The absence of C/EBP homologous protein induces a cytoptotective milieu in the postinfarct myocardium
Harold K. Elias, Guangming Cheng, Arash Davani, Magdy Girgis, Lei Chen, Yanjuan Yang, Santosh K. Sanganalmath, Carrie M. Quinn, Buddhadeb Dawn. Division of Cardiovascular Diseases, Cardiovascular Research Institute, University of Kansas Medical Center, Kansas City, KS
Background: C/EBP homologous protein (CHOP), a transcription factor activated during endoplasmic reticulum (ER) stress, has been implicated in proapoptotic signaling, and more recently, has been shown to inhibit gene expression of eNOS, a proangiogenic molecule. However, its role in the postinfarct myocardium remains poorly defined. Methods: Age-matched male CHOP+/+ littermates (n=10), and CHOP-/- (n=9) mice underwent a 30-min coronary occlusion followed by reperfusion for 35 d. Echocardiography was performed 4 d prior to (BSL) and at 48 h, and 35 d after coronary occlusion/reperfusion. Mice were sacrificed after 35 d for protein and histological analysis. Results: LV ejection fraction (EF) was significantly reduced in both groups at 48 h after MI, but at 35 d after MI, CHOP-/- mice exhibited improved EF compared with CHOP+/+ controls. Protein analysis of LV tissue at 35 d after MI revealed increased levels of heme oxygenase-1 (HO-1) in the infarcted CHOP-/- hearts compared with infarcted CHOP+/+ hearts as well as noninfarcted CHOP-/- hearts (Figure). Moreover, TNF-a levels were lower and eNOS levels were higher in both noninfarcted as well as infarcted CHOP-/- hearts compared with respective CHOP+/+ control hearts. Conclusions: We conclude that CHOP ablation mitigates LV dysfunction by promoting a prosurvival milieu in postinfarct myocardium. These findings may be utilized to prevent the development of ischemic cardiomyopathy after MI.
Key Words: CHOP, cytoprotection