Extracellular signal-regulated kinase (ERK) activation preserves cardiac function in pressure overload induced hypertrophy

Background: Chronic pressure overload and a variety ofmediators induce concentric cardiac hypertrophy.When prolonged, cardiac hypertrophy culminates in decreasedmyocardial function and heart failure. Activation of the extracellular signal-regulated kinase (ERK) is consistently observed in animal models of hypertrophy and in human patients, but its role in the process is controversial. Methods:We generated transgenicmouse lineswith cardiomyocyte restricted overexpression of intrinsically ac- tive ERK1,which similar to the observations in hypertrophy is phosphorylated on both the TEY and the Thr207 motifs and is overexpressed at pathophysiological levels. Results: The activatedERK1transgenicmicedeveloped amodest adaptivehypertrophywith increased contractile function and without fibrosis. Following induction of pressure-overload, where multiple pathways are stimu- lated, this activation did not further increase the degree of hypertrophy but protected the heart through a de- crease in the degree of fibrosis andmaintenance of ventricular contractile function. Conclusions: The ERK pathway acts to promote a compensated hypertrophic response,with enhanced contractile function and reduced fibrosis. The activation of this pathwaymay be a therapeutic strategy to preserve contrac- tile function when the pressure overload cannot be easily alleviated. The inhibition of this pathway,which is in- creasingly being used for cancer therapy on the other hand, should be used with caution in the presence of pressure-overload.