Abstract 3058: Cardiac Fibroblats Are Essential for the Adaptive Response of the Heart to Pressure Overload
Although cardiac fibroblasts are the most numerous cell type in the heart, they have been considered to play largely a secondary role in cardiac hypertrophy and failure. Haploinsufficiency of the transcription factor gene Klf5 suppressed cardiac hypertrophy and fibrosis elicited by moderate-intensity pressure overload induced by transverse aortic constriction (TAC). However, Klf5 is primarily expressed in cardiac fibroblasts and cardiomyocyte-specific deletion of Klf5 by αMHC-Cre did not alter the hypertrophic responses. In sharp contrast, cardiac fibroblast-specific deletion of Klf5 by Cre driven by periostin promoter ameliorated cardiac hypertrophy and fibrosis, indicating that KLF5 in fibroblasts is important for the response to pressure overload, and that cardiac fibroblasts are required for cardiomyocyte hypertrophy. Moreover, high-intensity TAC caused severe heart failure and early death in mice whose fibroblasts lack Klf5. The medium conditioned by fibroblasts induced cardiomyocyte hypertrophy and this hypertrophic response was inhibited by KLF5 knockdown, suggesting that the paracrine interaction is mediated by KLF5. Among downstream candidate genes identified by genome-wide gene expression profiling we found that KLF5 directly transactivates insulin growth factor 1 (IGF-1) gene in cardiac fibroblasts. IGF-1 acted in a paracrine fashion to induce hypertrophic responses in cardiomyocytes. This induction of IGF-1 was also essential for cardioprotective responses, as administration of a peptide inhibitor of IGF-1 severely exacerbated heart failure induced by high-intensity pressure overload. These results clearly demonstrate that cardiac fibroblasts play a pivotal role in the adaptive response of the myocardium to pressure overload, which is at least partly controlled by KLF5. Modulation of cardiac fibroblast function may thus provide a novel strategy for the treatment of heart failure, and KLF5 is an attractive target for that strategy.