Angiotensin II-induced cardiac hypertrophy and hypertension are attenuated by epidermal growth factor receptor antisense.
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.


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 micromol/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.


CONCLUSIONS
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.
Department of Physiology and Functional Genomics, University of Florida, Gainesville 32610-0274, USA.
Shuntaro
S
Kagiyama
Satoru
S
Eguchi
Gerald D
GD
Frank
Tadashi
T
Inagami
Yuan Clare
YC
Zhang
M Ian
MI
Phillips
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D006973:Hypertension / Q000139:chemically induced / Q000209:etiology* / Q000503:physiopathology / Q000628:therapy; D017379:Hypertrophy, Left Ventricular / Q000139:chemically induced / Q000209:etiology* / Q000628:therapy; D007700:Kinetics; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D020319:Oligodeoxyribonucleotides, Antisense; D000804:Angiotensin II; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases