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(Circulation Research. 2006;99:307.)
© 2006 American Heart Association, Inc.

Integrative Physiology

PICOT Inhibits Cardiac Hypertrophy and Enhances Ventricular Function and Cardiomyocyte Contractility

Dongtak Jeong^*, Hyeseon Cha^*, Eunyoung Kim^*, Misuk Kang, Dong Kwon Yang, Ji Myoung Kim, Pyoung Oh Yoon, Jae Gyun Oh, Oliver Y. Bernecker, Susumu Sakata, Le Thi Thu, Lei Cui, Young-Hoon Lee, Do Han Kim, Sun-Hee Woo, Ronglih Liao, Roger J. Hajjar, Woo Jin Park

From the Department of Life Science (D.J., H.C., E.K., M.K., D.K.Y., J.M.K., P.O.Y., J.G.O., D.H.K., W.J.P.), Global Research Laboratory on Cardiovascular Gene Therapy, Gwangju Institute of Science and Technology, Korea; Cardiovascular Research Center (O.Y.B., S.S., R.J.H.), Massachusetts General Hospital and Harvard Medical School, Charlestown; College of Pharmacy (L.T.T., S.-H.W.), Chungnam National University, Daejeon, Korea; Cardiovascular Division (L.C., R.L.), Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass; and Department of Oral Anatomy (Y.-H.L.), School of Dentistry, Chonbuk National University, Jeonju, Korea.

Correspondence to Woo Jin Park, Department of Life Science, Gwangju Institute of Science and Technology, 1 Oryong-dong, Buk-gu, Gwangju 500-712, Korea. E-mail wjpark{at}gist.ac.kr

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 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.

Key Words: cardiac hypertrophy • protein kinase C • PICOT • contractility

Related Article:

Containing Hypertrophy With a PICOT Fence

Gerald W. Dorn, II
Circ. Res. 2006 99: 228-230. [Extract] [Full Text] [PDF]

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