Mechanism and consequences of the shift in cardiac arginine metabolism following ischaemia and reperfusion in rats

Summary

Cardiac ischaemia and reperfusion leads to irreversible injury and subsequent tissue remodelling. Initial reperfusion seems to shift arginine metabolism from nitric oxide (NO) to polyamine formation. This may limit functional recovery at reperfusion. The hypothesis was tested whether ischaemia/reperfusion translates such a shift in arginine metabolism in a tumour necrosis factor (TNF)-α-dependent way and renin-angiotensin system (RAS)-dependent way into a sustained effect. Both, the early post-ischaemic recovery and molecular adaptation to ischaemia/reperfusion were analysed in saline perfused rat hearts undergoing global no-flow ischaemia and reperfusion. Local TNF-α activation was blocked by inhibition of TNF-α sheddase ADAM17. To interfere with RAS captopril was administered. Arginase was inhibited by administration of Nor-NOHA. Long-term effects of ischemia/reperfusion on arginine metabolism were analysed in vivo in rats receiving an established ischaemia/reperfusion protocol in the closed chest mode. mRNA expression analysis indicated a shift in the arginine metabolism from NO formation to polyamine metabolism starting within 2 hours (h) of reperfusion and translated into protein expression within 24 h. Inhibition of the TNF-α pathway and captopril attenuated these delayed effects on post-ischaemic recovery. This shift in arginine metabolism was associated with functional impairment of hearts within 24 h. Inhibition of arginase but not that of TNF-α and RAS pathways improved functional recovery immediately. However, no benefit was observed after four months. In conclusion, this study identified TNF-α and RAS to be responsible for depressed cardiac function that occurred a few hours after reperfusion.

^* These authors contributed equally to the study.

