The chest cavity was exposed by cutting open the proximal portion of the sternum. pressure overload and that cardiac fibroblasts are required for cardiomyocyte hypertrophy. High-intensity pressure overload caused severe heart failure and early death Serotonin Hydrochloride in mice withKlf5-null fibroblasts. KLF5 transactivatedIgf1in cardiac fibroblasts, and IGF-1 subsequently acted in a paracrine fashion to induce hypertrophic responses in cardiomyocytes.Igf1induction was essential for cardioprotective responses, as administration of a peptide inhibitor of IGF-1 severely exacerbated heart failure induced by high-intensity pressure overload. Thus, cardiac fibroblasts play a pivotal role in the myocardial adaptive response to pressure overload, and this role is usually partly controlled by KLF5. Modulation of cardiac fibroblast function may provide a novel strategy for treating heart failure, with KLF5 serving as a stylish target. == Introduction == Myocardial hypertrophy is an essential adaptive process through which the heart responds to various mechanophysical, metabolic, and genetic stresses. However, the hypertrophy induced by sustained overload eventually leads to contractile dysfunction and heart failure through mechanisms that remain poorly understood (1). In addition to enlargement of individual cardiomyocytes, the hypertrophied myocardium exhibits complex structural remodeling that involves rearrangement of the muscle fibers, interstitial fibrosis, accumulation of extracellular matrix, and angiogenesis (2,3), which implies that the non-muscle cells residing in the interstitium likely play important functions in both cardiac hypertrophy and heart failure. In fact, cells other than cardiomyocytes Serotonin Hydrochloride account for approximately 70% of the total cell number in the heart, with the majority being fibroblasts (4,5). In addition to extracellular matrix proteins (e.g., collagens), cardiac fibroblasts produce a variety of growth factors that likely mediate an interplay between cardiac fibroblasts and cardiomyocytes. For instance, several humoral factors secreted by cardiac fibroblasts, including cardiotrophin-1 (6), endothelin-1 (7), IL-6 (8), periostin (POSTN) (9), and leukemia inhibitory factor (10), have been shown to induce hypertrophic responses in cultured cardiomyocytes. Cardiac fibroblasts also promote proliferation of cardiomyocytes through paracrine interactions in developing hearts (11). And very recently it was shown that inhibition of a fibroblast-selective miRNA ameliorated cardiac fibrosis, hypertrophy, and dysfunction, suggesting that fibroblasts play a detrimental role in cardiac remodeling (12). Still, the precise function of cardiac fibroblasts during adaptive responses of the myocardium remains unclear (2). Members of the Krppel-like factor (KLF) family of transcription factors are important regulators of development, cellular differentiation and growth, and the pathogenesis of various diseases, including cancer and cardiovascular disease (13). We previously usedKlf5+/mice to show that KLF5 is required for cardiac hypertrophy and fibrosis in response to continuous infusion of angiotensin II (AII) (14,15). In primary cultured cardiac fibroblasts, KLF5 directly controls transcription ofPdgfa, encoding platelet-derived growth factor A (PDGF-A) (14), which is known to be involved in tissue remodeling and wound healing (1619). The precise role played by KLF5 in cardiac hypertrophy and heart failure remains unclear, however. In the present study, we developed conditionalKlf5-knockout mouse lines to examine the cell typespecific functions of KLF5 in cardiac hypertrophy and heart failure. While cardiomyocyte-specific deletion ofKlf5did not alter the hypertrophic responses to pressure overload, cardiac fibroblastspecific deletion ofKlf5ameliorated cardiac hypertrophy in a moderate-intensity pressure overload model, indicating that fibroblasts are essential for hypertrophic responses of the myocardium. Notably, however, cardiac fibroblastspecificKlf5-knockout mice developed severe heart failure when subjected to high-intensity pressure overload, suggesting cardiac fibroblasts have a cardioprotective function. We Mouse monoclonal to CD8/CD45RA (FITC/PE) further exhibited that KLF5 controls expression of Serotonin Hydrochloride IGF-1, which mediates the interplay between cardiomyocytes and fibroblasts. These data provide compelling evidence that cardiac fibroblasts play a pivotal role in the adaptive response of the myocardium. == Results == == KLF5 plays an important role in pressure overloadinduced cardiac hypertrophy. == To analyze KLF5s function in cardiac adaptive responses, we first established models of pressure overloadinduced cardiac hypertrophy using transverse aortic constriction (TAC). By applying a low-intensity TAC (LI-TAC) for 2 weeks, we were able to induce cardiac hypertrophy with preserved cardiac systolic function, while application of high-intensity TAC (HI-TAC) induced severe myocardial dysfunction and LV dilation (Supplemental Figures 1 and 2; supplemental material available online with this article; doi:10.1172/JCI40295DS1). The survival rates in the LI- and HI-TAC groups were 100% and 90%, respectively, after 2 weeks,.
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