UCL researchers have discovered a new mechanism at work in cardiac hypertrophy, which could pave the way to a more targeted treatment of this potentially harmful condition.
The least that can be said of the heart is that it never rests. It beats an average of 100,000 times a day. At each beat, it pumps the equivalent of an espresso cup of blood. And when, owing to pathology, it has to exert more effort to expel that blood, our heart muscle develops like any other muscle. ‘Cardiac hypertrophy is an abnormal increase in heart size’, says Prof. Luc Bertrand, a researcher at the UCL Institute for Experimental and Clinical Research. ‘This phenomenon is the consequence of a cardiovascular disease or, rather, an adaptation of the heart to the consequences of this disease.’
Cardiac hypertrophy causes and consequences
The main causes of this adaptive phenomenon: arterial hypertension and valvulopathy. Although we do not have precise figures, several thousand Belgians are directly affected. In fact, almost a quarter of the population suffers or will suffer from hypertension. One in two hypertension sufferers is unaware of their condition and only half of diagnosed patients are treated. Of these, 10 to 20% do not respond to treatment and can develop cardiac hypertrophy.
The consequences are far from trivial. ‘The hypertrophied heart weakens and the patient ends up suffering heart failure’, Prof. Bertrand says. ‘Not only do the symptoms (shortness of breath, severe fatigue, etc.) greatly affect the quality of life, but heart failure can threaten life itself since the heart can simply stop. Counteracting cardiac hypertrophy is therefore a vital issue.’
When cardiomyocytes grow
Unlike other cells of the body, those of the heart, cardiomyocytes, do not multiply. However, they can increase in volume. How? ‘In order for the heart to function as normally as possible, our body secretes certain hormones’, Prof. Bertrand explains. ‘These hormones attach to receptors on the surface of cardiomyocytes and, through several signals, transmit roughly the same message: “Grow!” Cardiomyocytes obey this order in several ways. The two main ones are an increase in protein synthesis and the expression of specific genes. Our team recently discovered a third: O-GlcNAcylation (O-G). This somewhat unusual term refers to a process by which a molecule derived from sugar (glucose) is added to proteins. This modifies the functioning of said proteins, which then make the cardiomyocytes swell.’ The researchers first discovered that cardiac hypertrophy goes hand in hand with an increase in O-G. And vice versa: if O-G is decreased, hypertrophic development stops.
Alternatives to ‘General AMPK’?
At the same time, Prof. Bertrand's team demonstrated that the pharmacological activation of a protein, AMPK, could inhibit O-G. ‘AMPK has been known for about 30 years and is particularly used as a target in the treatment of diabetes. This protein is expressed in all our cells. Its mission: to protect them against threats. The experiments we conducted revealed that pharmacological activation of AMPK inhibits O-G, which blocks cardiac hypertrophy.’(1)
Is AMPK the target of a new treatment for hypertrophy? Not so fast. AMPK is like a general in charge of defending the fort (the cell) by interrupting certain activities and/or engaging various defence mechanisms. ‘AMPK regulates dozens of molecular and cellular pathways’, Prof. Bertrand says. ‘Moreover, once stimulated, it is activated in all the body’s cells, not only in those of the heart. That’s why we probably couldn’t use it to treat cardiac hypertrophy: AMPK’s activity is too comprehensive. It may cause side effects in other tissues and organs by disrupting the normal functioning of too many cells.’
Toward new treatments?
That said, now that the link between AMPK, O-G and cardiac hypertrophy is established, scientists can deepen and refine their research. ‘There may be other molecules that, like AMPK activators, can inhibit O-G, but in a more targeted way, circumscribed to cardiomyocytes. We must also precisely identify the “O-GlcNAcylated” protein(s) which, in these cardiac cells, cause them to hypertrophy. We already have several leads and have obtained funding from the FNRS for this purpose.’ So, to be continued.
(1) R. Gélinas et al., « AMPK activation counteracts cardiac hypertrophy by reducing O-GlcNAcylation » in Nature Communications, janvier 2018 : https://www.nature.com/articles/s41467-017-02795-4
A glance at Luc Bertrand's bio
1991 Master’s Degree in Zoology, University of Namur
1997 PhD, Biology, University of Namur
1997-2000 FNRS Postdoctorate, de Duve Institute, UCL
1998 Postdoctorate, University of Dundee (Scotland)
2000-03 Postdoctorate, de Duve Institute, UCL
2003-15 FNRS Research Associate
2003-11 Associate Professor, UCL
Since 2003 Team Leader, Cardiovascular Research Centre, IREC, UCL
2007 Prix Camille et Germaine Damman, Fondation de recherche cardiologique
Since 2009 Visiting Professor, University of Namur
Since 2011 Biochemistry Professor, UCL
Since 2015 FNRS Senior Research Associate
Prof. Bertrand’s research is financed mainly by the FRNS, UCL and the Saint-Luc University Hospital.