Published online before print June 23, 2003, doi: 10.1161/01.CIR.0000074225.62168.68
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2003;108:104.)
© 2003 American Heart Association, Inc.
Basic Science Reports |
Inhibition of Granulation Tissue Cell Apoptosis During the Subacute Stage of Myocardial Infarction Improves Cardiac Remodeling and Dysfunction at the Chronic Stage
From the Second Department of Internal Medicine, Gifu University School of Medicine, Gifu, Japan; and the Department of Food Science (T.F.), Kyoto Women’s University, Kyoto, Japan.
Correspondence to Hisayoshi Fujiwara, MD, PhD, Second Department of Internal Medicine, Gifu University School of Medicine, 40 Tsukasa-Machi, Gifu 500-8705, Japan. E-mail gifuim-gif{at}umin.ac.jp
Background— Granulation tissue cells at the subacute stage of myocardial infarction (MI) are eliminated by apoptosis to finally make a scar at the chronic stage. We hypothesized that postinfarct inhibition of apoptosis might preserve myofibroblasts and endothelial cells in granulation and modulate chronic left ventricular (LV) remodeling and heart failure.
Methods and Results— A pancaspase inhibitor, Boc-Asp-fmk (BAF, 10 µmol/kg per day), or vehicle (control) was given to rats with experimental large MI. The treatment was started on the third day after MI and continued until 4-week-old MI. Two weeks later, the apoptosis of granulation tissue cells was significantly reduced and conversely, the cell population was greater in BAF. Twelve weeks later, BAF showed significantly greater survival rates (84% versus 42%) with significantly smaller LV cavity, lower LV end-diastolic pressure and central venous pressure, and higher LV dP/dt, which indicated improvement of LV remodeling and dysfunction. A scar was established in old infarct of control subjects, but in BAF, the infarct wall was thicker because of greater old infarct area, which contained abundant myofibroblasts and vessels. Surprisingly, many of the 
-smooth muscle actin–positive myofibroblast-like cells in BAF, making bundles and running parallel to the survived cardiomyocytes, were ultrastructurally mature smooth muscle cells with contractile phenotype. Cardiomyocyte apoptosis in the infarct area was equally rare in each group.
Conclusions— The postinfarct treatment with BAF improved LV remodeling and dysfunction through inhibition of granulation tissue cell apoptosis. These findings imply a new therapeutic strategy against postinfarct heart failure.
Key Words: apopstosis • heart failure • myocardial infarction • remodeling
This article has been cited by other articles:
 |
|
 |
|
  G. Takemura, M. Nakagawa, H. Kanamori, S. Minatoguchi, and H. Fujiwara Benefits of reperfusion beyond infarct size limitation Cardiovasc Res, July 15, 2009; 83(2): 269 - 276. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Okada, G. Takemura, K.-i. Kosai, A. Tsujimoto, M. Esaki, T. Takahashi, S. Nagano, H. Kanamori, S. Miyata, Y. Li, et al. Combined therapy with cardioprotective cytokine administration and antiapoptotic gene transfer in postinfarction heart failure Am J Physiol Heart Circ Physiol, March 1, 2009; 296(3): H616 - H626. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Abbate, G. G. L. Biondi-Zoccai, B. W. Van Tassell, and A. Baldi Cellular preservation therapy in acute myocardial infarction Am J Physiol Heart Circ Physiol, March 1, 2009; 296(3): H563 - H565. [Full Text] [PDF]
|
|
|
|
 |
|
 M. Nakagawa, G. Takemura, H. Kanamori, K. Goto, R. Maruyama, A. Tsujimoto, T. Ohno, H. Okada, A. Ogino, M. Esaki, et al. Mechanisms by Which Late Coronary Reperfusion Mitigates Postinfarction Cardiac Remodeling Circ. Res., July 3, 2008; 103(1): 98 - 106. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. D. Abel, S. E. Litwin, and G. Sweeney Cardiac Remodeling in Obesity Physiol Rev, April 1, 2008; 88(2): 389 - 419. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Sanchis, M. Llovera, M. Ballester, and J. X. Comella An alternative view of apoptosis in heart development and disease Cardiovasc Res, February 1, 2008; 77(3): 448 - 451. [Full Text] [PDF]
