title: PICOT inhibits cardiac hypertrophy and enhances ventricular function and cardiomyocyte contractility.
abstract: 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 (PKC-Interacting Cousin Of Thioredoxin) 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 Ca(2+) handing analysis revealed that increases in myofilament Ca(2+) responsiveness, together with increased rate of sarcoplasmic reticulum Ca(2+) 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.
authors.affiliation: Department of Life Science, Global Research Laboratory on Cardiovascular Gene Therapy, Gwangju Institute of Science and Technology, Korea.
authors.forename: Dongtak
authors.initials: D
authors.lastname: Jeong
authors.forename: Hyeseon
authors.initials: H
authors.lastname: Cha
authors.forename: Eunyoung
authors.initials: E
authors.lastname: Kim
authors.forename: Misuk
authors.initials: M
authors.lastname: Kang
authors.forename: Dong Kwon
authors.initials: DK
authors.lastname: Yang
authors.forename: Ji Myoung
authors.initials: JM
authors.lastname: Kim
authors.forename: Pyoung Oh
authors.initials: PO
authors.lastname: Yoon
authors.forename: Jae Gyun
authors.initials: JG
authors.lastname: Oh
authors.forename: Oliver Y
authors.initials: OY
authors.lastname: Bernecker
authors.forename: Susumu
authors.initials: S
authors.lastname: Sakata
authors.forename: Thi Thu
authors.initials: TT
authors.lastname: Le
authors.forename: Lei
authors.initials: L
authors.lastname: Cui
authors.forename: Young-Hoon
authors.initials: YH
authors.lastname: Lee
authors.forename: Do Han
authors.initials: DH
authors.lastname: Kim
authors.forename: Sun-Hee
authors.initials: SH
authors.lastname: Woo
authors.forename: Ronglih
authors.initials: R
authors.lastname: Liao
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Hajjar
authors.forename: Woo Jin
authors.initials: WJ
authors.lastname: Park
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D006332:Cardiomegaly / Q000517:prevention & control*; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology* / Q000627:therapeutic use; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D015316:Genetic Therapy; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000166:cytology; D011490:Protein Disulfide Reductase (Glutathione); D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D014162:Transfection
chemical_list: D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D011490:Protein Disulfide Reductase (Glutathione); C498606:Txnl2 protein, mouse; D011493:Protein Kinase C