Background

Insulin-like growth factor 1 (IGF1) is produced in numerous tissues particularly by the liver in response to growth hormone stimulation and is an important factor in the regulation of post-natal growth and development. IGF1 and IGF1 receptors (IGF1R) are present in the adult heart and have been shown to be essential for myocardial performance. (Ren et al 1999) Although the short term administration of IGF1 in animal studies has been reported to be beneficial by improving cardiac contractility and counteracting apoptosis, results from clinical trials in which IGF1 was administered chronically have been conflicting (Duerr et al 1995, Welch et al 2002, Ren et al 1999).

Transgenic mice over-expressing IGF1R in the heart display cardiac hypertrophy which is characteristic of physiological hypertrophy (i.e. normal organization of cardiac structure and normal or enhanced cardiac function) as opposed to pathological hypertrophy (i.e. altered pattern of gene expression, fibrosis, cardiac dysfunction, and increased morbidity and mortality) (McMullen et al 2003). Current evidence indicates that physiological hypertrophy involves the IGF1-PI3K(p110) pathway whereas pathological hypertrophy utilizes the Gq-pathway (McMullen et al. 2003, Shioi et al 2000, Wettschureck et al 2001, D'Angelo et al 1997, Akhter et al 1998).

PI3K is a major pathway downstream of IGF1R and we queried whether it would be a critical effector downstream of IGF1R in regulating heart size. We crossed IGF1R transgenics with mice expressing a dominant negative (dn)PI3K(p110) or constitutively active (ca)PI3K(p110) mutant. Mice over-expressing both IGF1R and the caPI3K(p110) mutant displayed cardiac hypertrophy which was not different from that in IGF1R transgenics alone. By contrast, the dnPI3K mutant significantly blocked IGF1R induced hypertrophy. This suggests that IGF1R promotes compensated cardiac hypertrophy in a PI3K(p110) dependent manner. (McMullen et al 2003)

Experimental Design

For details about the generation of IGF1R and PI3K transgenic mice, please refer to McMullen et al., 2003 & Shioi et al., 2000. The cDNA insert for human IGF1R was cloned into a SalI-digested MHC promoter construct (clone 26; a gift from J. Robbins)

We have generated and characterized transgenic mice over-expressing the IGF1R. We crossed IGF1R transgenic mice with dominant negative (dn)PI3K (p110) and with constitutively active (ca)PI3K(p110) transgenic mice. Expression profiling was performed on the ventricles of IGF1R, IGF1R-caPI3K, IGF1R-dnPI3K, caPI3K, dnPI3K transgenic female mice at 3 months of age. Non-transgenic littermates were used as controls.

McMullen JR, Shioi T, Huang W, Zhang L, Tarnavski O, Bisping E, Schinke M, Kong S, Sherwood M, Brown J, Riggi L, Kang PM, & Izumo S. The insulin-like growth factor 1 receptor induces physiological heart growth via the phosphoinositide 3-kinase (p110) pathway. J Biol Chem. 2003 Nov3 [PMID:14597618/Full Text]

Page last modified: 22-Mar-2004