Angiotensin II stimulates gene expression of cardiac insulin-like growth factor I and its receptor through effects on blood pressure and food intake.
Angiotensin II (Ang II) is known to act as a growth factor and may be involved in cardiac remodeling. We have shown that insulin-like growth factor-I (IGF-I) is an autocrine mediator of growth responses to Ang II in vascular smooth muscle cells in vitro, and we hypothesized that IGF-I also serves as an important modulator of cardiovascular growth in vivo. To study the effect of Ang II on cardiac IGF-I, we infused rats for 3, 7, or 14 days with Ang II through osmotic minipumps. After 7 days, left ventricular mass normalized for body weight was increased by 20% (P<0.01) in Ang II rats compared with pair-fed control rats that were given a restricted amount of food identical to that eaten by the anorexic, Ang II-infused rats. Ang II increased left ventricular IGF-I mRNA levels by 1.5- to 1.8-fold compared with ad libitum-fed or pair-fed control rats (P<0.05). Cardiac IGF-I protein was increased correspondingly and was localized on the cardiomyocytes. Treatment with hydralazine abolished the induction of IGF-I mRNA, which indicates that Ang II induces cardiac IGF-I mRNA expression through a pressor-mediated mechanism. IGF-I receptor (IGF-IR) mRNA was induced 2.1-fold in Ang II rats compared with ad libitum-fed rats (P<0.01). However, this increase was also observed in pair-fed controls and is thus due to the anorexigenic effect of Ang II. We have recently shown that circulating IGF-I levels are reduced in response to Ang II infusion. Elevation of IGF-I levels by coinfusion of IGF-I and Ang II significantly increased left ventricular index by 16% compared with rats infused with Ang II alone (P<0.05). In conclusion, autocrine upregulation of cardiac IGF-I and IGF-IR mRNA by Ang II occurs through hemodynamic and nonhemodynamic mechanisms, respectively, and may modulate cardiac structural changes that occur in hypertension.
Brink
M
M
Division of Cardiology, University Hospital of Geneva, Switzerland. marijke.brink@dim.hcuge.ch
Chrast
J
J
Price
S R
SR
Mitch
W E
WE
Delafontaine
P
P
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects*; D004435:Eating / Q000187:drug effects*; D017379:Hypertrophy, Left Ventricular / Q000209:etiology*; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis / Q000235:genetics* / Q000494:pharmacology; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D017526:Receptor, IGF Type 1 / Q000235:genetics*
D000959:Antihypertensive Agents; D012333:RNA, Messenger; D000804:Angiotensin II; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1