PICOT inhibits cardiac hypertrophy and enhances ventricular function and cardiomyocyte contractility

被引:74
作者
Jeong, Dongtak
Cha, Hyeseon
Kim, Eunyoung
Kang, Misuk
Yang, Dong Kwon
Kim, Ji Myoung
Yoon, Pyoung Oh
Oh, Jae Gyun
Bernecker, Oliver Y.
Sakata, Susumu
Thu, Le Thi
Cui, Lei
Lee, Young-Hoon
Kim, Do Han
Woo, Sun-Hee
Liao, Ronglih
Hajjar, Roger J.
Park, Woo Jin
机构
[1] Gwangju Inst Sci & Technol, Dept Life Sci, Kwangju 500712, South Korea
[2] Gwangju Inst Sci & Technol, Global Res Lab Cardiovasc Gene Therapy, Kwangju 500712, South Korea
[3] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA USA
[4] Harvard Univ, Sch Med, Charlestown, MA USA
[5] Chungnam Natl Univ, Coll Pharm, Taejon, South Korea
[6] Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA
[7] Harvard Univ, Sch Med, Boston, MA 02115 USA
[8] Chonbuk Natl Univ, Sch Dent, Dept Oral Anat, Jeonju, South Korea
关键词
cardiac hypertrophy; protein kinase C; PICOT; contractility;
D O I
10.1161/01.RES.0000234780.06115.2c
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Multiple signaling pathways involving protein kinase C (PKC) have been implicated in the development of cardiac hypertrophy. We observed that a putative PKC inhibitor, PICOT ((P) under bar KC-(I) under bar nteracting (C) under bar ousin (O) under barf (T) under bar hioredoxin) was upregulated in response to hypertrophic stimuli both in vitro and in vivo. This suggested that PICOT may act as an endogenous negative feedback regulator of cardiac hypertrophy through its ability to inhibit PKC activity, which is elevated during cardiac hypertrophy. Adenovirus-mediated gene transfer of PICOT completely blocked the hypertrophic response of neonatal rat cardiomyocytes to enthothelin-1 and phenylephrine, as demonstrated by cell size, sarcomere rearrangement, atrial natriuretic factor expression, and rates of protein synthesis. Transgenic mice with cardiac-specific overexpression of PICOT showed that PICOT is a potent inhibitor of cardiac hypertrophy induced by pressure overload. In addition, PICOT overexpression dramatically increased the ventricular function and cardiomyocyte contractility as measured by ejection fraction and end-systolic pressure of transgenic hearts and peak shortening of isolated cardiomyocytes, respectively. Intracellular Ca2+ handing analysis revealed that increases in myofilament Ca2+ responsiveness, together with increased rate of sarcoplasmic reticulum Ca2+ reuptake, are associated with the enhanced contractility in PICOT-overexpressing cardiomyocytes. The inhibition of cardiac remodeling by of PICOT with a concomitant increase in ventricular function and cardiomyocyte contractility suggests that PICOT may provide an efficient modality for treatment of cardiac hypertrophy and heart failure.
引用
收藏
页码:307 / 314
页数:8
相关论文
共 37 条
[1]   CHARACTERIZATION OF PROTEIN-KINASE-C ISOTYPE EXPRESSION IN ADULT-RAT HEART - PROTEIN-KINASE C-EPSILON IS A MAJOR ISOTYPE PRESENT, AND IT IS ACTIVATED BY PHORBOL ESTERS, EPINEPHRINE, AND ENDOTHELIN [J].
BOGOYEVITCH, MA ;
PARKER, PJ ;
SUGDEN, PH .
CIRCULATION RESEARCH, 1993, 72 (04) :757-767
[2]   Differential regulation of cardiac protein kinase C isozyme expression after aortic banding in rat [J].
Braun, MU ;
LaRosée, P ;
Schön, S ;
Borst, MM ;
Strasser, RH .
CARDIOVASCULAR RESEARCH, 2002, 56 (01) :52-63
[3]   PKC-α regulates cardiac contractility and propensity toward heart failure [J].
Braz, JC ;
Gregory, K ;
Pathak, A ;
Zhao, W ;
Sahin, B ;
Klevitsky, R ;
Kimball, TF ;
Lorenz, JN ;
Nairn, AC ;
Liggett, SB ;
Bodi, I ;
Wang, S ;
Schwartz, A ;
Lakatta, EG ;
DePaoli-Roach, AA ;
Robbins, J ;
Hewett, TE ;
Bibb, JA ;
Westfall, MV ;
Kranias, EG ;
Molkentin, JD .
NATURE MEDICINE, 2004, 10 (03) :248-254
[4]   Targeted inhibition of p38 MAPK promotes hypertrophic cardiomyopathy through upregulation of calcineurin-NEAT signaling [J].
Braz, JC ;
Bueno, OF ;
Liang, QR ;
Wilkins, BJ ;
Dai, YS ;
Parsons, S ;
Braunwart, J ;
Glascock, BJ ;
Klevitsky, R ;
Kimball, TF ;
Hewett, TE ;
Molkentin, JD .
JOURNAL OF CLINICAL INVESTIGATION, 2003, 111 (10) :1475-1486
[5]   PKCα regulates the hypertrophic growth of cardiomyocytes through extracellular signal-regulated kinase1/2 (ERK1/2) [J].
Braz, JC ;
Bueno, OF ;
De Windt, LJ ;
Molkentin, JD .
JOURNAL OF CELL BIOLOGY, 2002, 156 (05) :905-919
[6]   The MEK1-ERK1/2 signaling pathway promotes compensated cardiac hypertrophy in transgenic mice [J].
Bueno, OF ;
De Windt, LJ ;
Tymitz, KM ;
Witt, SA ;
Kimball, TR ;
Klevitsky, R ;
Hewett, TE ;
Jones, SP ;
Lefer, DJ ;
Peng, CF ;
Kitsis, RN ;
Molkentin, JD .
EMBO JOURNAL, 2000, 19 (23) :6341-6350
[7]   The transcriptional repressor Nab1 is a specific regulator of pathological cardiac hypertrophy [J].
Buitrago, M ;
Lorenz, K ;
Maass, AH ;
Maass, SO ;
Keller, U ;
Schmitteckert, EM ;
Ivashchenko, Y ;
Lohse, MJ ;
Engelhardt, S .
NATURE MEDICINE, 2005, 11 (08) :837-844
[8]   LOCALIZATION OF PROTEIN-KINASE-C ISOZYMES IN CARDIAC MYOCYTES [J].
DISATNIK, MH ;
BURAGGI, G ;
MOCHLYROSEN, D .
EXPERIMENTAL CELL RESEARCH, 1994, 210 (02) :287-297
[9]   Cardiac hypertrophy: The good, the bad and the ugly [J].
Frey, N ;
Olson, EN .
ANNUAL REVIEW OF PHYSIOLOGY, 2003, 65 :45-79
[10]   Mutations in the human muscle LIM protein gene in families with hypertrophic cardiomyopathy [J].
Geier, C ;
Perrot, A ;
Özcelik, C ;
Binner, P ;
Counsell, D ;
Hoffmann, K ;
Pilz, B ;
Martiniak, Y ;
Gehmlich, KA ;
van der Ven, PFM ;
Fürst, DO ;
Vornwald, A ;
von Hodenberg, E ;
Nürnberg, P ;
Scheffold, T ;
Dietz, R ;
Osterziel, KJ .
CIRCULATION, 2003, 107 (10) :1390-1395