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Aims: Kruppel-like factors (KLFs) are a family of transcription factors which play important roles in the heart under patho- g logical and developmental conditions. We previously identified and cloned Klf6 whose homozygous mutation in mice a. results in embryonic lethality suggesting a role in cardiovascular development. Effects of KLF6 on pathological regulation e of the heart were investigated in the present study. Methods: Mice heterozygous for Klf6 resulted in significantly diminished levels of cardiac fibrosis in response to angiotensin II 2 and results infusion. Intriguingly, a similar phenotype was seen in cardiomyocyte-specific Kf6 knockout mice, but not in cardiac 5 fibroblast-specific knockout mice. Microarray analysis revealed increased levels of the extracellular matrix factor, thrombospondin 4 (TSP4), in the Klf6-ablated heart. Mechanistically, KLF6 directly suppressed Tsp4 expression levels, and cardiac TSP4 regulated the activation of cardiac fibroblasts to regulate cardiac fibrosis. Conclusion: Our present studies on the cardiac function of KLF6 show a new mechanism whereby cardiomyocytes regulate cardiac fibrosis through transcriptional control of the extracellular matrix factor, TSP4, which, in turn, modulates activation of cardiac fibroblasts. [ABSTRACT FROM AUTHOR]