Cardiotrophin-1 and urocortin cause protection by the same pathway and hypertrophy via distinct pathways in cardiac myocytes.

Cardiotrophin-1 (CT-1) is an Interleukin-6 family cytokine with known hypertrophic and protective effects in cardiac cells. CT-1 and the corticotrophin releasing hormone-like hormone urocortin protect cardiac myocytes by the same p42/44 mitogen activated protein kinase (p42/44 MAPK) dependent pathway. We investigated whether urocortin is also hypertrophic in cardiac myocytes and whether it shares a common pathway with CT-1 for this effect. Moreover, we also investigated, for the first time whether CT-1 and urocortin can induce hypertrophy in cultured adult as opposed to neonatal cardiac cells. Urocortin and CT-1 caused hypertrophy (as measured by an increase in cell area and enhanced protein: DNA ratio) in both adult and neonatal rat cultured cardiac myocytes. The hypertrophic effect of CT-1 was dependent on the signal transducer and activator of transcription 3 (STAT3) pathway but the hypertrophic effect of urocortin was independent of this pathway. In contrast, inhibition of the protective p42/p44 MAPK pathway has no effect on the hypertrophic effect of CT-1 or urocortin. Additionally, inhibition of the STAT3 pathway has no effect on the protective effect of CT-1 or urocortin. These results identify urocortin as a novel hypertrophic and protective agent whose hypertrophic effect is mediated by a distinct pathway to that activated by CT-1, although the two factors mediate protection via the same pathway.