© 2004 by European Society of Cardiology
Copyright © 2004, European Society of Cardiology
Anti-apoptotic effects of rosiglitazone in hypercholesterolemic rabbits subjected to myocardial ischemia and reperfusion
Department of Emergency Medicine, Thomas Jefferson University, 1020 Sansom Street, Thompson Building, Room 241, Philadelphia, PA 19107, USA
* Corresponding authors. Tel.: +1-215-955-4994; fax: +1-215-503-4458. or: Tel.: +1-610-270-5313; fax: +1-610-270-5080. Email address: tian-li.yue{at}gsk.com xin.ma{at}jefferson.edu
Objectives: This study examined the effects of diet-induced hypercholesterolemia on the extent of postischemic myocyte apoptosis and elucidated the potential mechanisms involved. Furthermore, the effects of rosiglitazone (RSG) on postischemic myocardial apoptosis in HC rabbits were investigated. Methods: Male New Zealand rabbits were fed normal or high cholesterol diets for 8 weeks. Three weeks after being fed a high cholesterol diet, HC rabbits were randomized to receive vehicle or RSG during the remaining 5 weeks. Rabbits were then subjected to 60 min of coronary occlusion followed by 4 h of reperfusion. Results: Compared with rabbits fed with a normal diet, HC rabbits had increased caspase-3 activity, apoptotic cell death and retarded contractile function recovery after reperfusion. HC increased iNOS expression, total NOx and nitrotyrosine contents, indicating that an increased nitrative stress occurred in HC myocardial tissue. Activity of a hypertrophic/anti-apoptotic mitogen-activated protein kinase (MAPK), ERK1/2, was significantly decreased while activation of a pro-apoptotic MAPK, p38, was increased. Treatment with RSG in HC rabbits attenuated postischemic myocardial nitrative stress, restored a beneficial balance between pro- and anti-apoptotic MAPK signaling, reduced postischemic myocardial apoptosis, and improved cardiac functional recovery. Conclusions: Our results demonstrated that HC increased postischemic myocardial apoptosis likely by increasing the production of pro-apoptotic molecules, activating pro-apoptotic signaling pathways and inhibiting anti-apoptotic signaling. In addition, our results suggest that peroxisome proliferator-activated receptor (PPAR) 
agonists may not only attenuate the formation of atherosclerosis associated with hypercholesterolemia as previously reported, but may also protect the heart from subsequent ischemic/reperfusion-induced myocardial apoptosis.
KEYWORDS Hypercholesterolemia; Reperfusion injury; Nitric oxide
1 GlaxoSmithKline Pharmaceuticals, King of Prussia, PA.
Time for primary review 24 days
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  L. Tao, Y. Wang, E. Gao, H. Zhang, Y. Yuan, W. B. Lau, L. Chan, W. J. Koch, and X. L. Ma Adiponectin: An Indispensable Molecule in Rosiglitazone Cardioprotection Following Myocardial Infarction Circ. Res., February 5, 2010; 106(2): 409 - 417. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H.-R. Liu, L. Tao, E. Gao, Y. Qu, W. B. Lau, B. L. Lopez, T. A. Christopher, W. Koch, T.-L. Yue, and X.-L. Ma Rosiglitazone inhibits hypercholesterolaemia-induced myeloperoxidase upregulation--a novel mechanism for the cardioprotective effects of PPAR agonists Cardiovasc Res, February 1, 2009; 81(2): 344 - 352. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. J. H. Smeets, B. E. J. Teunissen, A. Planavila, H. de Vogel-van den Bosch, P. H. M. Willemsen, G. J. van der Vusse, and M. van Bilsen Inflammatory Pathways Are Activated during Cardiomyocyte Hypertrophy and Attenuated by Peroxisome Proliferator-activated Receptors PPAR{alpha} and PPAR{delta} J. Biol. Chem., October 24, 2008; 283(43): 29109 - 29118. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Chintalgattu, G. S. Harris, S. M. Akula, and L. C. Katwa PPAR-{gamma} agonists induce the expression of VEGF and its receptors in cultured cardiac myofibroblasts Cardiovasc Res, April 1, 2007; 74(1): 140 - 150. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Subramanian, P. Krishnamurthy, K. Singh, and M. Singh Lack of osteopontin improves cardiac function in streptozotocin-induced diabetic mice Am J Physiol Heart Circ Physiol, January 1, 2007; 292(1): H673 - H683. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. B Patle, J. A De Lemos, K. L Wyne, and D. K McGuire Thiazolidinediones and risk for atherosclerosis: pleiotropic effects of PPAR{gamma} agonism Diabetes and Vascular Disease Research, September 1, 2006; 3(2): 65 - 71. [Abstract] [PDF]
|
|
|
|
 |
|
 Y. Taniguchi, T. Ooie, N. Takahashi, T. Shinohara, M. Nakagawa, H. Yonemochi, M. Hara, H. Yoshimatsu, and T. Saikawa Pioglitazone but not glibenclamide improves cardiac expression of heat shock protein 72 and tolerance against ischemia/reperfusion injury in the heredity insulin-resistant rat. Diabetes, August 1, 2006; 55(8): 2371 - 2378. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Pesant, S. Sueur, P. Dutartre, M. Tallandier, P. A. Grimaldi, L. Rochette, and J.-L. Connat Peroxisome proliferator-activated receptor {delta} (PPAR{delta}) activation protects H9c2 cardiomyoblasts from oxidative stress-induced apoptosis Cardiovasc Res, February 1, 2006; 69(2): 440 - 449. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Lautamaki, K.E. J. Airaksinen, M. Seppanen, J. Toikka, M. Luotolahti, E. Ball, R. Borra, R. Harkonen, P. Iozzo, M. Stewart, et al. Rosiglitazone Improves Myocardial Glucose Uptake in Patients With Type 2 Diabetes and Coronary Artery Disease: A 16-Week Randomized, Double-Blind, Placebo-Controlled Study Diabetes, September 1, 2005; 54(9): 2787 - 2794. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Tao, H.-R. Liu, F. Gao, Y. Qu, T. A. Christopher, B. L. Lopez, and X. L. Ma Mechanical traumatic injury without circulatory shock causes cardiomyocyte apoptosis: role of reactive nitrogen and reactive oxygen species Am J Physiol Heart Circ Physiol, June 1, 2005; 288(6): H2811 - H2818. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Patel, K. L Wyne, and D. K McGuire Thiazolidinediones, peripheral oedema and congestive heart failure: what is the evidence? Diabetes and Vascular Disease Research, May 1, 2005; 2(2): 61 - 66. [Abstract] [PDF]
|
|
|
|
 |
|
 A. Sivarajah, M. C. McDonald, and C. Thiemermann The Cardioprotective Effects of Preconditioning with Endotoxin, but Not Ischemia, Are Abolished by a Peroxisome Proliferator-Activated Receptor-{gamma} Antagonist J. Pharmacol. Exp. Ther., May 1, 2005; 313(2): 896 - 901. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Abdelrahman, A. Sivarajah, and C. Thiemermann Beneficial effects of PPAR-{gamma} ligands in ischemia-reperfusion injury, inflammation and shock Cardiovasc Res, March 1, 2005; 65(4): 772 - 781. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H.-R. Liu, E. Gao, A. Hu, L. Tao, Y. Qu, P. Most, W. J. Koch, T. A. Christopher, B. L. Lopez, E. S. Alnemri, et al. Role of Omi/HtrA2 in Apoptotic Cell Death After Myocardial Ischemia and Reperfusion Circulation, January 4, 2005; 111(1): 90 - 96. [Abstract] [Full Text] [PDF]
|
|