scholarly journals Regulation of Vascular Proteoglycan Synthesis by Angiotensin II Type 1 and Type 2 Receptors

2001 ◽  
Vol 12 (12) ◽  
pp. 2609-2615
Author(s):  
Ryoko Shimizu-Hirota ◽  
Hiroyuki Sasamura ◽  
Mizuo Mifune ◽  
Hideaki Nakaya ◽  
Mari Kuroda ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Angiotensin Ii ◽  
Growth Factor ◽  
Growth Factor Receptor ◽  
Proteoglycan Synthesis ◽  
At2 Receptor ◽  
Receptor Stimulation ◽  
Epidermal Growth

ABSTRACT. Recent studies have shown that proteoglycans play an important role in the development of vascular disease and renal failure. In this study, the effects of angiotensin II (AngII) type 1 (AT1) and type 2 (AT2) receptor stimulation on glycosaminoglycan and proteoglycan core protein synthesis in vascular smooth muscle cells (VSMC) were examined. Treatment of AT1 receptor-expressing VSMC with AngII resulted in a dose-dependent and time-dependent increase (2- to 4-fold) in 3H-glucosamine/35S-sulfate incorporation, which was abolished by pretreatment with the AT1 receptor antagonist, losartan. The effects of AngII were inhibited by the epidermal growth factor receptor inhibitor, AG1478, and the mitagen-activated protein kinase kinase inhibitor, PD98059, but not the protein kinase C inhibitors, chelerythrine and staurosporine. AngII treatment also resulted in significant increases in the mRNA of the core proteins, versican, biglycan, and perlecan. The effects of AT2 receptor stimulation were examined by retroviral transfection of VSMC with the AT2 receptor. Stimulation of the AT2 receptor in these VSMC-AT2 cells resulted in a significant (1.3-fold) increase in proteoglycan synthesis, which was abolished by the AT2 receptor antagonist, PD123319, and attenuated by pretreatment with pertussis toxin. These results implicate both AT1 and AT2 receptors in the regulation of proteoglycan synthesis and suggest the involvement of epidermal growth factor receptor-dependent tyrosine kinase pathways and Gαi/o-mediated mechanisms in the effects of the two receptors.

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

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Jonathan Galeotti ◽  
Chiao Po Hsu ◽  
Peiyong Zhai ◽  
Junichi Sadoshima
Keyword(s):  
Myocardial Infarction ◽  
Epidermal Growth Factor Receptor ◽  
Angiotensin Ii ◽  
Growth Factor ◽  
Cardiac Function ◽  
Growth Factor Receptor ◽  
Left Ventricular ◽  
Type I ◽  
Epidermal Growth ◽  
Tibia Length

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).

Sign in / Sign up

Export Citation Format

Share Document