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(Circulation. 2002;106:909.)
© 2002 American Heart Association, Inc.

Brief Rapid Communications

Angiotensin II–Induced Cardiac Hypertrophy and Hypertension Are Attenuated by Epidermal Growth Factor Receptor Antisense

Shuntaro Kagiyama, MD, PhD; Satoru Eguchi, MD, PhD; Gerald D. Frank, PhD; Tadashi Inagami, PhD; Yuan Clare Zhang, PhD; M. Ian Phillips, PhD, DSc

From the Department of Physiology and Functional Genomics, University of Florida (S.K., Y.C.Z., M.I.P.), Gainesville, and the Department of Biochemistry, Vanderbilt University School of Medicine (S.E., G.D.F., T.I.), Nashville, Tenn.

Correspondence to M. Ian Phillips, University of Florida, Physiology and Functional Genomics, PO Box 100274, 1600 SW Archer Rd, Gainesville, FL 32610-0274. E-mail MIP{at}phys.med.ufl.edu

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 µmol/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±8 mm Hg; 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.

Key Words: oligodeoxyribonucleotides, antisense • receptor, epidermal growth factor • hypertrophy • angiotensin • mitogen-activated protein kinases

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