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

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 μM blebbistatin resulted in a ∼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.

The Mesolithic-Neolithic transition in the Channel Islands: maritime and terrrestrial perspectives

This paper investigates the Mesolithic-Neolithic transition in the Channel Islands. It presents a new synthesis of all known evidence from the islands c. 5000-4300 BC, including several new excavations as well as find spot sites that have not previously been collated. It also summarises – in English – a large body of contemporary material from north-west France. The paper presents a new high-resolution sea level model for the region, shedding light on the formation of the Channel Islands from 9000-4000 BC. Through comparison with contemporary sites in mainland France, an argument is made suggesting that incoming migrants from the mainland and the small indigenous population of the islands were both involved in the transition. It is also argued that, as a result of the fact the Channel Islands witnessed a very different trajectory of change to that seen in Britain and Ireland c. 5000-3500 BC, this small group of islands has a great deal to tell us about the arrival of the Neolithic more widely.