The levels of cardiotrophin CT-1, a protein which is essential to the development of the heart, are raised in cardiomyocytes exposed to hypoxia. Moreover, this protein is implicated in the cardiomyocyte survival process as a response to hypoxic stress. This can be seen in a study carried out by the team led by Dr Guillermo Zalba, of the Centre for Applied Medical Research (CIMA) of the University of Navarra, in collaboration with the laboratory directed by José Martínez-González, of the Cardiovascular Research Center in Barcelona. Both groups belong to the Red de Investigación Cardiovascular (RECAVA) of the Instituto de Salud Carlos III. The results were published in the November issue of Cardiovascular Research.

One of the main findings of this work is the identification of the transcription factor by hypoxia inducible (HIF-1) as the cause of this compensatory cell response, as it activates the expression of the CT-1 protein when oxygen is lacking. "We found that hypoxia favored an increase in the CT-1 protein levels, which fell when the HIF-1 factor was inhibited, and we identified the mechanism for transcriptional regulation in detail. But the most interesting point was the discovery that the silencing of CT-1 increased cell death", Dr Zalba explained.

A possible biomarker

The cardio-protective property of CT-1 in stress conditions suggests that its expression may be regulated in cardiac diseases linked to inflammation, oxidative stress and lack of oxygen. "Surprisingly, very little is known on the regulation mechanisms of this protein on cardiomyocytes exposed to hypoxia. On the one hand, in situations of acute ischemia, like that associated with acute myocardial infarction (AMI), the low availability of oxygen can promote the stabilization and activation of HIF-1α. This leads to a rise in the CT-1 levels, which increases the survival of the cardiomyocytes. On the other, in chronic ischemia conditions, such as hypertension cardiopathy and heart failure, the   cardiac and circulatory levels of expression of CT-1 are raised. It is essential to differentiate between these two ischemia situations, as an acute rise in CT-1 can carry out protective actions in AMI. However, in the heart pathologies associated with chronic ischemia conditions, an increasing, continued rise in CT-1 levels is associated with potential destructive effects of this cytokine". In this context and from a translational perspective, the CT-1 protein may constitute a new biomarker associated with heart physiopathology in a patient with hypertensive cardiopathy or heart failure. 

Further steps

The results of this work show that HIF-1 signaling is directly related with the increase in the expression of CT-1 in response to hypoxia in adult cardiomyocytes, and suggest that the induction of CT-1 may be involved in their adaptive response. Moreover, this study unlocks new paths for research to assess the interest of CT-1 as a therapeutic target. "Whatever the case, new trials must be carried out for more in-depth study of the implication of CT-1 as an adaptive mechanism for ischemia in adult cardiomyocytes" explained the CIMA specialist.