Host: The Japanese Pharmacological Society, The Japanese Society of Clinical Pharmacology
Name : WCP2018 (18th World Congress of Basic and Clinical Pharmacology)
Location : Kyoto
Date : July 01, 2018 - July 06, 2018
Background: Raf/MEK/ERK pathway plays a crucial role in the development of cardiac remodeling. Heat shock protein 90 (Hsp90) involves stability of its client proteins. It is considered that Hsp90 interacts with c-Raf and may regulate activity of Raf/MEK/ERK pathway. In this study, to clarify the role of Hsp90 and its client proteins in the development of cardiac remodeling, effects of Hsp90 inhibitor on signal transducers under in vivo and in vitro conditions were examined.
Methods: Myocardial infarction was produced by ligation of the left ventricular coronary artery in rats. Hsp90 inhibitor 17-(allylamino)-17-dimethoxy-geldanamycin (17-AAG) was administrated intraperitoneally to rats for six weeks from the second week after coronary artery ligation (CAL). Primary cultured cardiomyocytes were prepared from neonatal rats. Cultured cardiomyocytes were pre-treated with 17-AAG followed by an exposure to endothelin-1 (ET-1).
Results: Eight weeks following CAL, rats without 17-AAG treatment showed signs of chronic heart failure concomitant with cardiac hypertrophy. In contrast, cardiac function in CAL rats treated with 17-AAG was preserved. Increased heart weight was attenuated in CAL rats with 17-AAG treatment. ET-1-induced increase in cell size was also attenuated in cultured cardiomyocytes in the presence of 17-AAG. In immunoblot analyses, c-Raf content in the viable left ventricular myocardium (LV) of CAL rats was decreased by 17-AAG treatment. An increase in phosphorylation levels of Erk1/2 in the viable LV was also attenuated by 17-AAG treatment. Treatment of cultured cardiomyocytes with 17-AAG resulted in decreases in c-Raf content and Erk1/2 phosphorylation levels.
Conclusions: These findings suggest that Hsp90 involves activation of Raf/MEK/ERK pathway via stability of c-Raf in cardiomyocytes, leading to the development of cardiac remodeling.
