DY-9760e inhibits endothelin-1-induced cardiomyocyte hypertrophy through inhibition of CaMKII and ERK activities.

Abstract

Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and extracellular signal-regulated kinase (ERK) have pivotal roles in endothelin-1 (ET-1)-induced cardiomyocyte hypertrophy. We here tested whether a novel CaM antagonist, DY-9760e inhibits ET-1-induced hypertrophy through inhibition of CaMKII and ERK activities. We first confirmed that Ca(2+) oscillation induced by ET-1 treatment elicits transient activation of CaMKII and ERK in cultured cardiomyocytes. DY-9760e treatment with 3 microM totally and partially inhibited the ET-1-induced CaMKII and ERK activation, respectively. The ET-1-induced ERK activation was also partially blocked by a CaMKII inhibitor, KN93. To confirm involvement of CaMKII activity in the ERK activation by ET-1 and A23187, cultured cardiomyocytes were transfected with a constitutively active CaMKII. The transfection with the active CaMKII elicited ERK activation in cultured cardiomyocytes and cotransfection with dominant negative CaMKII eliminated its ERK activation. Consistent with inhibitory actions of DY-9760e on the ET-1-induced CaMKII and ERK activation, induction of hypertrophy-related genes including atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) was significantly inhibited by DY-9760e treatment. Combination treatment with DY-9760e and U0126, a MEK inhibitor, totally blocked the ET-1-induced ANP and BNP expression. DY-9760e treatment (3 microM) significantly inhibited the ET-1-induced hypertrophy and combination treatment with DY-9760e and U0126 totally blocked the ET-1-induced hypertrophy in cultured cardiomyocytes. These results suggest that DY-9760e elicits antihypertrophic action on ET-1-induced cardiac hypertrophy through inhibition of CaMKII and ERK activation and that CaMKII activity in part mediates ET-1-induced ERK activation.

• Authors: Ying-Mei Lu, Norifumi Shioda, Feng Han, Akifumi Kamata, Yasufumi Shirasaki, Zheng-Hong Qin, Kohji Fukunaga
• Journal: Cardiovascular therapeutics (Cardiovasc Ther) Vol. 27 Issue 1 Pg. 17-27 ( 2009) ISSN: 1755-5914 [Print] England
• PMID: 19207476 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 3-(2-(4-(3-chloro-2-methylphenyl)1-piperazinyl)ethyl)5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazol dihydrochloride 3.5 hydrate
• Benzylamines
• Butadienes
• Endothelin-1
• Indazoles
• Ionophores
• Nitriles
• Protein Kinase Inhibitors
• RNA, Messenger
• Sulfonamides
• U 0126
• Natriuretic Peptide, Brain
• KN 93
• Calcimycin
• Atrial Natriuretic Factor
• Calcium-Calmodulin-Dependent Protein Kinase Type 2
• Camk2g protein, rat
• Extracellular Signal-Regulated MAP Kinases

Topics

• Animals
• Animals, Newborn
• Atrial Natriuretic Factor (metabolism)
• Benzylamines (pharmacology)
• Butadienes (pharmacology)
• Calcimycin (pharmacology)
• Calcium Signaling (drug effects)
• Calcium-Calmodulin-Dependent Protein Kinase Type 2 (antagonists & inhibitors, genetics, metabolism)
• Cardiomegaly (enzymology, pathology, prevention & control)
• Cell Proliferation (drug effects)
• Cell Size (drug effects)
• Cells, Cultured
• DNA Replication (drug effects)
• Endothelin-1 (metabolism)
• Extracellular Signal-Regulated MAP Kinases (antagonists & inhibitors, metabolism)
• Indazoles (pharmacology)
• Ionophores (pharmacology)
• Myocytes, Cardiac (drug effects, enzymology, pathology)
• Natriuretic Peptide, Brain (metabolism)
• Nitriles (pharmacology)
• Phosphorylation
• Protein Kinase Inhibitors (pharmacology)
• RNA, Messenger (metabolism)
• Rats
• Rats, Wistar
• Sulfonamides (pharmacology)
• Time Factors
• Transfection