Inhibition of ADP-ribosyl cyclase attenuates angiotensin II-induced cardiac hypertrophy.
OBJECTIVE
Here, we report the discovery of a small molecule inhibitor, 2,2'-dihydroxyazobenzene (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 Ca(2+) [Ca(2+)](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-beta1 protein expression. Treatment of cardiomyocytes with Ang II generated a biphasic [Ca(2+)](i) increase that included an initial Ca(2+)peak and sustained Ca(2+) 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 Ca(2+) signal, but not the initial Ca(2+) 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.


CONCLUSIONS
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.
Gul
Rukhsana
R
Department of Biochemistry, Chonbuk National University Medical School, Keum-am Dong San 2-20, Duk-jin Ku, Jeonju 561-182, Republic of Korea.
Park
Jae-Hyeong
JH
Kim
Seon-Young
SY
Jang
Kyu Yoon
KY
Chae
Jei-Keon
JK
Ko
Jae-Ki
JK
Kim
Uh-Hyun
UH
D036541:ADP-ribosyl Cyclase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D001391:Azo Compounds / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D006332:Cardiomegaly / Q000201:enzymology / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D048429:Cell Size / Q000187:drug effects; D036563:Cyclic ADP-Ribose / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006978:Hypertension, Renovascular / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D009392:Nephrectomy; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012077:Renal Artery / Q000601:surgery; D019061:src-Family Kinases / Q000378:metabolism
C493642:8-bromo-cyclic-ADP-ribose; D001391:Azo Compounds; D004791:Enzyme Inhibitors; D000804:Angiotensin II; D036563:Cyclic ADP-Ribose; D019869:Phosphatidylinositol 3-Kinases; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; D036541:ADP-ribosyl Cyclase; D002118:Calcium