Abstract 1464: Cardiac Remodeling in Egr-1 Deficient Mice
A thorough comprehension of the molecular mechanisms promoting pathological hypertrophy is still lacking. Chronic pressure overload due to transverse aortic constriction (TAC) causes over-expression of the transcription factor Egr-1 at early stages of left ventricular (LV) remodeling. NCX1 and SERCA2, two crucial regulating factors of intracellular calcium homeostasis, are modulated by Egr-1. Based on this evidence, we investigated the effect of Egr-1 depletion on the regulation of (i) calcium channel handling mechanisms, (ii) extracellular matrix and (iii) GAP junction, of mice undergoing TAC. Egr-1 −/− mice were compared with wild type mice (wt) matched for sex, age and body weight, 7 days and 2 months after TAC. Patch-clamped isolated myocytes were used for electrophysiological/intracellular calcium recordings. Gene and protein expression was assessed by TaqMan Real Time, RT-PCR or immunoistochemistry. After TAC, LV weight/body weight ratio was significantly less pronounced in null mice compared to wt mice. Markers of fibrosis (TGFb1, fibronectin, collagen I and III) were significantly less expressed (35% – 80% p<0.01) in null vs. wt mice. Decreased expression in connexin 43 and increased number of apoptotic cells were observed in Egr1 −/−vs. wt mice. To investigate whether basal differences in calcium homeostasis may explain diverse remodeling, we studied functional properties of LV cardiomyocytes. In null vs. wt mice, AP duration was significantly prolonged and maximal diastolic potential decreased. Moreover, the decay time of calcium transient was slowed down (250 vs 150 ms, p<0.05) and ICa-L density reduced by 37% (p<0.05) in null mice. In parallel, quantitative expression of genes coding for L-Type calcium channels, RYR, and SERCA2 was significantly lessened in null vs. wt mice. Mice lacking Egr-1 display a serious impairment in intracellular calcium handling, partly due to altered gene transcription. After TAC, null mice showed reduced LV fibrosis but increased apoptosis and gap junction delocalization. Taken together, these results suggest that Egr-1 plays a pivotal role in regulating basic cardiomyocyte function and adaptive response to hypertrophic stimuli.