Inhibition of endoplasm reticulum stress by ghrelin protects against ischemia/reperfusion injury in rat heart
Introduction
Numerous data have shown that ghrelin, a bioactive peptide with multi-functions, has broad-spectrum cardiovascular protective actions, including reducing heart injury induced by ischemia/reperfusion (I/R) [6], [11] or isoprenaline [7], improving the prognosis of myocardial infarction [34], [36], enhancing cardiac performance [25], ameliorating cardiac cachexia in heart failure [26], vasodilation [16], [24], and blunting vascular calcification [18]. The extensive homeostatic regulatory effect of ghrelin on the cardiovascular system can be attributed to its various beneficial functions in anti-inflammatory [8], [19] and anti-oxidative effects [15], protection of the vascular endothelium [32], [38], inhibition of apoptosis in myocardial and endothelial cells [2], and improvement of myocardial energy metabolism [5], [6]. However, the exact mechanism of ghrelin in cardioprotection needs to be further elucidated.
Endoplasmic reticulum stress (ERS) is a sub-cellular pathological process of misbalance in endoplasmic reticulum (ER) homeostasis and physical function disorder, which can be induced by various pathophysiological stimuli [14]. In the early stages of ERS, a series of signaling pathways are activated, and ER chaperone proteins such as glucose-regulated protein78 (GRP78) and GRP94 are overexpressed to help cells manage the stress; however, when ERS is prolonged and excessive, C/EBP homologous protein (CHOP), caspase-12 (an ERS-specific proapoptotic molecule) and cJUN NH2-terminal kinase (JNK) are activated or upregulated, and the damaged cells undergo ERS-induced apoptosis [3]. ERS, extensively existing during many diseases, is considered an early or initial response of cells under stress or damage.
Previous studies have shown that ERS is involved in the pathogenesis of myocardial ischemia and I/R injury. In cultured cardiomyocytes, hypoxia/reoxygenation-induced injury was accompanied by overexpression of GRP78 protein and mRNA [21]. In isolated perfused rat hearts, GRP78, spliced X-box binding protein1 and phospho-JNK were increased in level with I/R (35/60 min) [31]. As well, myocardial GRP78 and GRP94 were overexpressed in mice hearts ex vivo with I/R (25/120 min) [22]. Serious myocardial ERS was also found in vivo in rats with I/R injury induced by ligation of the left anterior descending coronary artery [20], [35]. In addition, ERS extensively exists in other cardiovascular pathological processes, such as atherosclerosis, ischemic heart disease, cardiomyopathy, and heart failure. In these processes, ERS can cause cell damage and apoptosis while inhibiting or remodeling ERS response pathways may provide cardiovascular protection [39]. Ghrelin is a multi-functional polypeptide with cardiovascular protective effects. However, the relation between the cardiovascular protective effect of ghrelin and ERS has not been investigated.
The purpose of the present study was to verify whether ghrelin protect heart against I/R injury by inhibiting ERS. We studied the effect of ghrelin on myocardial ERS in an ex vivo heart I/R model and observed the direct effect of ghrelin on myocardial ERS in incubated cardiac tissue in vitro. And we found that ghrelin protects heart against I/R injury, at least partially by inhibiting myocardial ERS.
Section snippets
Materials
Male Sprague–Dawley (SD) rats (220 ± 10 g) were obtained from the Animal Center, Health Science Center, Peking University (Beijing, China). All animal care and experimental protocols complied with the Animal Management Rule of the Ministry of Health, People's Republic of China (documentation 55, 2001). Synthetic human ghrelin was produced by Phoenix Pharmaceuticals (Belmont, CA, USA). Dithiothreitol, tunicamycin and bovine serum albumin (BSA) were purchased from Sigma (St. Louis, MO, USA).
Ghrelin ameliorated the ex vivo I/R-induced depressed rat cardiac function
After preperfusion for 10 min (before ischemia), cardiac function parameters and CPF did not significantly differ among the three treatment groups (data not shown). Compared with the control group, the I/R group (40/120 min) showed significantly decreased left-ventricular pressure (ΔLVP, =LVESP − LVEDP, ±LVdp/dtmax, HR and CPF (all P < 0.01)) and significantly increased LVEDP (P < 0.01). Preadministration of ghrelin (in vivo 10−8 mol/kg, i.p. twice) significantly ameliorated the inhibited cardiac
Discussion
The endoplasmic reticulum (ER), one of the largest organelle in cell, plays an important role in the regulation of cellular homeostasis. It is responsible for protein synthesis, modification and processing; new peptide chain-folding, assembly and transportation; biosynthesis of steroids, cholesterol and many lipids; and intracellular calcium regulation [29]. Certain pathological conditions, such as hypoxia, ischemia, adenosine triphosphate depletion, viral infection, treatment with
Acknowledgments
This work was supported by the National Natural Science Foundation of China (30670847) and the State Major Basic Research Development Program of the People's Republic of China (2006CB503807).
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