Master Regulator of Heart Health

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Researchers find that p53, a protein implicated in most cancers, controls heart function.
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Over the course of a day, a healthy heart can beat over 100,000 times and pump more than 7,500 litres of blood.
Currently, around 600,000 Canadians are living with heart failure (HF), a serious condition for which there is no cure.

HF occurs when the heart—weakened by damage from heart attacks, high blood pressure or other disorders—can no longer pump enough blood and oxygen to meet the body’s needs. Although HF is a leading cause of death and disability, the molecular mechanisms underlying its initiation and progression are unclear.

Intriguingly, cardiac tissue from people with end-stage HF contains high levels of a protein called p53 that is most well-known for its role in cancer: over 50% of tumours have abnormal p53 proteins that promote unregulated growth and proliferation of cancer cells.

To define the role of p53 in the heart, TGHRI Scientist Dr. Filio Billia and PM Senior Scientist Dr. Tak Mak examined how the loss of the protein affected the heart in different experimental models.

The researchers discovered that p53’s role in the heart is very complex. The short-term loss of p53 in a healthy heart led to cardiac muscle thickening, a telltale sign of HF. However, when biomechanical stress was applied to the heart, simulating the physiological conditions that promote HF, the loss of p53 protected the cardiac muscles from thickening and HF.

The researchers also found that the loss of p53 changed the activity of over 1,000 cardiac genes that influence heart structure, muscle contraction and energy production. The wide-reaching influence of p53 on such a large number of cardiac genes may explain why the observed effects p53 were so complex.

‘Collectively, our findings show that p53 is not only implicated in HF, but is also a key regulator of  heart structure and function, a role that may be as equally important as its established function in cancer biology’, says Dr. Billia of the study.

This work was supported by the Canadian Institutes of Health Research and the Toronto General & Western Hospital Foundation. T Mak holds a Tier 1 Canada Research Chair in in Inflammation Responses and Traumatic Injury.

Mak TW, Hauck L, Grothe D, Billia F. p53 regulates the cardiac transcriptome. Proc Natl Acad Sci U S A. 2017 Feb 28. doi:10.1073/pnas.1621436114.