Telmisartan protects against microvascular dysfunction during myocardial ischemia/reperfusion injury by activation of peroxisome proliferator-activated receptor gamma

BMC Cardiovascular Disorders

Hong Wen¹  Xing-San Li¹  Xiao-Cong Zeng¹ 

[1] Department of Cardiology, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, People’s Republic of China

关键词: Peroxisome proliferator-activated receptor gamma;    Telmisartan;    Microvascular dysfunction;    Ischemia/reperfusion;   

Others  :  857669
DOI  :  10.1186/1471-2261-13-39

 received in 2013-03-03, accepted in 2013-05-31,  发布年份 2013

【 摘 要 】

Background

We investigated the potential of telmisartan to improve microvascular dysfunction induced by myocardial ischemia/reperfusion (I/R) injury by activating the peroxisome proliferator-activated receptor gamma (PPARG) pathway.

Methods

Forty-eight male rabbits were randomly allocated into sham-operated, I/R, GW9662, telmisartan, telmisartan–GW9662, or candesartan groups. Rabbits were anesthetized, and the left anterior descending coronary artery (LAD) was ligated for 60 minutes. Following reperfusion for 6 hours, angiotensin II content of the heart was determined using radioimmunoassay. Myocardial neutrophil accumulation and microvessel cross-sectional area were examined histologically. Myocardial capillaries were examined with transmission electron microscopy. Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in the myocardium were measured using enzyme-linked immunosorbent assay. Western blot was utilized for investigating the expression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and PPARG.

Results

Angiotensin II concentration was significantly increased in all treatment groups compared with the sham-operated group (P < 0.05, all). Accumulation of polymorphonuclear neutrophils was significantly lower, while microvessel cross-sectional area was significantly higher in the telmisartan, telmisartan-GW9662, and candesartan groups compared with the I/R group (P < 0.05). ICAM-1 and VCAM-1 levels were also significantly lower, and correlated with lower NF-κB expression in these groups. The effects were the most significant in the telmisartan group compared with the telmisartan–GW9662 and candesartan groups. Telmisartan significantly increased PPARG protein expression compared with all other groups (P < 0.05, all).

Conclusions

Except for the typical effects of angiotensin II-receptor blocker, telmisartan improved microvascular dysfunction during myocardial I/R injury via the PPARG pathway.

