Nuclear accumulation of myocyte muscle LIM protein is regulated by heme oxygenase 1 and correlates with cardiac function in the transition to failure Journal Article

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Authors: Paudyal, A.; Dewan, S.; Ikie, C.; Whalley, B. J.; de Tombe, P. P.; Boateng, S. Y.
Article Title: Nuclear accumulation of myocyte muscle LIM protein is regulated by heme oxygenase 1 and correlates with cardiac function in the transition to failure
Abstract: Impaired mechanosensing leads to heart failure and we have previously shown that a decreased ratio of cytoplasmic to nuclear CSRP3/Muscle LIM protein (MLP ratio) is associated with a loss of mechanosensitivity. Here we tested whether passive or active stress/strain was important in modulating the MLP ratio and determined whether this correlated with heart function during the transition to failure. We exposed cultured neonatal rat myocytes to 10% cyclic mechanical stretch at 1 Hz, or electrically paced myocytes at 6.8 V (1 Hz) for 48 h. The MLP ratio decreased 50% (P 0.05, n = 4) only in response to electrical pacing, suggesting impaired mechanosensitivity. Inhibition of contractility with 10 muM blebbistatin resulted in a approximately 3 fold increase in the MLP ratio (n = 8, P 0.05), indicating that myocyte contractility regulates nuclear MLP. Inhibition of histone deacetylase (HDAC) signaling with trichostatin A increased nuclear MLP following passive stretch, suggesting that HDACs block MLP nuclear accumulation. Inhibition of heme-oxygenase1 (HO-1) activity with PPZII blocked MLP nuclear accumulation. To examine how mechanosensitivity changes during the transition to heart failure, we studied a guinea pig model of angiotensin II infusion (400 ng/kg/min) over 12 weeks. Using subcellular fractionation we showed that the MLP ratio increased 88% (n = 4, P 0.01) during compensated hypertrophy, but decreased significantly during heart failure (P 0.001, n = 4). The MLP ratio correlated significantly with the E/A ratio (r = 0.71, P 0.01 n = 12), a clinical measure of diastolic function. These data indicate for the first time that myocyte mechanosensitivity as indicated by the MLP ratio is regulated primarily by myocyte contractility via HO-1 and HDAC signaling. This article is protected by copyright. All rights reserved.
Journal Title: The Journal of physiology
ISSN: 1469-7793; 0022-3751
Publisher: Unknown  
Date Published: 2016
Language: ENG
DOI/URL:

10.1113/JP271809
Notes: LR: 20160206; CI: This article is protected by copyright. All rights reserved.; JID: 0266262; 2015/10/30 [received]; 2016/01/25 [accepted]; aheadofprint