饱和脂肪酸致大鼠心肌细胞损伤凋亡的机制研究
摘要
糖尿病患者血浆脂质升高的同时，心肌内亦存在脂质蓄积，并伴有心肌细胞凋亡。体外培养也发现饱和脂肪酸可诱导多种细胞出现凋亡。为探讨饱和脂肪酸损伤心肌的机制，本文第一部分使用高脂喂养结合腹腔注射小计量链脲菌素构建2型糖尿病大鼠，观察大鼠脂质代谢紊乱、心肌细胞凋亡、心功能的变化情况，并使用代谢药物左旋卡尼汀进行干预，结果发现，糖尿病大鼠在血浆脂质升高的同时伴有心肌细胞膜上FAT／CD36蛋白含量增加、心肌脂质蓄积、心肌细胞凋亡、心功能受损；L-CN具有显著保护作用。为进一步研究饱和脂肪酸对心肌的损伤作用，本文第二部分使用palmitate处理乳鼠心肌细胞，结果发现palmitate可显著升高细胞凋亡率，CPT-1抑制剂perhexiline可加重palmitate诱导的心肌细胞凋亡，CPT-1辅助因子L-CN可减轻palmitate诱导的心肌细胞凋亡。既往研究发现饱和脂肪酸可诱导胰岛β细胞发生内质网应激，因此本文第三部分初步探讨了内质网应激在palmitate诱导心肌细胞凋亡中的作用，结果发现palmitate可激活心肌细胞多条参与内质网应激的信号通路。
Recently, Lipid accumulation in the heart has been observed under conditions of elevatedplasma free fatty acids, such as Type 2 diabetes mellitus and is linked with cardiomyocyte apoptosis. It isalso found that apoptosis can be induced by saturated fatty acid in cultured cell. In order to study themechanism of myocardial injury by saturated fatty acid, in first part of this study we got type 2 diabetic ratsby HFD-fed and STZ-treated, and observed metabolic disorder, cardiomyocyte apoptosis and heart functionof diabetic rats. At the same time diabetic rats were treated by metabolic drug L-CN. We found that plasmalipid level was increased followed by augment of FAT/CD36 on cardiomyocyte membrane, cardiomyocyteapoptosis, degresion of heart function, and L-CN showed significantly protective effect. For furtherstudying saturated fatty acid induced injury, we cultured neonatal rat cardiomyocytes with palmitate ofdifferent concentration. Significant effect of palmitate induced cardiomyocyte apoptosis was found, whitchcould be aggravated by CPT-1 inhibitor perhexiline and be lessened by CPT-1 cofactor L-CN. Previousstudies show ER stress occurs in palmitate-treated pancreaticβcell, therefore the effect of ER stress inpalmitate-induced cardiomyocyte apoptosis was approached in part 3 of this study. The results indicatedthat ER stress contributed to palmitate-induced cardiomyocyte apoptosis.
Recently, Lipid accumulation in the heart has been observed under conditions of elevatedplasma free fatty acids, such as Type 2 diabetes mellitus and is linked with cardiomyocyte apoptosis. It isalso found that apoptosis can be induced by saturated fatty acid in cultured cell. In order to study themechanism of myocardial injury by saturated fatty acid, in first part of this study we got type 2 diabetic ratsby HFD-fed and STZ-treated, and observed metabolic disorder, cardiomyocyte apoptosis and heart functionof diabetic rats. At the same time diabetic rats were treated by metabolic drug L-CN. We found that plasmalipid level was increased followed by augment of FAT/CD36 on cardiomyocyte membrane, cardiomyocyteapoptosis, degresion of heart function, and L-CN showed significantly protective effect. For furtherstudying saturated fatty acid induced injury, we cultured neonatal rat cardiomyocytes with palmitate ofdifferent concentration. Significant effect of palmitate induced cardiomyocyte apoptosis was found, whitchcould be aggravated by CPT-1 inhibitor perhexiline and be lessened by CPT-1 cofactor L-CN. Previousstudies show ER stress occurs in palmitate-treated pancreaticβcell, therefore the effect of ER stress inpalmitate-induced cardiomyocyte apoptosis was approached in part 3 of this study. The results indicatedthat ER stress contributed to palmitate-induced cardiomyocyte apoptosis.
引文
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2. Hajri T, Abumrad NA. Fatty acid transport across membranes: relevance to nutrition and metabolic pathology. Annu.Rev.Nutr. 2002;22:383-415.
3. Luiken JJ, Dyck DJ, et al. Insulin induces the translocation of the fatty acid transporter FAT/CD36 to the plasma membrane. Am J Physiol Endocrinol Metab 2002;282(2):E491-5.
4. Luiken JJ, Arumugam Y, et al. Increased rates of fatty acid uptake and plasmalemmal fatty acid transporters in obese Zucker rats. J.Biol.Chem. 2001;276(44):40567-40573.
5. Chai W, Liu Z. p38 mitogen-activated protein kinase mediates palmitate-induced apoptosis but not inhibitor of nuclear factor-kappaB degradation in human coronary artery endothelial cells. Endocrinology 2007;148(4):1622-8.
6. Staiger K, Staiger H, et al. Saturated, but not unsaturated, fatty acids induce apoptosis of human coronary artery endothelial cells via nuclear factor-kappaB activation. Diabetes 2006;55(11):3121-6.
