期刊
CIRCULATION
卷 106, 期 8, 页码 909-912出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/01.CIR.0000030181.63741.56
关键词
oligodeoxyribonucleotides, antisense; receptor, epidermal growth factor; hypertrophy; angiotensin; mitogen-activated protein kinases
资金
- NHLBI NIH HHS [HL 27334, HL58205] Funding Source: Medline
- NIDDK NIH HHS [DK20593] Funding Source: Medline
Background-Angiotensin II (Ang II) is a vasoconstrictor but also a growth factor. However, the Ang II type 1 receptor does not have a tyrosine kinase domain that mediates the cellular signals for mitosis. We have shown that Ang II acts via trans -activation of the epidermal growth factor receptor (EGFR) to induce activation of tyrosine kinase and mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) in vascular smooth muscle cells (VSMCs). To examine whether EGFR is involved in the development of left ventricular hypertrophy (LVH), we inhibited EGFR with a specific antisense oligodeoxynucleotide to attenuate the Ang II-induced cardiovascular hypertrophic effects. Methods and Results-The antisense oligodeoxynucleotide to EGFR (EGFR-AS) was designed and tested on Ang II-induced ERK activation in cultured VSMCs. We also investigated the effects of EGFR-AS on LVH and blood pressure (BP) in Ang II-infused hypertensive rats. In VSMCs, EGFR-AS (2.5 mumol/L) reduced EGFR expression and inhibited the Ang II-induced phosphorylation of ERK. In rats, Ang II (150 ng/h for 14 days) increased BP compared with controls (184+/-6 mm Hg versus 122+/-3 mm Hg; n=7; P<0.01). Continuous intravenous infusion of EGFR-AS (2 mg/kg) decreased BP (169+/-1-8 mmHg; n=8; P<0.05). Ang II infusion increased the left ventricular/body weight (LV/BW) ratio compared with control rats (2.75+/-0.08 versus 2.33+/-0.07; P<0.01). EGFR-AS, but not EGFR-sense, normalized the LV/BW in Ang II-infused rats (2.32+/-0.06; P<0.01) and attenuated Ang II- enhanced EGFR expression and ERK phosphorylation. Conclusion -Ang II requires EGFR to mediate ERK activation in VSMCs and the heart. EGFR plays a critical role in the LVH induced by Ang II.
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