In the case of Samson, it was the loss of his locks at the hands of his beloved that led to his downfall. For the heart under pressure, a study by Higashiyama's group finds that disaster can result from the enzyme-catalysed snipping off of growth factors that are bound to the membrane of cardiac myocytes. The paper in January's Nature Medicine pinpoints a matrix metalloprotease (MMP), ADAM12, as being a key element in the pathway that leads to cardiac hypertrophy, and often eventual heart failure.

Cardiac hypertrophy is an adaptive response to high blood pressure, and although initially protective, when prolonged, it can frequently result in sudden cardiac death. Following recent reports of the beneficial effects of MMP inhibitors during the development of congestive heart failure, attention has focused on how MMPs might contribute to the progression of heart disease. It seems that stimulation of G-protein-coupled receptors (GPCRs) by vasoactive substances such as angiotensin II leads to downstream activation of ADAM12, which cleaves membrane-bound heparin-binding epidermal growth factor-like growth factor (HB-EGF). The released HB-EGF then acts on the EGF receptor to stimulate cellular growth and the development of cardiac hypertrophy. Expression of non-functional mutant variants of ADAM12 in cultured cardiac myocytes almost abolished the shedding of HB-EGF in response to GPCR stimulation. Furthermore, blocking Adam12 function in mice with the inhibitor KB-R7785 drastically reduced the hypertrophic response. However, this inhibitor was not shown to be selective for ADAM12, and, indeed, many ADAMs might be involved in the cellular remodelling that accompanies cardiac hypertophy. Although both ADAM12 and HB-EGF are potential therapeutic targets, their involvement in the initially protective response of cardiac hypertrophy means that simple inhibition of their function is unlikely to be a successful strategy.