【 授权许可】

   
2013 Zeng et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 2.

【 参考文献 】

• [1]Antman EM, Hand M, Armstrong PW, Bates ER, Green LA, Halasyamani LK, Hochman JS, Krumholz HM, Lamas GA, Mullany CJ: 2007 focused update of the ACC/AHA 2004 guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2008, 51(2):210-247.
• [2]Stenestrand U, Lindback J, Wallentin L: Long-term outcome of primary percutaneous coronary intervention vs prehospital and in-hospital thrombolysis for patients with ST-elevation myocardial infarction. JAMA 2006, 296(14):1749-1756.
• [3]Eeckhout E, Kern MJ: The coronary no-reflow phenomenon: a review of mechanisms and therapies. Eur Heart J 2001, 22(9):729-739.
• [4]Ramjane K, Han L, Jin C: The diagnosis and treatment of the no-reflow phenomenon in patients with myocardial infarction undergoing percutaneous coronary intervention. Exp Clin Cardiol 2008, 13(3):121-128.
• [5]Abbo KM, Dooris M, Glazier S, O‘Neill WW, Byrd D, Grines CL, Safian RD: Features and outcome of no-reflow after percutaneous coronary intervention. Am J Cardiol 1995, 75(12):778-782.
• [6]Kotani J, Nanto S, Mintz GS, Kitakaze M, Ohara T, Morozumi T, Nagata S, Hori M: Plaque gruel of atheromatous coronary lesion may contribute to the no-reflow phenomenon in patients with acute coronary syndrome. Circulation 2002, 106(13):1672-1677.
• [7]Topol EJ, Yadav JS: Recognition of the importance of embolization in atherosclerotic vascular disease. Circulation 2000, 101(5):570-580.
• [8]Iwakura K, Ito H, Takiuchi S, Taniyama Y, Nakatsuchi Y, Negoro S, Higashino Y, Okamura A, Masuyama T, Hori M: Alternation in the coronary blood flow velocity pattern in patients with no reflow and reperfused acute myocardial infarction. Circulation 1996, 94(6):1269-1275.
• [9]Galiuto L: Optimal therapeutic strategies in the setting of post-infarct no reflow: the need for a pathogenetic classification. Heart 2004, 90(2):123-125.
• [10]Akiyoshi K, Akimitsu T, Hara M, Saikawa T, Yoshimatsu H: AT1 receptor blockade prevents microvascular dysfunction induced by ischemia/reperfusion injury. J Atheroscler Thromb 2006, 13(5):231-239.
• [11]Mersmann J, Tran N, Zacharowski PA, Grotemeyer D, Zacharowski K: Rosiglitazone is cardioprotective in a murine model of myocardial I/R. Shock 2008, 30(1):64-68.
• [12]Yue Tl TL, Chen J, Bao W, Narayanan PK, Bril A, Jiang W, Lysko PG, Gu JL, Boyce R, Zimmerman DM: In vivo myocardial protection from ischemia/reperfusion injury by the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone. Circulation 2001, 104(21):2588-2594.
• [13]Benson SC, Pershadsingh HA, Ho CI, Chittiboyina A, Desai P, Pravenec M, Qi N, Wang J, Avery MA, Kurtz TW: Identification of telmisartan as a unique angiotensin II receptor antagonist with selective PPARgamma-modulating activity. Hypertension 2004, 43(5):993-1002.
• [14]Schupp M, Janke J, Clasen R, Unger T, Kintscher U: Angiotensin type 1 receptor blockers induce peroxisome proliferator-activated receptor-gamma activity. Circulation 2004, 109(17):2054-2057.
• [15]Ikejima H, Imanishi T, Tsujioka H, Kuroi A, Kobayashi K, Shiomi M, Muragaki Y, Mochizuki S, Goto M, Yoshida K: Effects of telmisartan, a unique angiotensin receptor blocker with selective peroxisome proliferator-activated receptor-gamma-modulating activity, on nitric oxide bioavailability and atherosclerotic change. J Hypertens 2008, 26(5):964-972.
• [16]Goyal S, Arora S, Bhatt TK, Das P, Sharma A, Kumari S, Arya DS: Modulation of PPAR-gamma by telmisartan protects the heart against myocardial infarction in experimental diabetes. Chem Biol Interact 2010, 185(3):271-280.
• [17]Zhao ZQ, Nakamura M, Wang NP, Velez DA, Hewan-Lowe KO, Guyton RA, Vinten-Johansen J: Dynamic progression of contractile and endothelial dysfunction and infarct extension in the late phase of reperfusion. J Surg Res 2000, 94(2):133-144.
• [18]Chen LY, Li P, He Q, Jiang LQ, Cui CJ, Xu L, Liu LS: Transgenic study of the function of chymase in heart remodeling. J Hypertens 2002, 20(10):2047-2055.
• [19]Lowry OH, Rosebrough NJ, Farr AL, Randall RJ: Protein measurement with the Folin phenol reagent. J Biol Chem 1951, 193(1):265-275.
• [20]Shishido T, Nozaki N, Yamaguchi S, Shibata Y, Nitobe J, Miyamoto T, Takahashi H, Arimoto T, Maeda K, Yamakawa M: Toll-like receptor-2 modulates ventricular remodeling after myocardial infarction. Circulation 2003, 108(23):2905-2910.
