Abstract 3468: Significance of the Transcription Factor Klf5 in Myocardial Hypertrophy in Response to Pressure Overload
Non-cardiomyocytes impact myocardial development and appropriate remodeling through intercellular interactions. KLF5 is induced by angiotensin II in activated myofibroblasts and smooth muscle cells, however it is unknown whether KLF5 is involved during pressure overload-induced cardiac hypertrophy. To examine the pathophysiological role of KLF5 in pressure overload-induced cardiac hypertrophy, we subjected KLF5+/− mice aged 8 weeks to a hypertrophic stimulus, by loose transverse aortic constriction (TAC) using a 25-gauge needle for 2 weeks. KLF5 mRNA levels were several times higher in cultured cardiac non-cardiomyocytes than cardiomyocytes, and those of TAC hearts were significantly increased to >5-fold of the control levels 3 days after TAC. Chronic pressure overload in control mice (WT) induced marked cardiac hypertrophy, dilatation, and dysfunction. In contrast, KLF5+/− mice displayed less concentric hypertrophy to TAC with preserved LV function measured by echocardiography (heart weight/body weight ratio after TAC; WT 7.51 ± 0.16 versus KLF5+/−6.47 ± 0.13; P<0.05). In addition, KLF5+/− TAC hearts developed less myocyte hypertrophy, and fetal gene re-expression of β-myosin heavy chain (β-MHC) and atrial natriouretic peptide (ANP). Moreover, KLF5+/− TAC hearts showed less interstitial fibrosis, where the fibroblasts proliferation rate assessed by BrdU incorporation was dramatically decreased. Fibrosis-related factors (fibronectin, collagen type I and α-smooth muscle actin) and growth factors required for myofibroblast differentiation and/or cellular hypertrophy (fibroblast growth factor-2 (FGF2), connective tissue growth factor (CTGF), periostin, and osteopontin) were significantly down-regulated. There results demonstrate that cardiac KLF5 plays a critical role during process of pressure overload-induced cardiac hypertrophy and fibrosis, at least partially via suppression of KLF5-mediated myofibroblast activation and differentiation.