Regulation of insulin-like growth factor-1 by the renin–angiotensin system during regression of cardiac eccentric hypertrophy through angiotensin-converting enzyme inhibitor and AT₁ antagonist

Abstract

Angiotensin II (Ang II) mediates its effects through its non-tyrosine-kinase G protein coupled Ang-II type 1 receptor (AT1). Growing evidence indicates that a functional insulin-like growth factor-1 (IGF-1) tyrosine kinase receptor is required for Ang-II-induced mitogenesis. Along with Ang II, we have previously shown that changes in IGF-1 receptor binding at myofibers are causative agents for cardiac eccentric hypertrophy. This study investigated the interaction of the renin-angiotensin system with the IGF-1 receptor during the development and regression of cardiac hypertrophy. Alterations in IGF-1 binding were evaluated in the CHAPS-pretreated perfused heart. Four weeks of aortocaval shunt increased relative heart mass by 76% without a major change in body mass or systolic blood pressure. Binding studies showed that IGF-1 has a higher affinity for the cardiac myofibers of shunt than sham rats. Two weeks of treatment with the angiotensin-converting enzyme (ACE) inhibitor captopril (0.5 g/L in drinking water) or the AT1-antagonist losartan (10 mg/(kg x day)) reduced cardiac hypertrophy by 54 and 42%, respectively. However, while both ACE inhibition and AT1-antagonist treatments produced equivalent regression in ventricular hypertrophy, captopril was more efficacious than losartan in the regression of atrial hypertrophy. Regression of cardiac hypertrophy in the shunt by either captopril or losartan was accompanied with a reduction or normalization of the elevated IGF-1 affinity. Thus, the induction and regression of cardiac eccentric hypertrophy seems to be largely dependent on cross talk between the renin-angiotensin system and the IGF-1 axis at the receptor level.

Basal and IGF-I-dependent regulation of potassium channels by MAP kinases and PI3-kinase during eccentric cardiac hypertrophy

“…In addition, there is sufficient evidence showing that IGF-I mRNA and protein increase in parallel with the development of cardiac hypertrophy (9). Furthermore, in the volume-overload model we have shown that cardiac myofibers have an increased receptor affinity to IGF-I, which corroborated with the induction of eccentric hypertrophy (20).…”

Angiotensin II blockade: how its molecular targets may signal to mitochondria and slow aging. Coincidences with calorie restriction and mTOR inhibition

“…In cultured neonatal rat cardiac fibroblasts, ANG II was shown to increase IGF1R expression; also, the mitogenic effect of IGF-I was partly mediated by RAS activation and the ensuing upregulation of IGF1R expression, which was abolished by ACE inhibitors (moexiprilat or enalaprilat) and ARB (CV11974, the bioactive candesartan metabolite) (415). In a rat model of cardiac hypertrophy by aortocaval shunt, IGF-I binding to its receptor in the myofibers was elevated, and treatment with an ACE inhibitor (captopril) or an ARB (losartan) resulted in regression of cardiac hypertrophy accompanied by an attenuation or normalization of increased IGF-I affinity (162). In kidney transplant patients with posttransplant erythrocytosis, treatment with ACE inhibitors reduced both the hematocrit and serum IGF-I; hematocrit and circulating IGF-I levels were positively related, suggesting that IGF-I contributes to the ACE inhibitor-induced decrease of hematocrit in these patients (295).…”

Ras dexamethasone-induced protein 1 is a modulator of hormone secretion in the volume overloaded heart

“…In the work reported here, we carried out a time-course investigation in vivo to define the overall gene expression profile associated with stretch activation of the endocrine heart following an increase in venous return to the heart obtained by aorto-caval shunt (14,15,35). We found that the level of expression of the regulator of G-protein signaling Ras dexamethasone-induced protein 1 (RASD1) was particularly affected by VO.…”