Stretch-modulation of second messengers: effects on cardiomyocyte ion transport.
In cardiomyocytes, mechanical stress induces a variety of hypertrophic responses including an increase in protein synthesis and a reprogramming of gene expression. Recently, the calcium signaling has been reported to play an important role in the development of cardiac hypertrophy. In this article, we report on the role of the calcium signaling in stretch-induced gene expression in cardiomyocytes. Stretching of cultured cardiomyocytes up-regulates the expression of brain natriuretic peptide (BNP). Intracellular calcium-elevating agents such as the calcium ionophore A23187, the calcium channel agonist BayK8644 and the sarcoplasmic reticulum calcium-ATPase inhibitor thapsigargin up-regulate BNP gene expression. Conversely, stretch-induced BNP gene expression is suppressed by EGTA, stretch-activated ion channel inhibitors, voltage-dependent calcium channel antagonists, and long-time exposure to thapsigargin. Furthermore, stretch increases the activity of calcium-dependent effectors such as calcineurin and calmodulin-dependent kinase II, and inhibitors of calcineurin and calmodulin-dependent kinase II significantly attenuated stretch-induced hypertrophy and BNP expression. These results suggest that calcineurin and calmodulin-dependent kinase II are activated by calcium influx and subsequent calcium-induced calcium release, and play an important role in stretch-induced gene expression during the development of cardiac hypertrophy.
Department of Cardiology, Kanazawa Medical University, 1-1 Daigaku, Uchinada-cho, Kawakita-gun, 920-0265, Ishikawa, Japan.
Sumiyo
S
Kudoh
Hiroshi
H
Akazawa
Hiroyuki
H
Takano
Yunzeng
Y
Zou
Haruhiro
H
Toko
Toshio
T
Nagai
Issei
I
Komuro
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D000001:Calcimycin / Q000494:pharmacology; D019703:Calcineurin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D005786:Gene Expression Regulation; D006984:Hypertrophy; D007473:Ion Channels / Q000378:metabolism; D007477:Ions; D008954:Models, Biological; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism; D045283:Natriuretic Agents / Q000737:chemistry; D015398:Signal Transduction; D019284:Thapsigargin / Q000494:pharmacology; D013997:Time Factors; D015854:Up-Regulation
D007473:Ion Channels; D007477:Ions; D045283:Natriuretic Agents; D000001:Calcimycin; D019284:Thapsigargin; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D019703:Calcineurin; D000251:Adenosine Triphosphatases; D002118:Calcium