7. Hickson-Bick DL, Buja ML, et al. Palmitate-mediated alterations in the fatty acid metabolism of rat neonatal cardiac myocytes. J Mol Cell Cardiol 2000;32(3):511-9.
8. Zarain-Herzberg A, Rupp H. Therapeutic potential of CPT I inhibitors: cardiac gene transcription as a target. Expert Opin Investig Drugs 2002;ll(3):345-56.
9. Cook GA, Edwards TL, et al. Differential regulation of carnitine palmitoyltransferase-I gene isoforms (CPT-I alpha and CPT-I beta) in the rat heart. J Mol Cell Cardiol 2001;33(2):317-29.
10. Jeffrey FM, Alvarez L, et al. Direct evidence that perhexiline modifies myocardial substrate utilization from fatty acids to lactate. J Cardiovasc Pharmacol 1995;25(3):469-72.
11. Fantini E, Demaison L, et al. Some biochemical aspects of the protective effect of trimetazidine on rat cardiomyocytes during hypoxia and reoxygenation. J Mol Cell Cardiol 1994;26(8):949-58.
12. Lopaschuk G Regulation of carbohydrate metabolism in ischemia and reperfusion.Am Heart J 2000;139(2 Pt 3):S115-9.
13. Stein AB, Tang XL, et al. Delayed adaptation of the heart to stress: late preconditioning. Stroke 2004;35(11 Suppl 1):2676-9.
14. Szegezdi E, Duffy A, et al. ER stress contributes to ischemia-induced cardiomyocyte apoptosis. Biochem Biophys Res Commun 2006;349(4):1406-11.
15. Thuerauf DJ, Marcinko M, et al. Activation of the unfolded protein response in infarcted mouse heart and hypoxic cultured cardiac myocytes. Circ Res 2006;99(3):275-82.
16. Karaskov E, Scott C, et al. Chronic palmitate but not oleate exposure induces endoplasmic reticulum stress, which may contribute to INS-1 pancreatic beta-cell apoptosis.Endocrinology 2006;147(7):3398-407.
17. Devereux RB, Roman MJ, et al. Impact of diabetes on cardiac structure and function: the strong heart study. Circulation 2000;101(19):2271-2276.
18. Fonarow GC, Srikanthan P. Diabetic cardiomyopathy. Endocrinol.Metab Clin.North Am. 2006;35(3):575-99, ix.
19. Wijsman JH, Jonker RR, et al. A new method to detect apoptosis in paraffin sections: in situ end-labeling of fragmented DNA. J.Histochem.Cytochem. 1993;41(1):7-12.
20. Dong JW, Zhu HF, et al. Intermittent hypoxia attenuates ischemia/reperfusion induced apoptosis in cardiac myocytes via regulating Bcl-2/Bax expression. Cell Res.2003;13(5):385-391.
21. Bremer J, Woldegiorgis G, et al. Carnitine palmitoyltransferase. Activation by palmitoyl-CoA and inactivation by malonyl-CoA. Biochim.Biophys.Acta 1985;833(1):9-16.
22. Luo J, Quan J, et al. Nongenetic mouse models of non-insulin-dependent diabetes mellitus. Metabolism 1998;47(6):663-668.
23. Ghosh S, Qi D, et al. Brief episode of STZ-induced hyperglycemia produces cardiac abnormalities in rats fed a diet rich in n-6 PUFA. Am J Physiol Heart Circ Physiol 2004;287(6):H2518-27.
24. Storlien LH, James DE, et al. Fat feeding causes widespread in vivo insulin resistance, decreased energy expenditure, and obesity in rats. Am J Physiol 1986;251(5 Pt 1):E576-83.
25. Srinivasan K, Patole PS, et al. Reversal of glucose intolerance by by pioglitazone in high fat diet-fed rats. Methods Find Exp Clin Pharmacol 2004;26(5):327-33.
26. Srinivasan K, Viswanad B, et al. Combination of high-fat diet-fed and low-dose streptozotocin-treated rat: a model for type 2 diabetes and pharmacological screening.Pharmacol.Res. 2005;52(4):313-320.
27. Van der Lee KA, Willemsen PH, et al. Fasting-induced changes in the expression of genes controlling substrate metabolism in the rat heart. J Lipid Res 2001;42(11):1752-8.
28. Brinkmann JF, Abumrad NA, et al. New insights into long-chain fatty acid uptake by heart muscle: a crucial role for fatty acid translocase/CD36. Biochem J 2002;367(Pt 3):561-70.
29. Bonen A, Dyck DJ, et al. Muscle contractile activity increases fatty acid metabolism and transport and FAT/CD36. Am J Physiol 1999;276(4 Pt l):E642-9.
30. Luptak I, Balschi JA, et al. Decreased contractile and metabolic reserve in peroxisome proliferator-activated receptor-alpha-null hearts can be rescued by increasing glucose transport and utilization. Circulation 2005;112(15):2339-46.
31. Barger PM, Kelly DP. Fatty acid utilization in the hypertrophied and failing heart: molecular regulatory mechanisms. Am J Med Sci 1999;318(1):36-42.
32. Finck BN, Lehman JJ, et al. The cardiac phenotype induced by PPARalpha overexpression mimics that caused by diabetes mellitus. J Clin Invest 2002;109(1):121-30.
33.Mann DL. Stress-activated cytokines and the heart: from adaptation to maladaptation.Annu Rev Physiol 2003;65:81-101.
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