Abstract 5362: Inhibition Of The Epidermal Growth Factor Receptor Transactivation By The Angiotensin II Type I Receptor Prevents Compensatory Cardiac Hypertrophy And Worsens Cardiac Function Following Myocardial Infarction
The angiotensin II type I receptor (AT1R) has been shown to activate the epidermal growth factor receptor (EGFR). However, the downstream effects of this activation have not yet been elucidated in the heart. To examine the function of the AT1R-EGFR pathway, we have created an AT1R mutant in which amino acid 319 is mutated from tyrosine to phenylalanine (Y319F). The Y319F mutant lacks the ability to transactivate the EGFR. We generated transgenic lines overexpressing either wild type AT1R (Tg-WT) or Y319F (Tg-Y319F) only in the heart with similar levels of overexpression, and evaluated the contribution of the AT1R-EGFR pathway to cardiac responses against stress. Under baseline conditions at 3 months of age, cardiac function of Tg-WT and Tg-Y319F was not significantly different from non-transgenic mice (NTg) except that Tg-WT showed mild left ventricular hypertrophy. To examine the role of the AT1R-EGFR pathway under stress, we induced myocardial infarction (MI) by permanently ligating the left anterior descending coronary artery. Four weeks after MI, increases in heart weight/tibia length (Tg-WT, Tg-Y319F, NTg: 12.57, 10.11, 9.96, p<0.05 vs Tg-WT) and left ventricular myocyte cross sectional area (35, 5, 29% vs sham, p<0.05) were significantly attenuated in Tg-Y319F compared to Tg-WT. Fibrosis was also milder in Tg-Y319F than in Tg-WT (10.7% vs 22.9%). These results suggest that the AT1R-EGFR pathway plays an important role in mediating LV hypertrophy and fibrosis after MI. Interestingly, however, echocardiographic measurement showed that Tg-Y319F have impaired LV ejection fraction (Tg-WT, Tg-Y319F, NTg: 51, 19, 44%, p<0.05) and %fractional shortening (21.4, 6.7, 17.7%, p<0.05) compared with Tg-WT or NTg. Tg-Y319F showed an increase in mortality in days 0–28 following MI, when compared to Tg-WT and NTg (35, 67, 30%, p<0.5). Additionally, lung weight/tibia length was increased in Tg-Y319F (11.3, 24.7, 16.1, p<0.05) These results suggest that the lack of EGFR activation causes cardiac dysfunction after MI. In summary, transactivation of the EGFR following MI may play a compensatory role, thereby protecting the heart from further deterioration of cardiac function.
This research has received full or partial funding support from the American Heart Association, AHA Founders Affiliate (Connecticut, Maine, Massachusetts, New Hampshire, New Jersey, New York, Rhode Island, Vermont).