Novel mechanisms for caspase inhibition protecting cardiac function with chronic pressure overload

被引:19
作者
Park, Misun [1 ]
Vatner, Stephen F. [1 ]
Yan, Lin [1 ]
Gao, Shumin [1 ]
Yoon, Seunghun [1 ]
Lee, Grace Jung Ah [1 ]
Xie, Lai-Hua [1 ]
Kitsis, Richard N. [2 ]
Vatner, Dorothy E. [3 ]
机构
[1] Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Cell Biol & Mol Med, Cardiovasc Res Inst, Newark, NJ 07103 USA
[2] Albert Einstein Coll Med, Cardiovasc Res Inst, Dept Med & Cell Biol, Bronx, NY 10467 USA
[3] Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Med, Newark, NJ 07103 USA
基金
美国国家卫生研究院;
关键词
Apoptosis inhibition; Cardiac hypertrophy; Fibrosis; Angiogenesis; Myogenesis; LEFT-VENTRICULAR HYPERTROPHY; HEART-FAILURE; MYOCYTE APOPTOSIS; CARDIOMYOCYTE PROLIFERATION; MICE; FIBROSIS; RATS; TRANSITION; INFARCTION; CONNEXIN43;
D O I
10.1007/s00395-012-0324-y
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Myocyte apoptosis is considered a major mechanism in the pathogenesis of heart failure. Accordingly, manipulations that inhibit apoptosis are assumed to preserve cardiac function by maintaining myocyte numbers. We tested this assumption by examining the effects of caspase inhibition (CI) on cardiac structure and function in C57BL/6 mouse with pressure overload model induced by transverse aortic constriction (TAC). CI preserved left ventricular (LV) function following TAC compared with the vehicle. TAC increased apoptosis in non-myocytes more than in myocytes and these increases were blunted more in non-myocytes by CI. Total myocyte number, however, did not differ significantly among control and TAC groups and there was no correlation between myocyte number and apoptosis, but there was a strong correlation between myocyte number and an index of myocyte proliferation, Ki67-positive myocytes. Despite comparable pressure gradients, LV hypertrophy was less in the CI group, likely attributable to decreased wall stress. Since changes in myocyte numbers did not account for protection from TAC, several other CI-mediated mechanisms were identified including: (a) lessening of TAC-induced fibrosis, (b) augmentation of isolated myocyte contractility, and (c) increased angiogenesis and Ki67-positive myocytes, which were due almost entirely to the non-myocyte apoptosis, but not myocyte apoptosis, with CI. CI maintained LV function following TAC not by protecting against myocyte loss, but rather by augmenting myocyte contractile function, myocyte proliferation, and angiogenesis resulting in reduced LV wall stress, hypertrophy, and fibrosis.
引用
收藏
页数:13
相关论文
共 33 条
[1]   The possible role of caspase-3 in pathological and physiological cardiac hypertrophy in rats [J].
Balakumar, Pitchai ;
Singh, Manjeet .
BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY, 2006, 99 (06) :418-424
[2]   Long-term caspase inhibition ameliorates apoptosis, reduces myocardial troponin-I cleavage, protects left ventricular function, and attenuates remodeling in rats with myocardial infarction [J].
Chandrashekhar, Y ;
Sen, S ;
Anway, R ;
Shuros, A ;
Arland, I .
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 2004, 43 (02) :295-301
[3]   Assessment and prognostic significance of mitotic index using the mitosis marker phospho-histone H3 in low and intermediate-grade infiltrating astrocytomas [J].
Colman, H ;
Giannini, C ;
Huang, L ;
Gonzalez, J ;
Hess, K ;
Britner, J ;
Fuller, G ;
Langford, L ;
Pelloski, C ;
Aaron, J ;
Burger, P ;
Aldape, K .
AMERICAN JOURNAL OF SURGICAL PATHOLOGY, 2006, 30 (05) :657-664
[4]   Interleukin-18 knockout mice display maladaptive cardiac hypertrophy in response to pressure overload [J].
Colston, James T. ;
Boylston, William H. ;
Feldman, Marc D. ;
Jenkinson, Chris P. ;
de la Rosa, Sam D. ;
Barton, Amanda ;
Trevino, Rodolfo J. ;
Freeman, Gregory L. ;
Chandrasekar, Bysani .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2007, 354 (02) :552-558
[5]   Increased cardiomyocyte apoptosis and changes in proapoptotic and antiapoptotic genes bax and bcl-2 during left ventricular adaptations to chronic pressure overload in the rat [J].
Condorelli, G ;
Morisco, C ;
Stassi, G ;
Notte, A ;
Farina, F ;
Sgaramella, G ;
de Rienzo, A ;
Roncarati, R ;
Trimarco, B ;
Lembo, G .
CIRCULATION, 1999, 99 (23) :3071-3078
[6]   Heart-targeted overexpression of caspase3 in mice increases infarct size and depresses cardiac function [J].
Condorelli, G ;
Roncarati, R ;
Ross, J ;
Pisani, A ;
Stassi, G ;
Todaro, M ;
Trocha, S ;
Drusco, A ;
Gu, YS ;
Russo, MA ;
Frati, G ;
Jones, SP ;
Lefer, DJ ;
Napoli, C ;
Croce, CM .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2001, 98 (17) :9977-9982
[7]   P-1 ASPARTATE-BASED PEPTIDE ALPHA-((2,6-DICHLOROBENZOYL)OXY)METHYL KETONES AS POTENT TIME-DEPENDENT INHIBITORS OF INTERLEUKIN-1-BETA-CONVERTING ENZYME [J].
DOLLE, RE ;
HOYER, D ;
PRASAD, CVC ;
SCHMIDT, SJ ;
HELASZEK, CT ;
MILLER, RE ;
ATOR, MA .
JOURNAL OF MEDICINAL CHEMISTRY, 1994, 37 (05) :563-564
[8]  
Givvimani Srikanth, 2010, Archives of Physiology and Biochemistry, V116, P63, DOI 10.3109/13813451003652997
[9]   Inhibition of cardiac myocyte apoptosis improves cardiac function and abolishes mortality in the peripartum cardiomyopathy of Gαq transgenic mice [J].
Hayakawa, Y ;
Chandra, M ;
Miao, WF ;
Shirani, J ;
Brown, JH ;
Dorn, GW ;
Armstrong, RC ;
Kitsis, RN .
CIRCULATION, 2003, 108 (24) :3036-3041
[10]   Ultrastructure and Regulation of Lateralized Connexin43 in the Failing Heart [J].
Hesketh, Geoffrey G. ;
Shah, Manish H. ;
Halperin, Victoria L. ;
Cooke, Carol A. ;
Akar, Fadi G. ;
Yen, Timothy E. ;
Kass, David A. ;
Machamer, Carolyn E. ;
Van Eyk, Jennifer E. ;
Tomaselli, Gordon F. .
CIRCULATION RESEARCH, 2010, 106 (06) :1153-U327