INDUCTION OF MYOCARDIAL INSULIN-LIKE GROWTH FACTOR-I GENE-EXPRESSION IN LEFT-VENTRICULAR HYPERTROPHY

Background Left ventricular hypertrophy is a generalized adaptation to increased afterload, but the growth factors mediating this response h ave not been identified. To explore whether the hypertrophic response was associated with changes in local insulin-like growth factor-I (IGF -I) gene regulation, we examined the induction of the cardiac IGF-I ge ne in three models of systolic hypertension and resultant hypertrophy. Methods and Results The model systems were suprarenal aortic constric tion, uninephrectomized spontaneously hypertensive rats (SHR), and uni nephrectomized, deoxycorticosterone-treated, saline-fed rats (DOCA sal t). Systolic blood pressure reached hypertensive levels at 3 to 4 week s in all three systems. A differential increase in ventricular weight to body weight (hypertrophy) occurred at 3 weeks in the SHR and aortic constriction models and at 4 weeks in the DOCA salt model. Ventricula r IGF-I mRNA was detected by solution hybridization/RNase protection a ssay. IGF-I mRNA levels increased in all three systems coincident with the onset of hypertension and the development of ventricular hypertro phy. Maximum induction was 10-fold over control at 5 weeks in the aort ic constriction model, 8-fold at 3 weeks in the SHR, and 6-fold at 6 w eeks in the DOCA salt model. IGF-I mRNA levels returned to control val ues by the end of the experimental period despite continued hypertensi on and hypertrophy in all three systems. In contrast, ventricular c-my c mRNA content increased twofold to threefold at 1 week and returned t o control levels by 2 weeks. Ventricular IGF-I receptor mRNA levels we re unchanged over the time course studied. The increased ventricular I GF-I mRNA content was reflected in an increased ventricular IGF-I prot ein content, as determined both by radioimmunoassay and immunofluoresc ence histochemistry. Conclusions We conclude that (1) hypertension ind uces significant increases in cardiac IGF-I mRNA and protein that occu r coordinately with its onset and early in the development of hypertro phy, (2) IGF-I mRNA levels normalize as the hypertrophic response is e stablished, (3) in comparison to IGF-I, both c-myc and IGF-I receptor genes are differentially controlled in experimental hypertension. Thes e findings suggest that IGF-I may participate in initiating ventricula r hypertrophy in response to altered loading conditions. The consisten cy of these findings in models of high-, moderate-, and low-renin hype rtension suggests that they occur independently of the systemic renin- angiotensin endocrine axis.