Administration of tauroursodeoxycholic acid (TUDCA) reduces apoptosis following myocardial infarction in rat.
Black bear bile has been used in traditional Chinese medicine to treat liver and eye related illnesses for centuries. A major constituent of bile is ursodeoxycholic acid (UDCA). Recent analysis of the cellular effects of UDCA and its taurine conjugate tauroursodeoxycholic acid (TUDCA) have demonstrated their antiapoptotic properties through regulation of Bcl-2 family and survival signaling proteins (Bax, Bad, phosphatidylinositol-3-kinase). In this study, we tested the hypothesis that TUDCA administered to rats prior to a myocardial infarction (MI) would exhibit anti-apoptotic effects and improve cardiac function. Prior to ligation of the left anterior descending (LAD) coronary artery, TUDCA (50 mg/ml, 400 mg/kg, IV) or PBS was administered to rats. Animals were sacrificed 24 hours after ligation for terminal transferase-mediated dUTP-digoxigenin nick end-labeling (TUNEL) and caspase-3 activity to assess apoptosis. Additional TUDCA or PBS treated rats underwent pre-operative,1 and 4 week transthoracic ultrasounds to assess heart function by quantification of shortening fraction (SF) and infarct area. TUNEL labeling of the cardiac tissue revealed a significant reduction in apoptotic cells in rats given TUDCA prior to ischemic injury (p = 0.05). In support of reducing apoptosis, caspase-3 activity in the TUDCA treated animals also decreased (p = 0.02). By 4 weeks, a significantly smaller infarct area was present in the TUDCA group compared to the PBS group (0.05 vs. 0.13 cm(2), p = NS) and there was also an improvement in SF. The results provide evidence for TUDCA as a viable treatment for reducing apoptosis in a model of myocardial infarction. Additional studies will distinguish the functional result of improved cell survival following infarction, suggesting the potential for clinical application of this anti-apoptotic drug in treatment of acute MI.
Rivard
Andrew L
AL
Department of Surgery, Experimental Surgical Services, University of Minnesota, Minneapolis, MN 55455, USA. rivar011@umn.edu
Steer
Clifford J
CJ
Kren
Betsy T
BT
Rodrigues
Cecilia M P
CM
Castro
Rui E
RE
Bianco
Richard W
RW
Low
Walter C
WC
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D002756:Cholagogues and Choleretics / Q000494:pharmacology*; D004452:Echocardiography; D020287:In Situ Nick-End Labeling; D023421:Models, Animal; D009203:Myocardial Infarction / Q000201:enzymology / Q000473:pathology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D051381:Rats; D013318:Stroke Volume; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology*
D002756:Cholagogues and Choleretics; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; D053148:Caspase 3