|
|
|
|
 |
|
 V. El-Helou, C. Proulx, H. Gosselin, R. Clement, A. Mimee, L. Villeneuve, and A. Calderone Dexamethasone treatment of post-MI rats attenuates sympathetic innervation of the infarct region J Appl Physiol, January 1, 2008; 104(1): 150 - 156. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Ogino, G. Takemura, H. Kanamori, H. Okada, R. Maruyama, S. Miyata, M. Esaki, M. Nakagawa, T. Aoyama, H. Ushikoshi, et al. Amlodipine inhibits granulation tissue cell apoptosis through reducing calcineurin activity to attenuate postinfarction cardiac remodeling Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2271 - H2280. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Cimini, S. Fazel, S. Zhuo, M. Xaymardan, H. Fujii, R. D. Weisel, and R.-K. Li c-Kit Dysfunction Impairs Myocardial Healing After Infarction Circulation, September 11, 2007; 116(11_suppl): I-77 - I-82. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. L. Fujimoto, K. Tobita, W. D. Merryman, J. Guan, N. Momoi, D. B. Stolz, M. S. Sacks, B. B. Keller, and W. R. Wagner An Elastic, Biodegradable Cardiac Patch Induces Contractile Smooth Muscle and Improves Cardiac Remodeling and Function in Subacute Myocardial Infarction J. Am. Coll. Cardiol., June 12, 2007; 49(23): 2292 - 2300. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Kanamori, G. Takemura, Y. Li, H. Okada, R. Maruyama, T. Aoyama, S. Miyata, M. Esaki, A. Ogino, M. Nakagawa, et al. Inhibition of Fas-associated apoptosis in granulation tissue cells accompanies attenuation of postinfarction left ventricular remodeling by olmesartan Am J Physiol Heart Circ Physiol, May 1, 2007; 292(5): H2184 - H2194. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Khoynezhad Promising aspects and caveats of studies on anti-apoptotic therapies in patients with heart failure Eur J Heart Fail, February 1, 2007; 9(2): 120 - 123. [Full Text] [PDF]
|
|
|
|
 |
|
 J.-Y. Hahn, H.-J. Cho, J.-W. Bae, H.-S. Yuk, K.-i. Kim, K.-W. Park, B.-K. Koo, I.-H. Chae, C.-S. Shin, B.-H. Oh, et al. beta-Catenin Overexpression Reduces Myocardial Infarct Size through Differential Effects on Cardiomyocytes and Cardiac Fibroblasts J. Biol. Chem., October 13, 2006; 281(41): 30979 - 30989. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Roy, S. Khanna, D. E. Kuhn, C. Rink, W. T. Williams, J. L. Zweier, and C. K. Sen Transcriptome analysis of the ischemia-reperfused remodeling myocardium: temporal changes in inflammation and extracellular matrix Physiol Genomics, May 16, 2006; 25(3): 364 - 374. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. A. Mareninova, K.-F. Sung, P. Hong, A. Lugea, S. J. Pandol, I. Gukovsky, and A. S. Gukovskaya Cell Death in Pancreatitis: CASPASES PROTECT FROM NECROTIZING PANCREATITIS J. Biol. Chem., February 10, 2006; 281(6): 3370 - 3381. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Okada, G. Takemura, K.-i. Kosai, Y. Li, T. Takahashi, M. Esaki, K. Yuge, S. Miyata, R. Maruyama, A. Mikami, et al. Postinfarction Gene Therapy Against Transforming Growth Factor-{beta} Signal Modulates Infarct Tissue Dynamics and Attenuates Left Ventricular Remodeling and Heart Failure Circulation, May 17, 2005; 111(19): 2430 - 2437. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. von Harsdorf "Fas-ten" Your Seat Belt: Anti-apoptotic Treatment in Heart Failure Takes Off Circ. Res., September 17, 2004; 95(6): 554 - 556. [Full Text] [PDF]
|
|
|
|
|
|
Y. Li, G. Takemura, K.-i. Kosai, T. Takahashi, H. Okada, S. Miyata, K. Yuge, S. Nagano, M. Esaki, N. C. Khai, et al. Critical Roles for the Fas/Fas Ligand System in Postinfarction Ventricular Remodeling and Heart Failure Circ. Res., September 17, 2004; 95(6): 627 - 636. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Chandrashekhar, S. Sen, R. Anway, A. Shuros, and I. Anand Long-Term caspase inhibition ameliorates apoptosis, reduces myocardial troponin-I cleavage, protects left ventricular function, and attenuates remodeling in rats with myocardial infarction J. Am. Coll. Cardiol., January 21, 2004; 43(2): 295 - 301. [Abstract] [Full Text] [PDF]
|
|