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Cardiovascular Research Advance Access first published online on August 21, 2008
This version [Corrected Proof] published online on September 11, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn232
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Inhibition of ADP-ribosyl cyclase attenuates angiotensin II-induced cardiac hypertrophy

Rukhsana Gul1, Jae-Hyeong Park2, Seon-Young Kim1, Kyu Yoon Jang3, Jei-Keon Chae4,5, Jae-Ki Ko4,5 and Uh-Hyun Kim1,5,*

1 Department of Biochemistry, Chonbuk National University Medical School, Keum-am Dong San 2-20, Duk-jin Ku, Jeonju 561-182, Republic of Korea
2 Department of Internal Medicine, Chungnam National University Medical School, Daejeon, Republic of Korea
3 Department of Pathology, Chonbuk National University Medical School, Jeonju 561-182, Republic of Korea
4 Department of Internal Medicine, Chonbuk National University Medical School, Jeonju 561-182, Republic of Korea
5 Institute of Cardiovascular Research, Chonbuk National University Medical School, Jeonju 561-182, Republic of Korea

* Corresponding author. Tel: +82 63 270 3083; fax: +82 63 274 9833. E-mail address: uhkim{at}chonbuk.ac.kr

Aims: Here, we report the discovery of a small molecule inhibitor, 2,2'-dihydroxybenzene (DAB), of ADP ribosyl cyclase (ADPR-cyclase) and showed that this inhibitor attenuated angiotensin (Ang) II-induced hypertrophic responses.

Methods: and results The intracellular concentration of free Ca2+ [Ca2+]i in adult rat cardiomyocytes was measured by using a confocal microscope. Cardiac hypertrophy was induced by the two-kidney one-clip (2K1C) method. Hypertrophy was determined by de novo protein synthesis, cell volume, echocardiography, nuclear translocation of nuclear factor of activated T-cells, and transforming growth factor-β1 protein expression. Treatment of cardiomyocytes with Ang II generated a biphasic [Ca2+]i increase that included an initial Ca2+peak and sustained Ca2+ rise via inositol trisphosphate and cyclic ADP-ribose (cADPR) formation, respectively. A cADPR antagonistic analogue, 8-Br-cADPR, and an ADPR-cyclase inhibitor, DAB, blocked the sustained Ca2+ signal, but not the initial Ca2+ rise. Furthermore, DAB significantly inhibited Ang II-mediated cADPR formation and hypertrophic responses in vitro. Echocardiography and histological examination revealed significant cardiac hypertrophy in 2K1C rats that was potently inhibited by treatment with DAB. In addition, the hypertrophic responses induced by Ang II in vitro were significantly increased by 2K1C, and DAB treatment reversed these hypertrophic responses to the levels of sham Control.

Conclusion: ADPR-cyclase is an important mediator of cardiac hypertrophy, and inhibition of ADPR-cyclase by DAB may provide a new therapeutic strategy for cardiac diseases.

KEYWORDS Angiotensin II; Cardiomyocytes; Ca2+; ADPR-cyclase; Cardiac hypertrophy

Time for primary review: 19 days


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