Donohue T J, Dworkin L D, Lango M N, Fliegner K, Lango R P, Benstein J A, Slater W R, Catanese V M
Department of Medicine, New York University Medical Center, NY 10016.
Circulation. 1994 Feb;89(2):799-809. doi: 10.1161/01.cir.89.2.799.
Left ventricular hypertrophy is a generalized adaptation to increased afterload, but the growth factors mediating this response have 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 gene in three models of systolic hypertension and resultant hypertrophy.
The model systems were suprarenal aortic constriction, uninephrectomized spontaneously hypertensive rats (SHR), and uninephrectomized, deoxycorticosterone-treated, saline-fed rats (DOCA salt). Systolic blood pressure reached hypertensive levels at 3 to 4 weeks 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. Ventricular IGF-I mRNA was detected by solution hybridization/RNase protection assay. IGF-I mRNA levels increased in all three systems coincident with the onset of hypertension and the development of ventricular hypertrophy. Maximum induction was 10-fold over control at 5 weeks in the aortic constriction model, 8-fold at 3 weeks in the SHR, and 6-fold at 6 weeks in the DOCA salt model. IGF-I mRNA levels returned to control values by the end of the experimental period despite continued hypertension and hypertrophy in all three systems. In contrast, ventricular c-myc mRNA content increased twofold to threefold at 1 week and returned to control levels by 2 weeks. Ventricular IGF-I receptor mRNA levels were unchanged over the time course studied. The increased ventricular IGF-I mRNA content was reflected in an increased ventricular IGF-I protein content, as determined both by radioimmunoassay and immunofluorescence histochemistry.
We conclude that (1) hypertension induces significant increases in cardiac IGF-I mRNA and protein that occur coordinately with its onset and early in the development of hypertrophy, (2) IGF-I mRNA levels normalize as the hypertrophic response is established, (3) in comparison to IGF-I, both c-myc and IGF-I receptor genes are differentially controlled in experimental hypertension. These findings suggest that IGF-I may participate in initiating ventricular hypertrophy in response to altered loading conditions. The consistency of these findings in models of high-, moderate-, and low-renin hypertension suggests that they occur independently of the systemic renin-angiotensin endocrine axis.
左心室肥厚是对后负荷增加的一种全身性适应性反应，但介导这种反应的生长因子尚未明确。为了探究肥厚反应是否与局部胰岛素样生长因子-I（IGF-I）基因调控的变化有关，我们在三种收缩期高血压及由此导致的肥厚模型中检测了心脏IGF-I基因的诱导情况。
模型系统包括肾上腺主动脉缩窄、单侧肾切除的自发性高血压大鼠（SHR）以及单侧肾切除、脱氧皮质酮处理、以盐水喂养的大鼠（DOCA盐模型）。在所有这三种系统中，收缩压在3至4周时达到高血压水平。在SHR和主动脉缩窄模型中，3周时心室重量与体重之比（肥厚）出现差异性增加；在DOCA盐模型中，4周时出现这种情况。通过溶液杂交/核糖核酸酶保护分析检测心室IGF-I mRNA。在所有这三种系统中，IGF-I mRNA水平随着高血压的发生和心室肥厚的发展而升高。在主动脉缩窄模型中，5周时最大诱导倍数比对照高10倍；在SHR中，3周时为8倍；在DOCA盐模型中，6周时为6倍。尽管在所有这三种系统中高血压和肥厚持续存在，但在实验期末IGF-I mRNA水平恢复到对照值。相比之下，心室c-myc mRNA含量在1周时增加两倍至三倍，并在2周时恢复到对照水平。在所研究的时间过程中，心室IGF-I受体mRNA水平没有变化。通过放射免疫测定和免疫荧光组织化学确定，心室IGF-I mRNA含量的增加反映为心室IGF-I蛋白含量的增加。
我们得出结论：（1）高血压导致心脏IGF-I mRNA和蛋白显著增加，且这种增加与其发生及肥厚发展早期同步；（2）随着肥厚反应的建立，IGF-I mRNA水平恢复正常；（3）与IGF-I相比，在实验性高血压中，c-myc和IGF-I受体基因受到不同的调控。这些发现表明，IGF-I可能参与了因负荷条件改变而引发的心室肥厚。这些发现在高肾素、中肾素和低肾素高血压模型中的一致性表明，它们独立于全身肾素-血管紧张素内分泌轴而发生。