• [21]Dai SD, Zhang XW, Qi FJ, Xu HT, Wang EH: Expression of E-cadherin, beta-catenin and p120ctn in the pulmonary sclerosing hemangioma. Lung Cancer 2007, 57(1):54-59.
• [22]Rutanen J, Rissanen TT, Markkanen JE, Gruchala M, Silvennoinen P, Kivela A, Hedman A, Hedman M, Heikura T, Orden MR: Adenoviral catheter-mediated intramyocardial gene transfer using the mature form of vascular endothelial growth factor-D induces transmural angiogenesis in porcine heart. Circulation 2004, 109(8):1029-1035.
• [23]Zhong JQ, Zhang W, Gao H, Li Y, Zhong M, Li D, Zhang C, Zhang Y: Changes in connexin 43, metalloproteinase and tissue inhibitor of metalloproteinase during tachycardia-induced cardiomyopathy in dogs. Eur J Heart Fail 2007, 9(1):23-29.
• [24]Gu SS, Shi N, Wu MP: The protective effect of ApolipoproteinA-I on myocardial ischemia-reperfusion injury in rats. Life Sci 2007, 81(9):702-709.
• [25]Altavilla D, Saitta A, Guarini S, Galeano M, Squadrito G, Cucinotta D, Santamaria LB, Mazzeo AT, Campo GM, Ferlito M: Oxidative stress causes nuclear factor-kappaB activation in acute hypovolemic hemorrhagic shock. Free Radic Biol Med 2001, 30(10):1055-1066.
• [26]Li L, Su Q, Wang Y, Dai R, Lu Y, Su B, Zhao Y: Effect of atorvastatin (Lipitor) on myocardial apoptosis and caspase-8 activation following coronary microembolization. Cell Biochem Biophys 2011, 61(2):399-406.
• [27]Koda K, Salazar-Rodriguez M, Corti F, Chan NY, Estephan R, Silver RB, Mochly-Rosen D, Levi R: Aldehyde dehydrogenase activation prevents reperfusion arrhythmias by inhibiting local renin release from cardiac mast cells. Circulation 2010, 122(8):771-781.
• [28]Parlakpinar H, Ozer MK, Acet A: Effects of captopril and angiotensin II receptor blockers (AT1, AT2) on myocardial ischemia-reperfusion induced infarct size. Cytokine 2011, 56(3):688-694.
• [29]Muller DN, Dechend R, Mervaala EM, Park JK, Schmidt F, Fiebeler A, Theuer J, Breu V, Ganten D, Haller H: NF-kappaB inhibition ameliorates angiotensin II-induced inflammatory damage in rats. Hypertension 2000, 35(1 Pt 2):193-201.
• [30]Blake GJ, Ridker PM: Inflammatory bio-markers and cardiovascular risk prediction. J Intern Med 2002, 252(4):283-294.
• [31]Moens AL, Claeys MJ, Timmermans JP, Vrints CJ: Myocardial ischemia/reperfusion-injury, a clinical view on a complex pathophysiological process. Int J Cardiol 2005, 100(2):179-190.
• [32]Kang S, Yang Y: Coronary microvascular reperfusion injury and no-reflow in acute myocardial infarction. Clin Invest Med 2007, 30(3):E133-E145.
• [33]Sheridan FM, Dauber IM, McMurtry IF, Lesnefsky EJ, Horwitz LD: Role of leukocytes in coronary vascular endothelial injury due to ischemia and reperfusion. Circ Res 1991, 69(6):1566-1574.
• [34]Reffelmann T, Kloner RA: The no-reflow phenomenon: A basic mechanism of myocardial ischemia and reperfusion. Basic Res Cardiol 2006, 101(5):359-372.
• [35]Jugdutt BI, Idikio H, Uwiera RR: Angiotensin receptor blockade and angiotensin-converting-enzyme inhibition limit adverse remodeling of infarct zone collagens and global diastolic dysfunction during healing after reperfused ST-elevation myocardial infarction. Mol Cell Biochem 2007, 303(1–2):27-38.
• [36]Jugdutt BI, Menon V: AT1 receptor blockade limits myocardial injury and upregulates AT2 receptors during reperfused myocardial infarction. Mol Cell Biochem 2004, 260(1–2):111-118.
• [37]Hu T, Wang HC, Wang RT, Lv AL, Luan RH, Li CX, Cheng HX, Xia CH, Tao L: Effect of chronic pretreatment of angiotensin-converting receptor blocker on No-reflow phenomenon in patients with acute myocardial infarction undergoing percutaneous coronary intervention. Cardiovasc Ther 2013, 31(3):e7-e11.
• [38]Zhao Y, Foryst-Ludwig A, Bruemmer D, Culman J, Bader M, Unger T, Kintscher U: Angiotensin II induces peroxisome proliferator-activated receptor gamma in PC12W cells via angiotensin type 2 receptor activation. J Neurochem 2005, 94(5):1395-1401.
• [39]Jalowy A, Schulz R, Dorge H, Behrends M, Heusch G: Infarct size reduction by AT1-receptor blockade through a signal cascade of AT2-receptor activation, bradykinin and prostaglandins in pigs. J Am Coll Cardiol 1998, 32(6):1787-1796.
• [40]Unger T: Pharmacology of AT1-receptor blockers. Blood Press Suppl 2001, 3:5-10.