A heart-specific increase in cardiotrophin-1 gene expression precedes the establishment of ventricular hypertrophy in genetically hypertensive rats

Objective Cardiotrophin-1 is a cytokine, a novel member of the interleukin- 6 superfamily, which is isolated from mouse embryoid bodies. It is known to bind a gp130/leukemia inhibitory factor (LIF) receptor heterodimer and to induce myocyte hypertrophy Accumulating evidence indicates that a gp130 sig naling pathway is involved in cardiac development and ventricular hypertrop hy. Methods In order to elucidate the pathophysiologic significance of cardiotr ophin-1 in ventricular hypertrophy associated with hypertension, we examine d the level of cardiotrophin-1 mRNA in the ventricle of spontaneously hyper tensive rats/Izm stroke-prone (SHRSP/Izm) in neonates, and at 4-, 12- and 2 0-weeks of age by Northern blot analysis. We also examined the gene express ion of LIF by Northern blot and reverse transcription-polymerase chain reac tion analyses. Results No significant difference was observed in the level of cardiotrophi n-1 mRNA in the ventricle between SHRSP/Izm and Wistar-Kyoto/Izm (WKY/Izm) neonates. However, the level of cardiotrophin-1 mRNA in the ventricle was s ignificantly augmented in 4-week-old SHRSP/Izm, which did not yet show over t ventricular hypertrophy, and its augmented expression lasted for the dura tion of the experimental period. The difference in the level of cardiotroph in-1 mRNA between the two strains was most prominent at the age of 4 weeks. This augmented expression of the cardiotrophin-1 gene was not related to t he severity of left ventricular hypertrophy. The level of cardiotrophin-1 m RNA in other organs, including the kidney and lung, showed no significant c hange with aging and was not different between the two strains. After long- term treatment with lisinopril, levels of cardiotrophin-1 mRNA were not cha nged, although it morphologically prevented the development of left ventric ular hypertrophy. LIF mRNA was not detected in any ventricles examined by N orthern blot analysis. Conclusions The present study demonstrates that the expression of cardiotro phin-1 mRNA is increased in the early stage of ventricular hypertrophy in S HRSP/Izm and it remains elevated after hypertrophy has been established. Ho wever, it is unlikely that cardiotrophin-1 plays a mechanistic role in the development and maintenance of left ventricular hypertrophy in SHRSP/Izm. T he present study also suggests that cardiotrophin-1, but not LIF, is a poss ible candidate for natural ligand of a gp130 signaling pathway in the heart . J Hypertens 1999, 17:807-816 (C) Lippincott Williams & Wilkins.