated capsule. Reports suggest that oral administration of Br inhibits time-dependent thrombus formation in a laser thrombosis model and reduces human platelet aggregation both in vitro and in vivo (10). Br, when combined with rutin and trypsin, was also shown to have a protective effect on the skeletal muscle during I/R inju...

The role of E2F-1 and downstream target genes in mediating ischemia/reperfusion injury in vivo

“…For instance, they are substrates of Akt and have been implicated as negative regulators of cardiac hypertrophic growth [17,37]. However, cardioprotective signals that activate Akt-dependent survival pathways in the heart also result in enhanced phosphorylation and inactivation of FoxOs suggesting an important role in I/R injury [38]. Interestingly, CDK-2 is known to phosphorylate FoxO-1a during apoptosis [39], further linking growth pathways to the control of cell survival.…”

Bromelain: Methods of Extraction, Purification and Therapeutic Applications

“…Bromelain results in enhanced phosphorylation of Akt which causes inhibition of apoptotic cell death (Juhasz et al 2008). Bromelain inhibits clumping of platelets and also put a stop to thrombus formation (Metzag et al 1999;Bhatacharia 2008).…”

FGF-2 Transcriptionally Down-Regulates the Expression of BNIP3L via PI3K/Akt/FoxO3a Signaling and Inhibits Necrosis and Mitochondrial Dysfunction Induced by High Concentrations of Hydrogen Peroxide in H9c2 Cells

“…The FoxO3a transcription factor is one of the most important downstream targets of PI3K/Akt signaling and a crucial regulator of apoptosis [18,[31][32][33]. Sodium tanshinone IIA sulfonate [34] and bromelain [35] were reported to protect rat hearts from ischemia-reperfusion injury through activation of the PI3K/Akt/FoxO3a pathway. However, the roles of FGF-2 and the PI3K/AKT/FoxO3a signaling pathway in ROS-induced necrosis are not clear.…”