Abstract 21513: Heterozygous Heat Shock Factor-1 Knock Out Protects From Atherosclerosis In Mice
Introduction: Heat shock factor-1 (HSF-1) is a transcription factor for heat shock proteins (HSPs) that is activated upon various environmental stresses, such as heat and proteotoxicity. Higher levels of HSPs are found in atherosclerotic lesions, although their role in the pathogenesis is not known.
Hypothesis: HSF-1 knock out can attenuate atherosclerosis. To test this hypothesis we generated a new mouse model, namely HSF-1 and low density lipoprotein receptor (LDLr) double knock out (HSF-1−/−/LDLr−/−).
Methods and Results: Complete homozygous knock out of HSF-1 and LDLr (HSF-1−/−/LDLr−/−) was found to cause prenatal lethality (Mendelian ratio 8:1), and hence we used heterozygous HSF-1 knockout mice (HSF-1+/−/LDLr−/−) in our experiments. Mice (starting with 8 weeks old) were fed with atherogenic diet (modified western diet with 1% cholesterol, TD.09674) for a period of 12 weeks, and aortic atherosclerotic lesions were determined at the end of 12 weeks . HSF-1+/−/LDLr−/− mice behaved similar to wild type mice in terms of weight gain and life span. However, these mice showed less atherosclerotic lesions (Oil-Red O- staining) compared to HSF-1 wild type mice (HSF-1+/+/LDLr−/−). Furthermore, HSF-1+/−/LDLr−/− mice showed positive lipid profile (significantly lower levels of LDL and higher levels of HDL in the circulation), compared with HSF-1+/+/LDLr−/− mice. HSP25 in the lesions (Immunohistochemical staining) of HSF-1+/−/LDLr−/− mice was significantly lower than the HSF-1+/+/LDLr−/− mice.
Conclusions: We conclude from our novel findings that targeting HSF-1 may be an effective approach in preventing/attenuating atherosclerosis. HSF-1 is activated upon high cholesterol feeding and HSPs (especially HSP25) are expressed in higher order, resulting in the progression of atherosclerosis. Upon deletion of the transcription factor atherosclerosis is reduced due to lack of HSPs.
- © 2010 by American Heart Association, Inc.