• References

• 1 Goel K, Pinto DS, Gibson M. Association of time to reperfusion with left ventricular function and heart failure in patients with acute myocardial infarction treated with primary percutaneous coronary intervention: A systematic review. Am Heart J 2013; 165: 451-467.
• 2 Brodie BR, Stone GW, Cox DA. et al. Impact of treatment delays on outcomes of primary percutaneous coronary intervention for acute myocardial infarction: Analysis from the CADILLAC trial. Am Heart J 2006; 151: 1231-1238.
• 3 Schoemaker RG, Debets JJM, Struyker-Boudier HAJ. et al. Delayed but not immediate captopril therapy improves cardiac function in conscious rats, following myocardial infarction. J Mol Cell Cardiol 1991; 23: 187-197.
• 4 Litwin SE, Litwin CM, Raya TE. et al. Contractility and stiffness of noninfarcted myocardium after coronary ligation in rats. Effects of chronic angiotensin converting enzyme inhibition. Circulation 1991; 83: 1028-1037.
• 5 Pfeffer MA, Pfeffer JM, Steinberg C. et al. Survival after an experimental myocardial infarction: beneficial effects of long-term therapy with captopril. Circulation 1985; 72: 406-412.
• 6 Youn TJ, Kim HS, Oh BH. Ventricular remodelling and transforming growth factor-beta 1 mRNA expression after nontransmural myocardial infarction in rats: effects of angiotensin converting enzyme inhibition and angiotensin II type 1 receptor blockade. Basic Res Cardiol 1999; 94: 246-253.
• 7 Kingma JH, van Gilst WH, Peels CH. et al. Acute intervention with captopril during thrombolysis in patients with first anterior myocardial infarction. Eur Heart J 1994; 15: 898-907.
• 8 Divisova J, Vavrinkova H, Tutterova M. et al. Effect of ACE inhibitor captopril and L-arginine on the metabolism and on ischaemia-reperfusion injury of the isolated rat heart. Physiol Res 2001; 50: 143-152.
• 9 Jugdutt BI. Nitric oxide and cardioprotection during ischaemia-reperfusion. Heart Failure Reviews 2002; 7: 391-405.
• 10 Ferdinandy P, Schulz R. Nitric oxide, superoxide, and peroxynitrite in myocardial ischaemia-reperfusion injury and preconditioning. Br J Pharmacol 2003; 138: 532-543.
• 11 Csonka C, Szilvássy Z, Fülöp F. et al. Classic preconditioning decreases the harmful accumulation of nitric oxide during ischaemia and reperfusion in rat hearts. Circulation 1999; 100: 2260-2266.
• 12 Hein TW, Zhang C, Wang W. et al. Ischaemia-reperfusion selectively impairs nitric oxide-mediated dilation in coronary arterioles: counteracting role of arginase. FASEB J. 2003 doi 10.1096/fj.03-0115fje.
• 13 Sodha NR, Boodhwani M, Clements RT. et al. Coronary microvascular dysfunction in the setting of chronic ischaemia is independent of arginase activity. Microvascular Res 2008; 75: 238-146.
• 14 Tabor CW, Tabor H. 1, 4-Diaminobutane (putrescine), spermidine, spermine. Ann Rev Biochem 1976; 45: 285-306.
• 15 Giordano E, Flamigni F, Guarnieri C. et al. Poylamines in cardiac physiology and disease. Open Heart Failure Journal 2010; 3: 25-30.
• 16 Schlüter K-D, Frischkopf K, Flesch M. et al. Central role for ornithine decarboxylase in β-adrenoceptor mediated hypertrophy. Cardiovasc Res 2000; 45: 410-417.
• 17 Shimizu M, Irimajiri O, Nkano T, et al. Yamada H, Sasaki H, Isogai Y. Effect of captopril on isoproterenol-induced myocardial ornithine decarboxylase activity. J Mol Cell Cardiol 1991; 23: 665-670.
• 18 Jung C, Gonon AT, Sjoquist PO. et al. Arginase inhibition mediates cardiac protection during ischaemia-reperfusion. Cardiovasc Res 2010; 85: 147-154.
• 19 Fischer S, Grantzow T, Pagel JI. et al. Extracellular RNA promotes leukocyte recruitment in the vascular system by mobilising proinflammatory cytokines. Thromb Haemost11 2012; 108: 730-741.
• 20 Harpster MH, Bandyopadhyay S, Thomas P. et al. Earliest changes in the left ventricular transcriptosome post-myocardial infarction. Mammalian Genome 2006; 17: 701-715.
• 21 Gao X, Xu X, Belmadini S. et al. TNF-α contributes to endothelial dysfunction by upregulating arginase in ischaemia/reperfusion injury. Arterioscler Thromb Vasc Biol 2007; 27: 1269-1275.
• 22 Zhang C, Wu J, Xu X, et al. Potter BJ, Gao X. Direct relationship between levels of TNF-α expression and endothelial dysfunction in reperfusion injury. Basic Res Cardiol 2010; 105: 453-464.
• 23 Frascarelli S, Ghelardoni S, Ronca-Tzestoni S. et al. Cardioprotective effect of zofenopril in perfused rat hearts subjected to ischaemia and reperfusion. J Cardiovasc Pharmacol 2004; 43: 294-299.
• 24 Bencsik P, Kupai K, Giricz Z. et al. Role of iNOS and peroxynitrite-matrix metalloproteinase-2 signalling in myocardial late preconditioning in rats. Am J Physiol Heart Circ Physiol 2010; 299: H512-H518.
• 25 Da Costa Rebelo RM, Schreckenberg R, Schlüter K-D.. Adverse cardiac remodelling in spontaneously hypertensive rats: acceleration by high aerobic exercise intensity. J Physiol 2012; 590: 5389-5400.
• 26 Kocsis GF, Sárkøzy M, Bencsik P. et al. Preconditioning protects the heart in a prolonged uremic condition. Am J Physiol Heart Circ Physiol 2012; 303: H1229-1236.
• 27 Livak KJ, Schmittgen TD. Analysis of relative gene expression data using realtime quantitative PCR and the 2(-AACT). Methods 2001; 25: 402-408.
• 28 Maxeiner H, Krehbiel N, Müller A. et al. New insights into paracrine mechanisms of human cardiac progenitor cells. Eur J Heart Fail 2010; 12: 730-737.
• 29 Canton M, Skyschally A, Menabo R. et al. Oxidative modification of tropomyosin and myocardial dysfunction following coronary microembolisation. Eur Heart J 2006; 27: 875-881.
• 30 Deignan JL, Livesay JC, Shantz LM. et al. Polyamine homeostasis in arginase knockout mice. Am J Physiol Cell Physiol 2007; 293: C1296-C1301.
• 31 Flesch M, Höper A, Dell’Italia L. et al. Activation and functional significance of the renin-angiotensin system in mice with cardiac restricted overexpression of tumor necrosis factor. Circulation 2003; 108: 598-604.
• 32 Mörlein C, Schreckenberg R, Schlüter K-D.. Basal ornithine decarboxylase activity modifies apoptotic and hypertrophic marker expression in post-ischaemic hearts. Open Heart Failure J 2010; 3: 31-37